顧 問 委 員 會Comissão de AssessoresAdvisory Committee編 輯 委 員Membros da Secção EditorialMembers of Editorial Office編 輯 部Secção EditorialEditorial Office主 任Coordenador EditorialEditorial Coordinator劉百球 Edmundo Patricio LOPES LAO技 術 顧 問 Assessores TécnicosTechnical Consultants李 然 LEE Yan 李 靜 LEI Cheng 洪順家 HONG Shun Jia胡 峰 HU Feng 范嘉儀 FAN Ka I 徐義祥 CHOI I Cheong區德偉 AU Tak Wai 張曉戰 ZHANG Xiao Zhan 梁 棋 LEUNG Ki許主平 HOI Chu Peng 許 萍 HUI Ping 陳丹梅 CHAN Tan Mui陳惟蒨 CHAN Wai Sin 陳新野 CHEN Xin Ye 彭洪泉 PENG Hong Quan黃嘉東 WONG Ka Tong 趙振鋒 CHIO Chan Fong 劉水明 LIU Shui Ming劉咏儀 LAO Weng I 劉 紅 LIU Hong 蕭文傑 SIU Man Kit簡焰森 JIAN Yan Sen 羅光輝 LUO Guang Hui 譚 蕾 TAN LeiJosé COSTA MAIA林如波 LAM U Po 曹亞兵 CAO Ya Bing 戴華浩 TAI Wa Hou方慧瑩 FONG Wai Ieng 王 燕 WONG In 白琪文 PAI Ki Man伍家驥 NG Ka Kei 朱文立 ZHU Wen Li 江瑞洲 KONG Soi Chau何舜發 HO Son Fat 何澄幫 HE Cheng Bang 余國威 IU Kuok Wai余漢濠 YU Hon Ho 吳少芬 NG Sio Fan 吳 浩 NG Hou吳曉林 NG Hiu Lam 李佩儀 LEE Pui I 李 杰 LI Jie李 峻 LI Jun 李偉成 LEI Wai Seng 李達濱 LI Da Bin李 靜 LEI Cheng 李鵬斌 LI Peng Bin 官建泳 KOON Kin Veng林如波 LAM U Po 林 松 LAM Chong 林 果 LAM Kuo林俊華 LAM Chon Wa 林美鳳 LAM Mei Fong 林 路 LAM Lou林肇聰 LAM Sio Chong David 侯偉堅 HOU Wei Jian 徐松波 CHOI Chong Po高景輝 Fernando C. GOMES 高進新 Ricardo COELHO 區德偉 AU Tak Wai區 曦 AO Hei 張振榮 CHEUNG Chun Wing 張 康 ZHANG Kang張德洪 CHEONG Tak Hong 曹亞兵 CAO Ya Bing 曹美芳 CHOU Mei Fong曹國希 CHOU Kuok Hei 曹麗勤 CHO Lai Kan 梁亦好 LEONG Iek Hou梁 珍 LEONG Chan 梁家寶 LEUNG Ka Pou 梁根發 LEONG Kan Fat梁逸倫 LEONG Iat Lon 梁雅晶 LEONG Nga Cheng 梁 暉 LEONG Fai符 丹 FU Dan 莫天浩 MOK Tin Hou 許主平 HOI Chu Peng許 萍 HUI Ping 陳建勇 CHAN Kin Iong 陳泰業 CHAN Tai Ip陳嘉明 CHAN Ka Ming 陸美娟 LOK Mei Kun 彭向紅 PENG Xiang Hong彭 莉 PENG Li 彭蓬光 PANG Fong Kuong 曾潭飛 CHANG Tam Fei温樹堂 WAN Shu Tong Elmer 程 鯤 CHENG Kun 黃子秉 WONG Chi Peng黃小彥 WONG Sio In 黃立正 WONG Lap Cheng 黃鳳欣 WONG Fong Ian黃穗濤 WONG Soi Tou 葉志達 IP Chi Tat 廖永賢 LIO Weng In劉中良 LAO Chong Leong 劉百球 Edmundo Patricio LOPES LAO 劉懷烈 LAU Wai Lit潘詠紅 PUN Weng Hong 潘寶全 PAN Bao Quan 蔡 念 CHOI Nim談光濠 TAM Kwong Ho 鄭燕芳 ZHENG Yan Fang 黎卓先 LAI Cheuck Seen Edward黎啓盛 LAI Kai Seng 錢 偉 CHIN Wai 錢曉暉 CHIN Hiu Fai戴華浩 TAI Wa Hou 謝 昕 CHE Ian 謝師輝 TSE See Fai謝學斌 XIE Xue Bin 譚廣亨 TAM Kwong Hang Pedro RESENDE
秘 書SecretárioSecretary出 版 與 發 行Publicação e distribuiçãoPublishing and distribution設 計 與 印 刷Desenho e impressãoDesign and printing林俊傑 LAM Chon Kit Manuel澳門人出版有限公司Os Macaenses Publicações LDA.The Macanese PubIishing LTD.澳門醫學專科學院Academia Médica de MacauMacao Academy of Medicine電 子 郵 箱E-mailE-mailmmj@ssm.gov.mo官 方 網 址Site OficialOfficial Websitehttps://www.am.gov.mo二 維 碼Código QRQR code《 澳 門 醫 學 雜 誌 》 電 子 版Versão electrónica da "Revista Médica de Macau"E-version of "Macao Medical Journal "澳門東望洋新街339 號衛生局行政樓五樓5/F, Administration Building of the Health Bureau, Rua Nova à Guia n.º 339, MacaoRua Nova à Guia, n.º 339, Edifício da Administração dos Serviços de Saúde, 5.º andar, Macau10.30224/MMJ非 賣 品Não está à vendaNot for Sale排名按中文姓氏筆劃順序a ordem é feita de acordo com o número dos traços dos apelidos em caracteres chinesesIn the order of the number of strokes of Chinese surnames
第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2 1目錄ÍndiceContents李濤 羅英浛 錢曉暉 黃鍇亮 曹麗勤Tao LI Ieng Ham LO Hiu Fai CHIN Kai Leong WONG Lai Kan CHOIo Hong CHOU Si Man LEONG Wai Kuan LAM Im Heng WONG Xiao Yi YANG Lan Heng HOI Van Ieng TONG Xiao Li XU Wai Ieng FONG12硬膜外鎮痛對孕前低體重初產婦分娩結局的影響The impact of labor epidural analgesia on the delivery outcome of primigravida with progestational low body weight: A clinial retrospective study The Prenatal Testing in Conde de São Januário General HospitalClinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in MacaoThe Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in childrenResearch on COVID-19 treatment guidelines and expert consensus: Findings from a bibliometric perspective Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomaFong Chon CHOI Io Chon VONG Ki Fung LEE João LEI Weng CHIOWai Hoi LEONG Hei AO Yan LEE Seong In NENG Fong I SIO Ka Kei KUOKZhen GUI Pan CHEN Qinge ZHANG Xiao Hong LI Zhao Hui SU Teris CHEUNG Xi Ling CUI Robert D. SMITH Gabor S. UNGVARI Chee H. NG Yuan FENG Yu-Tao XIANGGuo Liang ZHANG Yi Tan CAO Ki Man PAI Wan Pang SAM Tin Seak MOK Xin Ye CHEN Xian Zhong WANG Chon Man KAN Choeng Un SIO Kit Ian LIO Ut Man IONG31624415058Review of Clostridioides difficile infectionIp Pio SAM Hou NG Tak Ming LI Yun Ming FAN Ya Kun TIAN In Ha CHAN Yi LIN64Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancer
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal2Unveiling the mystery: A toddler’s recurrent intussusception caused by a hidden cecal duplication cystChon Man IEONG Man Pan TAM Wai Lon NG Chi Ian KUOK Soi Chau KONG 69Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptomsSpontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature reviewImmune checkpoint inhibitors induced haematological toxicity: A double-edged swordKin Sing WONGIan Ian KOU Lai Fong KOK Si Leong CHEONG Sio In WONGIsabel LOURENCO Thazin HLAINGIngrid Karmane SUMOU Sok Cheng LAI Kan Fat LEONG737885Zhi Xiong XIANG Mei Ha LEONG Ting LIAO Chun Lin MA91Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case series
Fong Chon CHOI et al.第 12 卷第 2 期 3 Volume 12 Número 2 Volume 12 Number 2Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in MacaoAbstractBackground: In-hospital drug-related issues (DRIs) are common and can significantly affect patient outcomes. The presence of clinical pharmacists has shown potential to mitigate various DRIs. This study evaluated the impact of clinical pharmacist services in Macao. Methods: Retrospectively review data between January 2023 and September 2023 in the Emergency Unit (EU) of Conde de São Januário General Hospital (CHCSJ), a public hospital in Macao. All patients hospitalized in this setting with at least one DRI documented were included in the study. During this period, the clinical pharmacist’s interventions and other clinical services for patients were recorded. DRIs were classified according to the Pharmaceutical Care Network Europe (PCNE) Classification v.7.00. We primarily focused on quantifying and identifying the causes of potential DRIs.Results: Among 190 patients with DRIs, the average age was 69.9 ± 15.0 years, with a majority being male (58.4%). The average number of medications per patient was 11.9 ± 6.0 , with 81.6% experiencing polypharmacy. A total of 283 DRIs were identified, with the most common DRIs related to drug omission (55.1%) and inappropriate drug therapy (12.4%). The main interventions included starting new medications or stopping current ones, with a 94.3% acceptance rate of pharmacist recommendations.Conclusion: This study highlighted the vital contributions of clinical pharmacists in optimizing drug therapy and enhancing patient safety within emergency settings. Expanding this role may help promote safer and more effective medication use, thereby enhancing overall patient care.Keywords: Clinical pharmacist; Drug-Related Issue; Emergency Unit; Pharmaceutical Care Network Europe (PCNE)1Division of Pharmacy, Conde de São Januário General Hospital, Health Bureau, Macao SAR Government, China2Chief of Division of Pharmacy, Conde de São Januário General Hospital, Health Bureau, Macao SAR Government, China3Chief of Department of Administration, Conde de São Januário General Hospital, Health Bureau, Macao SAR Government, China*Corresponding author: João LEI, E-mail: Joaolei@ssm.gov.moDOI : 10.30224/MMJ.202507_12(2).0001Fong Chon CHOI1, Io Chon VONG1, Ki Fung LEE1, João LEI2*, Weng CHIO31. BackgroundA Drug-Related Problem is defined as “an event or circumstance involving drug therapy that actually or potentially interferes with desired health outcomes.” [1] As the admission hub of diverse patients into a hospital, the Emergency Department (ED) experiences a high frequency of medication
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal4Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macaoissues. A prospective observational study identified at least 1 error in 59.4% of patients admitted to a tertiary ED in the US. [2] Overcrowding in the ED has been associated with an increased frequency of medication errors. [3] The situation is further complexed by the diverse nature of patients. [4] Patients attending the ED typically present with a broad variety of illnesses and injuries. They tend to be previously unfamiliar to the ED doctors and some of them may not present with immediate access to medical records or even incommunicable. The bene f i t s o f c l i n i ca l pha rmac i s t s i n emergency medicine setting have been recognized in the literature. Mills et al. had shown that formal medicine reconciliation within the ED could reduce prescribing error from 3.3 errors to 0.04 errors per patient. [5] A recent review had confirmed ED pharmacists’role in reducing medication errors, providing more complete medication histories and timely initiation of critical medications. [6] However, publications regarding ED pharmacist service in the Southern China area are lacking.We sought to fill the research gap by presenting a comprehensive assessment of ED pharmacist service in Macao, China. The study was carried out in Conde de São Januário General Hospital (CHCSJ), a public tertiary hospital in Macao with approximately 1100 beds and almost 4500 emergency admissions during 2023. The ED in CHCSJ, as in most countries, is saturated. An Emergency Unit (EU), similar to the short stay units found in other countries, was introduced as an alternative to conventional Emergency Department (ED) admissions. The EU provides targeted care for patients who require brief hospitalization and are ready to be discharged as soon as their clinical condition is resolved. [7] Due to the nature of multi-disciplinary staff caring diverse unfamiliar patients in EU, we postulate that a pharmacist may help in identifying drug-related issues. Various classification systems have been utilized for categorizing drug-related problems (DRPs). In CHCSJ, the Pharmaceutical Care Network Europe (PCNE) system was used for classification of DRPs, and drug-related issues (DRIs) would be used instead of DRPs inside CHCSJ and in this paper due to historical reasons. This study aims to assess the impact of clinical pharmacist services in a public hospital in Macao.2. Methods2.1 Study design and participantsThis study was conducted retrospectively from January 2023 to September 2023 in the Emergency Unit (EU) of CHCSJ, which is equipped with 43 beds. All patients hospitalized in this setting with at least one DRI documented were included in the study. The research team comprised one clinical pharmacist and several resident pharmacists . Approval for the study was granted by the CHCSJ Research Ethics Committee.2.2 Data collectionThroughout the study, interventions made by the clinical pharmacist, along with other clinical services provided to patients, were documented and recorded. The data included patient demographics, history, diagnosis, chief complaint, history of active illness, comorbidities, family history, laboratory parameters, past medication history, and current medication list. The research team collected data through various methods such as accessing paper-based and electronic medical records, direct observation, and patient interviews. Additionally, clinical decision-making tools such as UpToDate®, Micromedex®, and Sanford Guide to Antimicrobial Therapy® were utilized. Once the clinical pharmacist identified suspicious drug-related issues (DRIs), they engaged in discussions with physicians and nurses to make informed decisions regarding the appropriate course of action. PCNE Classification v.7.00 for was used to categorize DRIs by problem type, cause, planned intervention, proposed intervention, and outcome (http://europharm.pbworks.com/w/file/113186797/PCNE%20classification%20V7-0.pdf). DRIs per pat ient were used to assess the incidence of DRI.2.3 Data analysisData were analyzed using Microsoft Excel. The study evaluated the characteristics of DRIs, causative
5Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macao第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2agents, interventions by clinical pharmacists, and the acceptance of these interventions. Descriptive statistics were employed, specifically frequency and percentage for categorical variables, and mean ± standard deviation (SD) for quantitative variables3. ResultsThis study involved 190 patients with DRIs admitted to the EU. 58.4% were male with a mean age of 69.9 ± 15.0 years. The average number of medications taken per patient was 11.9 ± 6.0. Polypharmacy, defined as patients receiving more than five medications simultaneously, was observed in 155 patients (81.6%), while 102 patients (53.7%) were taking more than ten medications. After clinical pharmacist evaluation, a total of 283 DRIs were identified in this study. The mean number of DRIs per patient was 1.5. 135 patients had 1 DRIs (71.1%), while 55 patients had more than 1 DRIs (28.9%, Figure 1). Table 1 highlights the most common diagnosis among 190 patients, categorized using ICD-9-CM classification system was "symptoms, signs, and ill-defined conditions," accounting for 72 patients (38%), followed by "diseases of the respiratory system" with 38 patients (20%) and "diseases of the circulatory system" with 23 patients (12%).Table 2 presents data on the acceptance and implementation of DRIs, indicating that interventions were accepted at a rate of 94.3% and were fully implemented. Table 3 outlines the causes of DRIs, where the most significant observed cause was "No drug treatment in spite of existing indication" (55.1%), followed by "Inappropriate drug (within guidelines but otherwise contraindicated)" (12.4%).Table 4 categorizes the DRIs, revealing that the most common type is adverse events (62.2%), with the leading cause being "Effect of drug treatment not optimal" (14.1%).Table 5 presents the top DRIs classified by drug type, with low molecular weight heparin accounting for the highest percentage (9.5%). Table 6 details the planned interventions for DRIs, showing that the highest percentage of planned interventions was "New drug started" (54.1%), followed by "Drug stopped" (19.1%). These data indicate a significant prevalence of adverse drug events, with most interventions being accepted and implemented. The primary cause of DRIs appears to be the lack of appropriate d rug t rea tment desp i te ex is t ing ind ica t ions . Examples of DRIs include the underdosing or omission of enoxaparin despite the need for venous thromboembolism (VTE) prophylaxis, as well as the absence of a proton pump inhibitor (PPI) or H2 blocker for stress ulcer prophylaxis. Figure 1. Figure 1. Number of DRIs per patients
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal6Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in MacaoTable 1. Distribution of patient diagnoses by ICD-9-CM classification categories.Classification Patient Count PercentageSymptoms, Signs, and Ill-Defined Conditions 72 38%Diseases of the Respiratory System 38 20%Diseases of the Circulatory System 23 12%Injury and Poisoning 15 8%No record 8 4%Diseases of the Musculoskeletal System and Connective Tissue 7 4%Diseases of the Blood and Blood-Forming Organs 7 4%Factors Influencing Health Status and Contact with Health Services 5 3%Diseases of the Digestive System 4 2%Diseases of the Genitourinary System 4 2%External Causes of Injury and Poisoning 3 2%Endocrine, Nutritional, and Metabolic Diseases 3 2%Neoplasms 1 1%Total 190 100%Table2. DRI numbers and percentage classification by acceptance.Acceptance Count PercentageIntervention accepted and fully implemented 267 94.3%Intervention accepted, partially implemented 8 2.8%Intervention not accepted: unknown reason 4 1.4%Intervention not accepted: no agreement 2 0.7%Intervention accepted but not implemented 1 0.4%Intervention accepted, implementation unknown 1 0.4%Total 283 100.0%Table 3. DRI numbers and percentage classification by cause.Cause Count PercentageNo drug treatment in spite of existing indication 156 55.1%Inappropriate drug (within guidelines but otherwise contra-indicated) 35 12.4%Inappropriate combination of drugs, or drugs and herbal medication 20 7.1%Drug dose too high 14 5.0%Inappropriate drug form (for this patient) 10 3.5%Drug dose too low 9 3.2%Inappropriate drug according to guidelines/formulary 9 3.2%Too many drugs prescribed for indication 4 1.4%
7Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macao第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Dosage regimen too frequent 3 1.1%Unnecessary drug-treatment 3 1.1%Inappropriate duplication of therapeutic group or active ingredient 3 1.1%Dosage regimen not frequent enough 2 0.7%optimize therapy 2 0.7%No indication for drug 2 0.7%Patient's adherence 1 0.4%mismatch between the medical record and the real situation. 1 0.4%Drug dose too low, Dosage regimen not frequent enough 1 0.4%Missing Allergy record 1 0.4%Patient administers/uses drug in a wrong way 1 0.4%Inappropriate drug (within guidelines but otherwise contra-indicated) Inappropriate drug form (for this patient)1 0.4%Drug dose too high, Dosage regimen too frequent 1 0.4%Inappropriate drug form (for this patient) Drug dose too low 1 0.4%Incorrect inhaler administration technique 1 0.4%medication side effect 1 0.4%Other cause; specify below 1 0.4%Total 283 100.00%Table 4. DRI numbers and percentage classification by problems.Problem Count PercentageAdverse event 176 62.2%Effect of drug treatment not optimal 40 14.1%Untreated symptoms or indication 27 9.5%Untreated indication 20 7.1%Unnecessary drug-treatment 17 6.0%No effect of drug treatment 3 1.1%Total 283 100%Table 5. DRI numbers and percentage classification by drugs.Drugs Count PercentageEnoxaparin 27 9.5%Metformin 12 4.2%Pantoprazole 9 3.2%Bisoprolol 8 2.8%Insulin glulisine 7 2.5%Aspirin 7 2.5%Atorvastatin 5 1.8%Nirmatrelvir + ritonavir 5 1.8%
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal8Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in MacaoCalcium carbonate 5 1.8%Tenofovir 4 1.4%Simvastatin 4 1.4%Losartan 4 1.4%Insulin glargine 4 1.4%Tamsulosin 4 1.4%Rivastigmine 3 1.1%Latanoprost+ timolol 3 1.1%Eplerenone 3 1.1%Esomeprazole 3 1.1%Lorazepam 3 1.1%Ciprofloxacin 3 1.1%Total 283 100%Table 6. RI numbers and percentage classification by Planned Intervention.Planned Intervention Count PercentageNew drug started 153 54.1%Drug stopped 54 19.1%Drug changed 35 12.4%Dosage changed 31 11.0%Formulation changed 4 1.4%instructions for use changed 4 1.4%Other 1 0.4%Dosage changed 1 0.4%Total 283 100%4. DiscussionThis study evaluated 283 DRIs over a 9-month period at a public hospital in Macao. It underscores the pivotal role of clinical pharmacists in the Emergency Unit (EU). An impressive 94.3% of recommendations made by clinical pharmacists were accepted and fully implemented by physicians. This led to significant modifications in drug therapy, ultimately preventing potential adverse health outcomes. Our findings align with similar studies from other countries, where a high acceptance rate was reported to be more than 90% [8-10].In the s tudy by Grain e t a l . [11], pa t ients hospitalized in medical wards are particularly susceptible to DRIs. The prevalence of DRI varies between studies, ranging from 10.8% to 45.1% [11-12]. In our study, the most common DRIs were caused by drug omission (55.1%), inappropriate medication therapy (12.4%) and inappropriate drug combinations (7.1%). Considering the other studies, inappropriate dose and dose adjustment [13], treatment omission [14], inappropriate drug combination [15] constituted most DRIs. Characteristics of DRIs among studies may vary due to the classification system, different populations, disease severity, and healthcare services in each setting.On the basis of our findings, 62.2% of the DRIs were associated with adverse events, all of which
9Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macao第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2were deemed “potentially harm” under the PCNE classification system. Similar trends were noted in a tertiary teaching hospital in China, where DRIs were predominantly classified as either 'no harm' or 'potentially harm' varied from 75% to 89% [16-18]. This result also implied that clinical pharmacists could detect and manage DRIs prior to being harmed. For the drug identified, enoxaparin was among the drugs most frequently associated with DRIs in this setting. The characteristics of DRIs associated with this medication were diverse, including drug omission, suboptimal dosing, and duplication with other therapeutic groups. Of these DRIs, the most prevalent was the omission of the drug in patients with risk factors for developing VTE while hospitalized. As stated by Frederick et al. [19] , it is estimated that over half of hospitalized medical patients are at risk for VTE (ie, deep vein thrombosis and/or pulmonary embolism). In addition, pharmacological interventions play a critical role in the prevention of VTE and its associated unexpected hospital deaths [20]. The result clearly points to the imperative for instituting a standardized protocol to prevent VTE. On top of enoxaparin, metformin was the most common oral agent identified. The primary concern is its continuation of home medication when admitted to the hospital. However, during hospitalization, particularly in the context of an acute illness, metformin may not be suitable due to the potential instability of the patient's hemodynamics and liver or renal function. Additionally, some patients may require immediate imaging studies, such as CT scans, or surgical interventions. Continuing metformin in these circumstances can significantly increase the risk of occurrence of severe adverse events, such as lactic acidosis, although this is a rare complication [21]. This highlighted the importance of thorough medication reconciliation with all medical diagnoses to enhance the effectiveness and safety of therapy during transition of care.Proton pump inhibitors (PPIs) are often used during acute illnesses to prevent complications such as stress ulcers. Among these, pantoprazole is the PPI most commonly associated with DRIs in our facility, primarily in its oral formulation. In this setting, patient may sometimes occur dysphagia or the necessity of placement of nasogastric tube, whereas pantoprazole tablets are gastro-resistant. According to the manufacture labeling [22], these tablets should not be crushed for administration through a tube, as this could compromise the drug's effectiveness by affecting its release and absorption characteristics. This may indicate that establishing a system-based do-not-crush protocol could preemptively prevent medication errors.This study has revealed significant DRIs, emphasizing the necessity for the implementation and expansion of cl inical pharmacy services. However, our study has some limitations as follows. Firstly, it is a retrospective descriptive analysis based on data from routine clinical pharmacist service records, a prospective study may provide more details to elucidate the results. Secondly, this study was conducted in a single centre, making that the results may not be generalizable to other settings. Thirdly, our intervention focused on hospital reports and only provided drug information on identified DRIs. Different physicians often had different types of prescription-related DRIs. Thus, future studies should validate these findings with a prospective designs. 5. ConclusionsThis study highlights the vital contributions of clinical pharmacists in optimizing drug therapy and enhancing patient safety within emergency department settings. The high acceptance rate of pharmacist recommendations led to substantial i m p r o v e m e n t s i n m e d i c a t i o n m a n a g e m e n t , demonstrating the value of integrating clinical pharmacy services as a routine part of the healthcare team. Expanding this role may help promote safer and more effective medication use, thereby enhancing overall patient care. Further prospective studies are needed to investigate the impact of ward-
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal10Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macaobased pharmacy services.AcknowledgementsWe appreciate the Macao health bureau for permission to publish this article.Conflicts of interestWe declare no conflicts of interest. This study did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.References[1] Hepler CD, Strand LM. Opportunities and responsibilities in pharmaceutical care. Am J Hosp Pharm. 1990 Mar;47(3):533-43. [2] Patanwala AE, Warholak TL, Sanders AB, et al . A prospective observational study of medication errors in a tertiary care emergency department. Ann Emerg Med. 2010 Jun;55(6):522-6. doi: 10.1016/j.annemergmed.2009.12.017. Epub 2010 Jan 15. [3] Kulstad EB, Sikka R, Sweis RT, et al . ED overcrowding is associated with an increased frequency of medication errors. Am J Emerg Med. 2010 Mar;28(3):304-9. doi: 10.1016/j.ajem.2008.12.014. [4] Peth HA J r. Medica t ion e r ro r s in the emergency department: a systems approach to minimizing risk. Emerg Med Clin North Am. 2003 Feb;21(1):141-58. doi: 10.1016/s0733-8627(02)00085-8.[5] Mills PR, McGuffie AC. Formal medicine r e c o n c i l i a t i o n w i t h i n t h e e m e rg e n c y department reduces the medication error rates for emergency admissions. Emerg Med J. 2010 Dec;27(12):911-5. doi: 10.1136/emj.2009.082255. Epub 2010 Oct 25. [6] Atey TM, Peterson GM, Salahudeen MS, et al. Impact of pharmacist interventions provided in the emergency department on quality use of medicines: a systematic review and meta-analysis. Emerg Med J. 2023 Feb;40(2):120-127. doi: 10.1136/emermed-2021-211660. Epub 2022 Aug 1. [7] Damiani G, Pinnarelli L, Sommella L, Vena V, Magrini P, Ricciardi W. The Short Stay Unit as a new option for hospitals: a review of the scientific literature. Med Sci Monit. 2011 Jun;17(6):SR15-9. doi: 10.12659/msm.881791.[8] Reinau D, Furrer C, Stämpfli D, et al . E v a l u a t i o n o f d r u g - r e l a t e d p r o b l e m s and subsequen t c l i n i ca l pha rmac i s t s ' interventions at a Swiss university hospital. J Clin Pharm Ther. 2019 Dec;44(6):924-931. doi: 10.1111/jcpt.13017. Epub 2019 Aug 13.[9] F r a n c i s c o D B , D a l P a z K , D i d o n e TVN. Pat ient Factors Associated with Pharmaceutical Interventions for Inpatients at a Brazilian Teaching Hospital. Can J Hosp Pharm. 2021 Summer;74(3):211-218. doi: 10.4212/cjhp.v74i3.3148. Epub 2021 Jul 1. PMID: 34248161; PMCID: PMC8237951.[10] Lombard i N , Wei L , Gha leb M,e t a l . Evaluation of the implementat ion of a c l inical pharmacy service on an acute in ternal medicine ward in I ta ly. BMC Health Serv Res. 2018 Apr 10;18(1):259. doi: 10.1186/s12913-018-2988-y. [11] Garin N, Sole N, Lucas B, et al , Fonts N . Drug r e l a t ed p rob lems in c l in i ca l practice: a cross-sectional study on their prevalence, risk factors and associated pharmaceutical interventions. Sci Rep. 2021 Jan 13;11(1):883. doi: 10.1038/s41598-020-80560-2.[12] Gorgas Torner MQ, Odena Est radé E, Pastor Solernou F. Atención farmacéutica en los problemas relacionados con los medicamentos en enfermos hospitalizados [Pharmaceut ica l care for drug-re la ted
11Clinical pharmacist interventions: Impact on drug-related issues in emergency unit at a government hospital in Macao第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2problems in inpatients]. Farm Hosp. 2003 Sep-Oct;27(5):280-9. Spanish. [13] Reinau D, Furrer C, Stämpfli D, et al . Eva lua t i on o f d rug - r e l a t ed p rob l ems and subsequen t c l i n i ca l pha rmac i s t s ' interventions at a Swiss university hospital. J Clin Pharm Ther. 2019 Dec;44(6):924-931. doi: 10.1111/jcpt.13017. Epub 2019 Aug 13. [14] Requejo, C. C., Saez, C. G., Ruiz, A. T. et al. (2017). CP-133 drug related problems in emergency department patients: Role of clinical pharmacist. European Journal of Hospital Pharmacy.Science and Practice, Suppl.1, 24 doi:https://doi.org/10.1136/ejhpharm-2017-000640.132[15] Albayrak A, Başgut B, Bıkmaz GA, et a l . Cl in ica l pharmacis t assessment of drug-related problems among intensive care unit patients in a Turkish university hospital. BMC Health Serv Res. 2022 Jan 15;22(1):79. doi: 10.1186/s12913-022-07494-5. [16] Liu H, Zhong Y, Zeng Z, et al. Drug-related problems in hospitalized Parkinson's disease pat ients in China . Eur J Hosp Pharm. 2022 Nov;29(6):308-312. doi: 10.1136/ejhpharm-2020-002356. Epub 2020 Oct 30. [17] Meng L, Qu C, Qin X, et al. Drug-Related Problems among Hospitalized Surgical Elderly Patients in China. Biomed Res In t . 2021 Feb 15;2021:8830606. doi : 10.1155/2021/8830606. [18] Liu P, Li G, Han M, et al. Identification and solution of drug-related problems in the neurology unit of a tertiary hospital in China. BMC Pharmacol Toxicol. 2021 Oct 26;22(1):65. doi: 10.1186/s40360-021-00530-w. [19] Anderson FA Jr, Zayaruzny M, Heit JA, et al, Cohen AT. Estimated annual numbers of US acute-care hospital patients at risk for venous thromboembolism. Am J Hematol. 2007 Sep;82(9) :777-82. doi : 10.1002/ajh.20983. [20] Onwuzo C, Olukorode J , Sange W, e t al. Review of the Preventive Strategies f o r Ve n o u s T h r o m b o e m b o l i s m i n H o s p i t a l i z e d P a t i e n t s . C u r e u s . 2 0 2 3 N o v 7 ; 1 5 ( 11 ) : e 4 8 4 2 1 . d o i : 1 0 . 7 7 5 9 /cureus.48421. [21] Inzucchi SE. Management of d iabetes me l l i tu s in hosp i t a l i zed pa t i en t s . In : UpToDa te , Connor RF (Ed ) , Wol t e r s Kluwer. (Accessed on August 6, 2024.)[22] Takeda Pharmaceuticals. (2023). Pantoloc [Package insert]. Deerfield, IL: Takeda Pharmaceuticals America.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal12Tao LI et al.硬膜外鎮痛對孕前低體重初產婦分娩結局的影響The impact of labor epidural analgesia on the delivery outcome of primigravida with progestational low body weight: A clinical retrospective studyAbstractObjective: To explore the impact of labor epidural analgesia (LEA) on the delivery consequences of primigravida with progestational low body weight. Methods: This retrospective study assesses delivery records in 252 primigravida with progestational low body of Kiang Wu Hospital in 2022, who had undergone vaginal labor. Divided equally into non-labor epidural analgesia (Group I) and labor epidural analgesia (Group II), the analysis focused on delivery approach, duration of stages, blood loss, body weight of neonates, Apgar scores of neonates, dilation of the cervix and the dosage of oxytocin. Results: The duration of stage 1 and stage 2 of group II is longer than group I, however, there is no statistical significant. Increased oxytocin usage in Group II and the spontaneous vaginal birth (SVB) rate of Group II is higher than Group I. Conclusion: Although the duration of stage 1 and stage 2 of Group II is prolonged, the SVB rate is 澳門鏡湖醫院麻醉科*Corresponding author: Lai Kan CHO, E-mail: cholkeva@gmail.com DOI : 10.30224/MMJ.202507_12(2).0002李濤，羅英浛，錢曉暉，黃鍇亮，曹麗勤 *Tao LI, Ieng Ham LO, Hiu Fai CHIN, Kai Leong WONG, Lai Kan CHO*摘要目的：探討硬膜外分娩鎮痛（LEA）對孕前低體重初產婦分娩結局的影響。方法：回顧分析鏡湖醫院2022年全年經陰道分娩的孕前低體重初產婦共252位產婦分娩記錄。以是否接受LEA將其分為兩組。I組，非LEA組：不接受LEA且沒有使用止痛藥。II組，LEA組：接受LEA。記錄孕婦分娩方式、產程時間、出血量、新生兒體重、新生兒Apgar評分、產婦要求鎮痛時宮口擴張程度和是否使用縮宮素等。結果：接受LEA組產婦的第一、二產程時間均長於非LEA產婦，但無統計學意義；接受LEA組產婦使用縮宮素的比率顯著高於非LEA組；接受LEA的產婦順產率顯著高於非LEA組。結論：雖然接受LEA的孕前低體重初產婦的產程延長，但其順產率明顯升高。所以，對於所有孕前低體重初產婦值得推廣LEA。關鍵詞：低體重；分娩鎮痛；順產率
15The impact of labor epidural analgesia on the delivery outcome of primigravida with progestational low body weight: A clinial retrospective study 第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2長不低於 12.5Kg 時低體重組的妊娠結局並不亞於正常組，甚至優於正常組。本研究中孕前低體重孕婦孕期增重大於 11Kg 的占 76.7%，以當前澳門地區的生活水準要達到孕期增重 12.5Kg 這個條件應該不難，所以經過孕期的適當準備，孕前低體重孕婦也可以放心考慮自然分娩。強烈的產痛會引發產婦內分泌狀態變化，進而導致腎上腺素、兒茶酚胺等激素水準持續上升，造成產婦心率增快、心血管意外風險增加，還可使產婦出現焦慮、抑鬱等負性心理情緒。很多產婦因懼怕產痛而選擇非醫學指徵剖宮產術終止妊娠，使母兒的遠期併發症增加。LEA 減輕了產婦的產痛，減少其早期能量消耗，讓產婦充分休息，提高了產婦的順產率，特別對於營養儲備較少的孕前低體重孕婦，LEA 的效果更加理想，本研究中接受 LEA 產婦的順產率顯著高於非 LEA 組。本研究中接受 LEA 產婦的第一、二產程時間均長於非 LEA 產婦，此結果與鏡湖醫院孕前體重正常孕婦的分娩結局相同 [4]。接受 LEA 產婦的第一產程較長可能與大部分產婦在剛進入產程時立即要求 LEA 有關。本研究接受 LEA 的孕婦中要求鎮痛時宮口擴張小於 3cm 的占了總數的 61.5%。有研究指出過早的 LEA 介入會對產婦提肛肌和腹肌產生影響，容易產生肌肉鬆弛現象，使產程時間延長 [5]。但本研究接受 LEA 的產婦中按接受分娩鎮痛時宮口擴張小於 3cm 和大於或等於 3cm分組後，其第一產程分別為 727 ± 281、633 ±304min，雖然早接受 LEA 產婦的第一產程較長，但差異無統計學意義，其順產率分別為 80.7%、91.0%，差異也無統計學意義（見表 3），可能與本研究樣本量較少有關，有待於進一步的研究。接受 LEA 產婦的第二產程較長可能是由於鎮痛使產婦無痛，部分產婦對胎頭下降及相應刺激減弱，產婦使用腹壓的時機推後，從而影響了第二產程的時長，此結果與其他人的研究結果一致 [6、7]。如果在第二產程適當改用更低濃度的局麻藥理論上應可以縮短第二產程，有待進一步研究證明。本研究中 LEA 組產婦使用縮宮素數量明顯高於非 LEA 組，與目前臨床上大多數研究的結果相符。本研究中 LEA 組有 5 例需助產，而非 LEA組無需助產。就分娩方式進行分析，LEA 不增加剖宮產風險，但是否增加陰道助產率各家報道不一，有待於進一步大樣本量研究。綜上所述，LEA 雖然延長了孕前低體重產婦的產程，並增加縮宮素的使用，但其可以大大提高孕前低體重產婦的順產率，值得在臨床上推廣。4. 參考文獻[1] 中國營養學會團體標準《中國婦女妊娠期體重監測與評價》 ( T / C N S S - 0 0 9 -2021)2021.[2] G o l d s t e i n R F , A b e l l S K，R a n a s i n h a S e t a 1 . G e s t a t i o n a l w e i g h t g a i n a c r o s s c o n t i n e n t s a n d e t h n i c i t y ：systematicreviewandmeta-analysisofmaternaland infantoutcomesinmorethanonemillionwomen[J]．BMCMed，2018，16(1)：153．[3] 李青，劉小華 .孕前低體重指數對妊娠結局的影響.同濟大學學報，2021,42（4）：541-545.[4] 李濤，羅英浛，廖婧等 . 硬膜外鎮痛對不同孕期增重初產婦分娩結局的影響.鏡湖醫學，2023,23（1）：36-38.[5] 徐勤莉 , 楊傳智 . 腰麻 - 硬膜外聯合麻醉對比硬膜外自控分娩鎮痛始於產程潜伏期、活躍期作用 . 健康必讀 ( 下旬刊 ) , 2018(1):231.[6] Naito Y, Ida M, Yamamoto R et al. The e ffec t o f l abor ep idura l ana lges ia on labor，delivery，and neonatal outcomes：a propensity score-matched analysis in a single Japanese institute [J]. JA Clin Rep,2019,5(1)：1-7.[7] Anim-Somuah M, Smyth RM, Cyna AM et al. Epidural versus non-epidural or no analgesia for pain management in labour [J]. Cochrane Database Syst Rev,2018,5(5)：1-149.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal16Wai Hoi LEONG et al.1. IntroductionThere have been 643 million confirmed cases of COVID-19, including 6.6 million deaths, reported to WHO[1]. Multiple public health policies, such as city lockdowns, school closures, self-antigen detection, and community-wide COVID-19 testing, have been released to deter the transmission in Macau before[2], and the “6.18 outbreak” in 2022 was the most significant outbreak so far. As a result, a total of 1821 confirmed cases and 6 deaths in this period. This outbreak was dominated by the Omicron variant strain, BA 5.1 subtype. It is important to summarize the characteristics of the new sub-type, therefore, we conducted this study to compare the clinical manifestations and identify the sources of infection among children in this outbreak. Vaccination for children aged 3 to 6 years was already available in Macau, and children aged 0-3 will be the final age group taking vaccination in the future. This study will help facilitate vaccine implementation in these young children.The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in childrenAbstractObjective: To determine the clinical characteristics of infected children in the outbreak in Macau in 2022, and analyse whether the public health policies and vaccination halter the outcomes.Methods: This cross-sectional study involved 150 children under 13 years old with COVID-19 in the outbreaks from June 18 through August 2, 2022.Results: Among 150 children under 13 years confirmed with COVID-19 infections, the mean age was 6.9 years old, and 65 individuals (43%) were male. 35 individuals (23%) were asymptomatic and the rest were all mild cases. The mostly presented symptoms were fever (66%), cough (37%), runny nose (19%) and sore throat (17%). Ct values of RT-qPCR were significantly lower among cases who re-ceived the vaccine for more than 180 days(17.2 VS 24.9). Among ages 3 to 6, the incidence of the unvaccinated group was higher than that of the vaccinated group (0.234% VS 0.110%), and no difference was noticed in the elder children.Conclusion: All children under 13 years old with COVID-19 in this outbreak were either asymptomatic or had a mild illness. Fever and respiratory symptoms were the main clinical manifestations. Our study showed the efficacy of vaccination among those ages 3 to 6, and further promotion of vaccination in this age group is reasonable.Keywords: Children; COVID-19; Outbreak; Macau1Paediatric Department, Conde de São Januário General Hospital2Pneumology Department, Conde de São Januário General Hospital*Corresponding author: Hei AO, E-mail: ouxicn@gmail.comDOI : 10.30224/MMJ.202507_12(2).0003Wai Hoi LEONG1, Hei AO1*, Yan LEE1, Seong In NENG2, Fong I SIO2, Ka Kei KUOK2
17The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in children第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 22. Materials and Methods2.1 General informationFrom June 18 through August 2, 2022, a total of 150 children with COVID-19 were included in this study, all cases in this outbreak had a domestic infection; the mean age was 6.9 years old, 65 individuals (43%) were male. 35 individuals (23%) were asymptomatic and the rest were all mild cases. None of our patients developed severe manifestations or required intensive care treatment.2.2 MethodsThis cross-sectional study involved all the children under 13 years old with COVID-19 in the outbreaks from June 18 through August 2, 2022. Data were analysed from August 2022 through September 2022. Demographic characteristics, travel and contact histories, lengths of hospital stay, and symptoms were collected by the physicians in charge of the isolation wards or hotels. The collect-ed data included age at diagnosis, gender, clinical symptoms, vaccination status and outcome after ini-tial discharge. The vaccine data was up to June 18, 2022 (data from Health Bureau, Macau). The gen-eral population by age groups was referred to end-2021 resident population (data from Statistics and Census Service, Macau). 2.3 Statistical AnalysisAnalyses were conducted using SPSS statistical software version 29. Data was presented as counts and percentages, mean values, and median (IQR) values. Categorical variables were compared using the χ 2 test. Median values were compared using Kruskal-Wallis test or Mann-Whitney test ac-cordingly. A 2-tailed P value less than 0.05 was considered statistically significant.3. ResultsFrom June 18 through August 2, 2022, a total of 150 children with COVID-19 were included in this study, all cases in this outbreak had a domestic infection; the mean age was 6.9 years old, 65 individuals (43%) were male. 35 individuals (23%) were asymptomatic and the rest were all mild cases. None of our patients developed severe manifestations or required intensive care treatment (Table 1).Wi t h m u l t i p l e C O V I D t e s t i n g f i n i s h e d (shadow in the background), the new confirmed case dramatically decreased in the mid-term of July, and the outbreak had been controlled within 6 weeks (Figure 1).Total 15 kinds of symptoms were collected, the mostly presented symptoms were fever (66%), cough (37%), runny nose (19%) and sore throat (17%), and a certain percentage of gastroin-testinal symptoms (Table 2).Among symptomatic patients, fever is still the most frequently reported symptom, especially in preschool children, the report rate was as high as 80%. Compare to other prospective studies, which were dominated by beta and delta variants, the respiratory symptoms are more common in children, and fever was reported less than 40% (Figure 2).Ct values of RT-qPCR were significantly lower among cases who received the vaccine for more than 180 days (17.2 VS 24.9). Among ages 3 to 6, the incidence of the unvaccinated group was higher than that of the vaccinated group (0.234% VS 0.110%), and no difference was noticed in the elder children (Table 3).Two types of COVID-19 vaccines are available in Macau: Inactivated vaccines and mRNA vaccines. The inactivated vaccine was available for those over 3-year-old since November 2021, and children's dosage of mRNA vaccine was available since May 24, 2022. Including the adults, 94.9% received at least one dose of vaccine and 91% finished 2 doses of vaccine (up to October 2022). As of June 18, 2022, around 80% coverage between ages 5 to 13 in Macau, and the vaccination rate were very low in children aged 3 to 4, only 40% (Figure 3). Overall, our pediatric vaccination rate was significantly lower than neighbouring area like Hong Kong.Among ages 3 to 6 , the incidence of the unvaccinated group was higher than that of the vac-cinated group (P<0.05). Among ages 7 to 13, the vaccination status did not make a difference in the COVID-19 incidence (Table 4).
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal18The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in childrenTable 1. Clinical features in COVID-19 children. Figure 1. Figure 1. Daily new confirmed cases during the period
19The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in children第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Table 2. Clinical symptoms in COVID-19 children.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal20The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in childrenFigure 2. Figure 2. Comparison of clinical symptoms between different age group
21The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in children第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Table 3. Comparison of Ct values in different subgroups. Figure 3. Figure 3. COVID-19 vaccination coverage among children in Macau
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal22The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in children4. ConclusionTo our knowledge, this cross-sectional study is the first study comparing the clinical character-istics and vaccination data among children with COVID-19 in Macau. Mult iple publ ic heal th policies may be helpful in reducing the spread of COVID-19. As shown in our data, the number of confirmed cases decreased after serial community-wide COVID screening.Af t e r be ing in f ec t ed , t he p ropor t i on o f deve lop ing symptoms was h igh in ch i ld ren , compared with the neighbouring areas[3,4]. Most children presented with 1 to 2 symptoms, but all of them were mild cases in this outbreak. Fever was the main reported symptom, then the respiratory symptoms, corresponding to worldwide data[5].5. RecommendationStudies showed tha t the cur ren t COVID v a c c i n e s w a s l e s s e f f e c t i v e i n p r e v e n t i n g symptomatic infection during the Omicron period[4]. But our study still showed some efficacy among those ages 3 to 6. Ct values were lower among cases who received the full dose vaccination beyond a half year, which may indicate booster vaccine after 6 months may be reasonable. The vaccines surely decrease the severity of the disease in children. The mortality rate may even drop to 0 after finishing full doses of vaccines according to data from Hong Kong. Our studies showed that the vaccination rate was low among 3 to 4-year-old children in Macau. Unvaccinated young children may be more susceptible to COVID-19 infection. Further promotion of vaccination in this group is needed, so as to prevent criti-cal cases.This study has recorded the characteristics of infected children, including the asymptomatic and mild cases. Further studies will surely focus on severe cases, like those with MIS-C[7,8], and long-COVID among children[9].Reference[1] WHO coronavirus disease (COVID-19) dashboard. World Health Organization. Accessed De-cember 11 2022. ht tps: / / covid19.who.int/[2] I e n g S M , C h e o n g I H . A n O v e r v i e w o f E p i d e m i o l o g y o f C O V I D - 1 9 i n Table 4. Comparison of COVID-19 incidence between unvaccinated and vaccinated groups.
23The Omicron outbreak in Macau during the lock-down era: A retrospective study of COVID-19 infection in children第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2M a c a u S . A . R . F r o n t P u b - l i c H e a l t h . 2020 Oct 30 ;8 :550057 . do i : 10 .3389/fpubh.2020.550057[3] Chua GT, Wong JSC, Lam I, Ho PPK, Chan WH, Yau FYS, Rosa Duque JS, Ho ACC, Siu KK, Cheung TWY, Lam DSY, Chan VCM, Lee KP, Tsui KW, Wong TW, Yau MM, Yau TY, Chan KCC, Yu MWL, Chow CK, Chiu WK, Chan KC, Wong WHS, Ho MHK, Tso WWY, Tung KTS, Wong CS, Kwok J, Leung WH, Yam JC, Wong ICK, Tam PKH, Chan GCF, Chow CB, To KKW, Lau YL, Yuen KY, Ip P, Kwan MYW. Clinical Characteristics and Transmission of COVID-19 in Children and Youths During 3 Waves of Outbreaks in Hong Kong. JAMA Netw Open. 2021 May 3;4(5):e218824. doi: 10.1001/jamanetworkopen.2021.8824[4] Karron RA, Hetrich MK, Na YB, Knoll MD, Schappell E, Meece J, Hanson E, Tong S, Lee JS, Veguilla V, Dawood FS; SEARCH Study Team. Assessment of Clinical and Virological Charac-teristics of SARS-CoV-2 Infection Among Children Aged 0 to 4 Years and Their Household Members. JAMA Netw Open. 2022 Aug 1;5(8):e2227348. doi: 10.1001/jamanetworkopen.2022.27348[5] Vi n e r R M , e t a l . S y s t e m a t i c r e v i e w of rev iews of symptoms and s igns o f COVID-19 in children and adolescents. A r c h D i s C h i l d 2 0 2 1 ; 1 0 6 : 8 0 2 – 8 0 7 . doi:10.1136/archdischild-2020-320972[6] Hoang A, Chorath K, Moreira A, Evans M, Burmeister-Morton F, Burmeister F et al. COVID-19 in 7780 pediatric patients: A systematic review. EClinicalMedicine. 2 0 2 0 J u l ; 2 4 : 1 0 0 4 3 3 . d o i : 1 0 . 1 0 1 6 /j.eclinm.2020.100433[7] S h e i n S L , C a r r o l l C L , R e m y K E , Rogerson CM, McCluskey CK, Lin A, Rotta AT. Epidemiology and Outcomes of SARS-CoV-2 Infection or Multisystem I n f l a m m a t o r y S y n d r o m e i n C h i l d r e n v s I n f l u e n z a A m o n g C r i t i c a l l y I l l C h i l d r e n . J A M A N e t w O p e n . 2 0 2 2 J u n 1 ; 5 ( 6 ) : e 2 2 1 7 2 1 7 . d o i : 1 0 . 1 0 0 1 /jamanetworkopen.2022.17217[8] Funk AL, Kuppermann N, F lo r in TA, Tancredi DJ, Xie J, Kim K, Finkelstein Y, Neuman MI, Salvadori MI, Yock-Corrales A, Breslin KA, Ambroggio L, Chaudhari PP, Bergmann KR, Gar-diner MA, Nebhrajani JR, Campos C, Ahmad FA, Sartori LF, Navanandan N, Kannikeswaran N, Caperell K, Morr is CR, Mintegi S , Gangoi t i I , Sabhaney VJ, Plint AC, Klassen TP, Avva UR, Shah NP, Dixon AC, Lunoe MM, Becker SM, Rogers AJ, Pavlicich V, Dalziel SR, Payne DC, Malley R, Borland ML, Morrison AK, Bhatt M, Rino PB, Beneyto Ferre I, Eckerle M, Kam AJ, Chong SL, Palumbo L, Kwok MY, Cherry JC, Poonai N, Waseem M, Simon NJ, Freedman SB; Pediatric Emergency Research Network–COVID-19 Study Team. Post-COVID-19 Conditions Among Children 90 Days After SARS-CoV-2 Infection. JAMA Netw Open. 2022 Jul 1;5(7):e2223253. doi: 10.1001/jamanetworkopen.2022.23253[9] B u o n s e n s o D , M u n b l i t D , D e R o s e C , S i n a t t i D , R i c c h i u t o A , C a r f i A , Va len t in i P. P re l imina ry ev idence on long COVID in children. Acta Paediatr. 2021 Jul;110(7):2208-2211. doi: 10.1111/apa.15870
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal24Zhen GUI et al.Research on COVID-19 treatment guidelines and expert consensus: Findings from a bibliometric perspectiveAbstractObjective: Many guidelines and expert consensus arising from research on Coronavirus disease 2019 (COVID-19) have been published. This study aimed to explore and map the research outputs of COVID-19 related guidelines and expert consensus from a bibliometric perspective.Methods: Information on the relevant publications was retrieved from the Web of Sciences Core Collection. “Bibliometrix” package in R software and VOSviewer software were used for performance analysis, scientific mapping, and graphical visualization.Results: In total, 14,530 relevant publications, with 363,432 citations, were published from 2019 to 2024. Based on corresponding authors alone, the countries with the most publications were the USA (2,947, 20.3%), China (1,037, 7.1%), India (996, 6.9%). In terms of individual authors, Kumar A. contributed to the most publications (51; 0.35%) with 882 citations, while Wang Y had the highest h-index value (H-index = 17). International Journal of Environmental Research and Public Health (Number of publications: 263; 1.81%) was the most productive journal, while Harvard Medical School (943, 6.49%) was the most productive institution. The ten most cited articles mainly focused on the clinical treatment of COVID-19. Conclusion: The large number of publications and citations within a brief period reflects the remarkable attention given to research on COVID-19 related guidelines and expert consensus. The key research hotspots 1Unit of Psychiatry, Department of Public Health and Medicinal Administration, & Institute of Translational Medicine, University of Macau, Macao SAR, China;2Centre for Cognitive and Brain Sciences, University of Macau, Macao SAR, China;3Beijing Key Laboratory of Mental Disorders, National Clinical Research Center for Mental Disorders & National Center for Mental Disorders, Beijing Anding Hospital; Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, China4Beijing Huilongguan Hospital, Peking University Huilongguan Clinical Medical School, Beijing, China;5School of Public Health, Southeast University, Nanjing, China6School of Nursing, Hong Kong Polytechnic University, Hong Kong SAR, China;7Beijing Institute of Petrochemical Technology, China,8Section of Psychiatry, University of Notre Dame Australia, Fremantle, Australia;9Division of Psychiatry, School of Medicine, University of Western Australia, Perth, Australia;10Department of Psychiatry, The Melbourne Clinic and St Vincent's Hospital, University of Melbourne, Richmond, Victoria, Australia;*Corresponding author: Yu-Tao XIANG, E-mail: xyutly@gmail.comDOI : 10.30224/MMJ.202507_12(2).0004Zhen GUI1,2, Pan CHEN1,2, Qinge ZHANG3, Xiao Hong LI4, Zhao Hui SU5, Teris CHEUNG6, Xi Ling CUI7, Robert D. SMITH1, Gabor S. UNGVARI8,9, Chee H. NG10, Yuan FENG3, Yu-Tao XIANG1,2*
25COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 21. IntroductionSince the onset of the Coronavirus disease 2019 (COVID-19) pandemic, as of February 22, 2023, there have been over 757 million confirmed cases of COVID-19, and more than 6.85 million confirmed deaths [1]. This global health crisis has resulted in huge disease burden, as COVID-19 patients may suffer from multiple system dysfunctions and long-term post-COVID-19 symptoms, including fatigue, dyspnea, sleep disorder, difficulty concentrating, anxiety, and depression [2].Clinical practice guidelines (CPGs) and expert consensus are important tools for improving the effectiveness and efficiency of medical care. In response to the COVID-19 pandemic, numerous COVID-19 related guidelines and expert consensus have been published globally to improve COVID-19-related prevention and treatment [3]. These publications encompass a wide range of topics such as crisis care standards and guidelines for allocating scarce critical care resources to COVID-19 patients [4], COVID-19 related personal protective equipment guidance for maximizing adherence and improving health care worker (HCPs) safety [3], vaccination guidelines during and after COVID-19, and expert consensus on COVID-19 diagnosis and treatment [5]. Additionally, guidelines and expert consensus on mental health and dietary interventions for COVID-19 patients have also been developed, as well as other pivotal strategies to battle against the pandemic [6]. Bibliometric analysis is a research method that integrates mathematics, statistics and literature analysis. It enables the quantitative and qualitative assessment of diverse literature data, as a widely used approach for examining the intel lectual structure and emerging trends within a research topic or field [7]. Unlike traditional descriptive reviews, bibliometric analysis unveils various characteristics of research publications through performance analysis (e.g., journals, authors, publication years, countries, institutions, and number of publications). Additionally, it allows for the examination and visualization of relationships between research components through scientific mapping analysis, including co-citation analysis, co-keyword analysis, and co-au thorsh ip ana lys i s [8]. Fur thermore , bibliometric analysis can also provide an overview of the evolution, development and hotspots within specific research fields. Since the onset of the pandemic, bibliometric analysis has been extensively employed to explore topics related to the prevention and treatment of COVID-19, as well as emerging trends in COVID-19 research [9]. However, to date, no bibliometric analysis of COVID-19 related guidelines and expert consensus has been published. Therefore, we conducted a bibliometric analysis to examine the characteristics of publications related to COVID-19 guidelines and expert consensus. 2. Methods2.1 Data source and search strategyFollowing previous bibliometric analyses [10], relevant information was retrieved from the Web of Sciences Core Collection (WoSCC). This is the most widely used academic information resource database in bibliometric analysis which contains all eight databases. Relevant publications were searched from the inception to December 12, 2024. See supplementary material for detailed search terms. There was no restriction on language or type encompassed the diagnosis, management and treatment of COVID-19 patients and their close contacts, as well as vaccination and mental health impacts. These findings provide researchers and policymakers with a comprehensive overview of the broader research landscape concerning COVID-19 related guidelines and expert consensus.Keywords: COVID-19; Bibliometric Analysis; Guideline; Expert Consensus
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal26COVID-19 related guidelines and expert consensusof publications. The exported related articles were recorded as " Fully record and cited references " 2.2 Data analysisR software (version 4.2.2) and VOSviewer software (version 1.6.18) were used to perform qualitative and quantitative analyses on COVID-19-related guidelines and expert consensus. The Bibliometrix package in R was used for performance analysis and scientific mapping of publications, including the following information: countries, authors , journals , ins t i tut ions , and ci ta t ions . Furthermore, Sankey diagram was used to visualize the relationship between the three fields of author, institution, and keyword respectively. Journal quality was evaluated using 2023 Impact Factor (IF) and Journal Citation Reports (JCR), while publication quality was evaluated using H-index.VOSviewer was used to visualize bibliometric maps. For instance, network visualization maps were created to illustrate author co-citation, keywords co-occurrence, inst i tut ion co-authorship, and countries co-authorship. A node in the visual map represents an item (e.g., keyword, author, institution or country), while the size of the node reflects the number of occurrences of the keyword and the number of publications (NP) published by authors, institutions or countries. The thickness of the lines connecting the nodes reflects the strength of collinear and cooperative associations, while the total link strength (TLS) represents the total number of co-occurrences between a particular node and other nodes. Moreover, the online data visualization tool datawrapper (“https://www.datawrapper.de/”) was used to visualize the distribution of publications by country on a world map.Figure 1. Figure 1. Flowchart of data collection and study designand the export format was "Plain text file" or "Tab delimited file" (Figure 1).
27COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 23. Results A total of 14,530 publications from 2019 to 2024 with 363,432 citations on COVID-19 related guidelines and expert consensus in WoSCC were included. Specifically, there were 2,963 publications in 2020; followed by 4,125 in 2021, 3,576 in 2022, 2,391 in 2023 and 1,458 in 2024. There was one publication each in 2019. The number of publications showed a trend of first increasing and then decreasing, reaching its highest in 2021. The published papers between 2020 and 2024 accounted for 99.88% of all relevant publications. 3.1 CountriesA total of 152 countries were involved in COVID-19 related guidelines and expert consensus. Figure 2 shows the distribution of publications on COVID-19 related guidelines and expert consensus by country. The top 10 countries with the most publications were the USA (14,789), UK (5,144), China (5,111), Italy (5,170), India (4,019), Canada (4,013), Germany (3,163), Spain (2,767), Australia (2,543), and France (2,357), eight of which were high-income countries. Based on only corresponding authors, 125 countries were involved in the research on COVID-19 related guidelines and expert consensus. Table 1 summarizes the 10 most productive countries and their distribution as single-country publication (SCP) or multiple-country publication (MCP). Of them, the top four countries with the most publications were the USA (2,947, 20.3%, Total Citations (TC): 72,423), China (1,037, 7.1%, TC: 36,380), India (996, 6.9%, TC: 13,742) and the UK (915, 6.3%, TC: 31,791). Collaboration among countries in academic research was analyzed by comparing the nationalities of corresponding authors with the remaining coauthors; articles were classified as SCPs when all authors share the same nationality, or as MCPs when ≥ 1 authors had different nationalities. The higher the MCP ratio, the stronger the transnational cooperation among countries. Of the top 10 countries, the USA has the strongest national collaborations but had a moderate level of MCP (MCP ratio = 0.211). Additionally, Australia, the UK and Canada were the countries that had the strongest international cooperation with high MCP/SCP ratios of 42.8%, 38.5%, and 35.2%, respectively.Figure 2. Figure 2. World map for the distribution of publications by country on COVID-19 related guidelines and expert consensus
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal28COVID-19 related guidelines and expert consensus3.2 Authors and institutions A t o t a l o f 8 5 , 6 8 0 a u t h o r s f r o m 1 9 , 2 8 9 inst i tut ions contr ibuted to COVID-19 related guidelines and expert consensus. The top 10 most active authors and institutions are shown in Table 2. Kumar A contributed to the most publications (51; 0.35%) with 882 citations, followed by Kumar S (44; 0.30%), and Wang Y (44; 0.30%). Among the top ten authors, Wang Y has the highest h-index value (H-index = 137 and the most citations (4,165). The Harvard Medical School (943, 6.49%) was the most productive institution, followed by University of Toronto (905, 6.23%) and University of London (885, 6.09%).Furthermore, the Three-Fields Plot shows the collaboration among institutions, authors, and research hotspot keywords, respectively. As shown in Figure S3, Harvard university published the most articles with the key words “COVID-19” through Kim J. Figure S2a shows the network of co-cited authors, including 60 authors, each with at least 224 citations (TLS: 56,335). The WHO (TLS: 16,707) shared the strongest cooperation with other cited authors, followed by Center for Disease Control and Prevention, United States (CDC) (TLS: 8,023). In addition, the thick lines between WHO and CDC, United States (green color) indicate the strongest co-citation cooperation between the two organizations. Moreover, as shown in the density visualization in Table 1. Top 10 most productive countries based on corresponding authors on COVID-19 related guidelines and expert consensus.SCR CountryIncome levelArticles Percent TC AAC SCP MCP MCP_Ratio1 USA High 2,947 20.3% 72,423 24.6 2,326 621 21.1%2 ChinaUpper middle1,037 7.1% 36,380 35.1 765 272 26.2%3 IndiaLower middle996 6.9% 13,742 13.8 847 149 15.0%4 UK High 915 6.3% 31,791 34.7 563 352 38.5%5 Italy High 870 6.0% 18,044 20.7 649 221 25.4%6 Canada High 603 4.2% 17,654 29.3 391 212 35.2%7 Germany High 431 3.0% 6,224 14.4 306 125 29.0%8 Australia High 407 2.8% 8,682 21.3 233 174 42.8%9 Spain High 378 2.6% 7,829 20.7 284 94 24.9%10 BrazilUpper middle366 2.5% 2,767 7.6 285 81 22.1%Notes: SCR: Standard Competition Ranking; TC: Total Citations; AAC: Average Article Citations; SCP: Single Country Publications; MCP: Multiple Country Publications
29COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Figure S2b, two clusters of high author co-citation related to WHO and CDC were observed.Figure S1a shows the collaboration among 69 institutions (total TLS: 4,982), with at least 61 articles in each institution. Harvard Medical School had the strongest collaboration with other institutions (TLS: 503), followed by the University of Toronto (TLS: 494) and McMaster University (TLS: 401). In addition, McMaster University had the highest number of citations of 10,293. Moreover, in recent years (green color) University of Toronto (average publication year (APY): 2021.57; NP:284; TLS: 494) also published more publications on COVID-19 related guidelines and expert consensus and collaborated more with others, followed by the Harvard Medical School (APY: 2021.52; NP:268; TLS: 503) and All India Institute of Medical Sciences (APY: 2021.29; NP:171; TLS: 19) (Figure S1b).Table 2. Top 10 most active authors contributing to COVID-19 related guidelines and expert consensus.SCR Author(N=85,680) H-index TC NP Institution (N=19,289) NP Percent1 Kumar A 15 882 51 Harvard University 943 6.49%2 Kumar S 13 621 44 University of Toronto 905 6.23%3 Wang Y 17 4,165 44 University of London 885 6.09%4 Sharma A 14 553 40 University Of California System 649 4.47%5 Sharma S 10 669 39 Assistance Publique Hopitaux Paris (APHP) 516 3.55%6 Gupta S 10 1,021 38 Egyptian Knowledge Bank (EKB) 509 3.50%7 Kim J 9 247 37 Universite Paris Cite 451 3.10%8 Lee J 14 1,091 36 University College London 418 2.88%9 Singh S 10 607 36 Institut National De La Sante Et De La Recherche Medicale (INSERM) 405 2.79%10 Wang J 14 1,668 36 Johns Hopkins University 403 2.77%Notes: NP: Number of publications
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal30COVID-19 related guidelines and expert consensus1.2 Supplementary FiguresSupplementary Figure 1A.Supplementary Figure 1B.Supplementary Figure 1. Map of collaboration networks of co-authorship analysis (A. Network visualization map of institution co-authorship; B. Overlay visualization map of institution)
31COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Supplementary Figure 2A.Supplementary Figure 2B.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal32COVID-19 related guidelines and expert consensusSupplementary Figure 3.Supplementary Figure 3. Three-Fields Plot of the keywords analysis (institution-author-keyword)3.3 Journals Table S1 shows the top 10 journals with the most relevant publications out of the 4,323 journals with 14,530 relevant publications included in this study. International Journal of Environmental Research and Public Health had the most publications (NP: 263; 1.81%), followed by Plos One (NP: 251; 1.73%) and Cureus Journal of Medical Sciences (NP: 209; 1.44%). Three out of the ten journals are classified as Public, Environmental & Occupational Health (Q2). The 2023 Impact Factors (IFs) among the top ten journals ranged from 2.4 to 5.2. According to the Journal Citation Reports (JCR) partition, 60% of the journals were classified as Q1, and 20% were classified as Q2.3.4 Most cited articles Table S2 d isp lays the top 10 most c i ted articles on COVID-19 related guidelines and expert consensus, with citation counts ranging from 1,481 to 3,210. The topics covered by the highly cited articles primarily focused on COVID-19 related guidelines as well as research and guidance on clinical treatment of COVID-19. Additionally, the other six articles were systematic reviews on mental health and clinical research related to COVID-19. The article entitled “Clinical and immunological features of severe and moderate coronavirus disease 2019” from the Journal of Clinical Investigation had the most citations (N = 3,210).
33COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 21.1 Supplementary TablesSupplementary Tables 1. Top 10 productive journals on COVID-19 related guidelines and expert consensusSources NP Percent IF (2023)Category (JCR)/ Category Rank/ Category QuartileInternational Journal of Environmental Research and Public Health263 1.81% 4.6Environmental Sciences (Q2);Public, Environmental & Occupational Health (Q2);Plos One 251 1.73% 2.9 Multidisciplinary Sciences (Q1)Cureus Journal of Medical Sciences 209 1.44% NR NRFrontiers in Public Health 184 1.27% 3.0 Public, Environmental & Occupational Health (Q2)BMJ Open 152 1.05% 2.4 Medicine, General & Internal (Q1)Journal of Clinical Medical 114 0.78% NR NRBMC Public Health 104 0.72% 3.5 Public, Environmental & Occupational Health (Q1)Frontiers in Medicine 96 0.66% 3.1 Medicine, General & Internal (Q1)Vaccines 86 0.59% 5.2 Immunology(Q1); Medicine, Research & Experimental (Q1)Scientific reports 81 0.56% 3.8 Multidisciplinary Sciences(Q1)Notes: IF:Impact Factor; NP: Number of publications
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal34COVID-19 related guidelines and expert consensusSupplementary Table 2. Top 10 most cited articles on COVID-19 related guidelines and expert consensusSCR Author & Year Title Journal (IF-2023) TC TC/Y1Chen G, 2020Clinical and immunological features of severe and moderate coronavirus disease 2019Journal of Clinical Investigation (13.3)3,210 642.02Xiong JQ, 2020Impact of COVID-19 pandemic on mental health in the general population: A systematic reviewJournal of Affective Disorders (4.9)3,192 638.43Chu DK, 2020Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysisLancet (98.4) 2,552 510.44Jin YH,2020A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)Military Medical Research (16.7)2,316 463.25Rajkumar RP, 2020COVID-19 and mental health: A review of the existing literatureAsian Journal of Psychiatry (3.8)2,080 416.06Bikdeli B, 2020,COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art ReviewJournal of the American college of cardiology (21.7)2,031 406.27Wynants L, 2020Prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisalBMJ-British Medical Journal (93.7)1,916 383.208Connors JM, 2020 COVID-19 and its implications for thrombosis and anticoagulationBlood (21.1) 1,614 322.89Gao JJ, 2020Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studiesBioscience Trends (5.7)1,613 322.610Lopez-leon S, 2021More than 50 long-term effects of COVID-19: a systematic review and meta-analysisScientific Reports (3.8)1,481 370.25Notes: SCR: Standard Competition Ranking; TC: Total Citations; TC/Y: Average per Year Total Citation
35COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 23.5 Keywords co-occurrence networksFigure 3a illustrates 61 keywords, each with at least 63 citations (TLS: 14,068). The most frequent keywords were “COVID-19” (9,340), “sars-cov-2” (2,032) and “pandemic” (1,844). The 61 keywords in 8 clusters are displayed in Figure 3a. Cluster 1 refers to the pandemic and risk factors associated with COVID-19 (red color), including keywords such as " COVID-19", "mortality" and " risk factors ". Cluster 2 refers to infection and prevention of the COVID-19 (green color), including keywords such as " pandemic ", "health policy", and "telemedicine". Cluster 3 refers to guidelines and treatment for COVID-19 patients (blue color), incorporating keywords such as "guidelines", "diagnosis", "management". Cluster 4 refers to psychological and mental health effects of the COVID-19 (yellow color), encompassing keywords such as "anxiety", "depression" and "stress". Figure 3b shows 61 keywords that have changed over time. Keywords related to COVID-19 outbreaks appeared earlier, with an APY mostly in 2020, such as “guideline” (APY: 2020.95) and “protocol” (APY: 2020.67). In contrast, other keywords such as "vaccine" (2022.29), "qualitative research" (2022.44) and "mental health" (2021.95), were more frequently used in recent years, as indicated by the yellow color highlighting.4. DiscussionThis is the f i rs t b ibl iometr ic analysis of COVID-19 related guidelines and expert consensus. Out of the 14,530 publications identified from the WOSCC database, 9,981 (68.7%) were original research articles and 3,274 (22.5%) were reviews. There was a substantial growth in the number of relevant publications between 2020 and 2023, with the highest annual publications of 4,125 (28.4%) in 2021, which coincided with the major economic and productivity losses caused by the COVID-19 pandemic and the global focus on COVID-19 [11].Scientif ic outputs and academic capacity are closely related to the socioeconomic status and the financial powers of countries to provide research funding for the corresponding field of research. Not surprisingly, our study showed that the top 10 countries with the most publications on COVID-19 related guidelines and expert consensus were p redominan t ly h igh- income coun t r i e s . Corresponding authors from the US and the UK had far more publications than those from other countries. The stronger the economy, the greater the financial resources could be provided by the government for medical and scientific research that informs COVID-19-related guidelines and expert consensus [12]. Indeed, consistent with past reports, high-income countries had significantly more research on COVID-19 related guidelines and expert consensus than low- and middle-income countries. Furthermore, in terms of cooperation between countries in this field, the US had the strongest domestic cooperation, while Australia had the most international cooperation. This might be related to the fact that the US has the most number of elite research universities, while Australia has stronger international research cooperation compared to most other countries [13].Analyzing publication patterns in international journals can assist research authors in understanding the current research trends and selecting suitable journals to submit their work. Among the 10 most active journals that published COVID-19 related guidelines and expert consensus, seven were from Europe, including Switzerland (N = 4) and the UK (N = 3), while the remaining were from the USA (N = 1). The International Journal of Environmental Research and Public Health was the most productive journal in terms of COVID-19 related guidelines and expert consensus research, accounting for 1.81% of the total publications, followed by Plos One (1.73%) and Cureus Journal of Medical Sciences (1.44%), which is consistent with other bibliometric analyses on COVID-19 related research [14]. The top three journals in terms of publication volume were all journals with a high Impact Factor, and wide influence in the field of public health. This is not surprising given
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal36COVID-19 related guidelines and expert consensusFigure 3A. Figure 3B. Figure 3. Figure 3. Analysis of research hotspots on COVID-19 related guidelines and expert consensus (A. Network visualization map of keywords co-occurrence; B. Overlay visualization map of keywords)
37COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2that COVID-19 is a pandemic that has resulted in serious fatality rate and disease burden globally. Furthermore, the publication volume of the top 10 journals for COVID-19 related guidelines and expert consensus has been steadily increasing in recent years. For example, data from the WoSCC indicated that the publication count of COVID-19 related guidelines and expert consensus in the International Journal of Environmental Research and Public Health journals increased surged from 43 in 2020 to 263 in 2023/2024.The Harvard Medical School, University of Toronto, and University of London emerged as the most active institutions, with the highest total number of publications and the strongest research collaboration with other institutions in the field of COVID-19 related guidelines and expert consensus. Further, Harvard Medical School demonstrated the most collaborations with other institutions (TLS: 503), while McMaster University had the most citations (10,293) for the relevant publications. As strict research requirements and advanced experimental instruments are needed to support infectious diseases research, the top universities in the field of public health medicine in the world, such as Harvard Medical School, University of Toronto and University of London, are likely to have large research resources and infrastructure to conduct COVID-19 related research. Hence, they would have greater research output and stronger research collaboration relative to other institutions with less resources. Given that McMaster University was the epicenter of the COVID-19 pandemic, local medical and academic institutions swiftly directed their efforts toward COVID-19-related research, thus generating some of the earliest data in this field. In addition, co-cited authors network analyses showed that the WHO and the CDC in the USA exhibited the strongest cooperation with other cited authors. When the COVID-19 pandemic was declared, the WHO assumed a leadership role in global prevention and control measures for COVID-19. As of early 2023, COVID-19 related advice, guidelines, and research data were being published on the WHO homepage as emergency issues [1]. Co-author analysis is an important method to understand the current partnerships in a particular research field and to facilitate future research partnerships. This may assist researchers and institutions across the world to strengthen cooperation, promote research advancement, enhance publication volume and quality, and propel the field forward [8].The citation count can reflect the scientific impact and interest in an area of research, while highly cited research articles may indicate the level of scientific quality published in a specific area. In addition, the most frequently cited articles can also provide a historical perspective of the scientific advancement within a research field. In this study, four out of the 10 most-cited articles focused on COVID-19 related guidelines, research and clinical management for COVID-19 [16]. The remaining six articles were systematic reviews of COVID-19 related mental health and clinical research. Among them, the article entitled “Clinical and immunological features of severe and moderate coronavirus disease 2019” from the Journal of Clinical Investigation (IF = 13.3) had the most citations (N = 3,210). The article provided timely COVID-19 related information in May 2020. The article analyzes the clinical and immunological characteristics of COVID-19 patients, including that SARS-CoV-2 infection may mainly affect T lymphocytes, especially CD4(+) and CD8(+) T cells, leading to a decrease in the number of CD4(+) T cells and a decrease in IFN- γ production. This information plays an important role in the diagnosis and treatment of COVID-19 patients. Of note, the COVID-19 related guidelines and expert consensus have provided healthcare workers globally with essential information for tackling and managing COVID-19 and its adverse impact. Keyword co-occurrence analysis can reflect the research hotspots within a specific field and outline the distribution of research topics. Our study found five primary research clusters on COVID-19
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal38COVID-19 related guidelines and expert consensusrelated guidelines and expert consensus. Cluster 1 predominantly focused on "mortality", and "risk factors". In the initial phase of the COVID-19 pandemic, a plethora of studies scrutinized the mortality rates of COVID-19 patients and other comorbid diseases [17]. Given the urgent need to control the severe disease burden posed by the COVID-19 pandemic, the swift development of efficacious and safe COVID-19 vaccines was a high priority that demanded global attention.In Cluster 2, "pandemic" and "telemedicine". were the central keywords. Since the WHO declared the COVID-19 outbreak a global pandemic on 11 March 2020, the volume of published studies on the treatment of COVID-19, its impact, and mental health effects on the general population surged. For example, one report indicated that COVID-19 patients were susceptible to thrombotic disease in both venous and arterial circulation due to excessive inflammation, platelet act ivation, endothelial dysfunc t ion , and s tas i s [18]. A s tudy en t i t l ed “COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow” reviewed and summarized the pathogenesis, epidemiology, management, and outcomes in COVID-19 patients with venous or arterial thrombosis, patients with pre-existing thrombotic disease who contracted COVID-19, and other vulnerable patients. Due to the particularity of transmission during the COVID-19 epidemic, some areas have adopted strict isolation measures to avoid contact to reduce the spread of infection. Therefore, telemedicine research has been more utilized and studied during this period.In Cluster 3, the keywords were "guidelines", "diagnosis" and "management". As COVID-19 is a novel infectious disease, diagnostic and management guidelines for COVID-19 patients undoubtedly became a crucial priority for medical research. A study involving 30 guidelines on COVID-19 treatment found a high degree of consistency in the diagnostic and treatment recommendations, which inc luded computed tomography (CT) , X-rays, reverse transcription polymerase chain reaction (RT-PCR) and routine blood tests as the primary diagnostic methods for COVID-19, with ultrasound serving only as a potential diagnostic tool. Another study recommended evidence-based, real-time guidance to support patients and healthcare professionals in making informed decisions about the t reatment and management of COVID-19 patients [19]. Finally, Cluster 5 focused on "acute respiratory syndrome". As a viral respiratory disease caused by the Coronavirus 2 (SARS-CoV-2), the transmission of COVID-19 is based on the patient viral load, proximity to the patient, and the level of indoor ventilation. Our study also noted a shift in terms of research hotspots from “outbreak” and “transmission” in the early stage of the COVID-19 pandemic to more recent hotspots such as the “impact” on health and “vaccines”. The transmission and high mortality rate of COVID-19 init ial ly sparked widespread anxiety and fear regarding the virus [20]. However, with the advent of effective treatment methods and vaccines, research focus pivoted to the impact of COVID-19 on human health and other aspects related to vaccination. Cluster 4 mainly addressed the psychological conditions associated with COVID-19 such as "anxiety", "depression" and "stress". A multi-national study involving eight countries discovered a high prevalence of anxiety, depression, posttraumatic stress disorder, psychological distress and stress within the general population during the COVID-19 pandemic. Consequently, mitigating the detrimental effects of COVID-19 on mental health was another key priority. This bibliometric analysis revealed the research patterns and features of COVID-19 related guidelines and expert consensus, including the authors , institutions, countries and journals which had had the most publications, as well as the prominent keywords. However, this study has the several limitations. First, non-English articles were not included. Second, the publications included were solely retrieved from WoSCC, the most frequently
39COVID-19 related guidelines and expert consensus第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2used academic information resource database in bibliometric analysis, which might cause selection bias. In conclusion, the substant ia l volume of publications and citations within a span of a few years indicates that research on COVID-19 related guidelines and expert consensus has received unprecedented attention. The diagnosis, management and treatment of COVID-19 patients and their close contacts, as well as the mental health effects and vaccination, were identified as research hotspots in this field. These findings can provide COVID-19 researchers and policymakers with a comprehensive overview of the broad research landscape concerning COVID-19 related guidelines and expert consensus. References[1] World Health Organization. Coronavirus disease (COVID-2019) situation reports [Internet]. Available online at: https://www.who.int (Accessed February 23, 2023). 2023.[2] Alkodaymi MS, Omrani OA, Fawzy NA, Abou Shaar B, Almamlouk R, Riaz M, et al. Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: A systematic review and meta-analysis. Clin Microbiol Infect 2022; 28 (5): 657-666. doi: 10.1016/j.cmi.2022.01.014.[3] Darwish OA, Aggarwal A, Karvar M, Ma CH, Haug V, Wu MF, et al. Adherence to personal protective equipment guidelines during the COVID-19 pandemic among health care personnel in the United States. Dis Med Public Health Prep 2022; 16 (4): 1331-1333. doi: 10.1017/dmp.2021.12.[4] Jezmir JL , Bharadwaj M, Chai toff A, Diephuis B, Crowley CP, Kishore SP, et al. Performance of crisis standards of care guidelines in a cohort of critically ill COVID-19 patients in the United States. Cell Rep Med 2021; 2 (9): 12. doi: 10.1016/j.xcrm.2021.100376.[5] Song JC, Wang G, Zhang W, Zhang Y, Li WQ, Zhou Z, et al. Chinese expert consensus on diagnosis and treatment of coagulation dysfunction in COVID-19. Military Med Res 2020; 7 (1): 10. doi: 10.1186/s40779-020-00247-7.[6] Tavares A, de Melo AKG, Cruz VA, de Souza VA, de Carvalho JS, Machado K, et al. Guidelines on COVID-19 vaccination i n p a t i e n t s w i t h i m m u n e - m e d i a t e d rheumatic diseases: A Brazilian Society of Rheumatology task force. Adv Rheumatol 2022; 62 (1): 11. doi: 10.1186/s42358-022-00234-7.[7] Fahimnia B, Sarkis J, Davarzani H. Green s u p p l y c h a i n m a n a g e m e n t : A r e v i e w and b ib l iomet r i c ana lys i s . In t J P rod Econ 2015; 162 101-114. doi: 10.1016/j.ijpe.2015.01.003.[8] Sun HL, Bai W, Li XH, Huang HH, Cui XL, Cheung T, et al. Schizophrenia and inf lammation research: A bibl iometr ic analysis. Front Immunol 2022; 13 10. doi: 10.3389/fimmu.2022.907851.[9] Verma S, Gustafsson A. Investigating the emerging COVID-19 research trends in the field of business and management: A bibliometric analysis approach. J Bus Res 2020; 118 253-261. doi : 10.1016/j.jbusres.2020.06.057.[10] Donthu N, Kumar S, Mukherjee D, Pandey N, Lim WM. How to conduct a bibliometric analysis: An overview and guidelines. J Bus Res 2021; 133 285-296. doi: 10.1016/j.jbusres.2021.04.070.[11] Huang CL, Huang LX, Wang YM, Li X, Ren LL, Gu XY, et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021; 397 (10270): 220-232. doi: 10.1016/s0140-6736(20)32656-8.[12] Gantman ER. Economic, linguistic, and
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal40COVID-19 related guidelines and expert consensuspolitical factors in the scientific productivity of countries. Scientometrics 2012; 93 (3): 967-985. doi: 10.1007/s11192-012-0736-3.[13] Butler J, Foot C, Bomb M, Hiom S, Coleman M, Bryant H, et al. The international cancer benchmarking partnership: An international collaboration to inform cancer policy in Austra l ia , Canada, Denmark, Norway, Sweden and the United Kingdom. Health Pol icy 2013; 112 (1-2) : 148-155. doi : 10.1016/j.healthpol.2013.03.021.[14] Zhang YT, Chen MT, Liu CL, Zhang ZJ, Fu XH. A bibliometric analysis of COVID-19 and physical activity. Medicine (Baltimore) 2 0 2 2 ; 1 0 1 ( 3 9 ) : 1 2 . d o i : 1 0 . 1 0 9 7 /md.0000000000030779.[15] Li X, Zhou L, Jia T, Peng R, Fu XW, Zou YL. Associating COVID-19 severity with urban factors: A case study of Wuhan. Int J Environ Res Public Health 2020; 17 (18): 20. doi: 10.3390/ijerph17186712.[16] Chen G, Wu D, Guo W, Cao Y, Huang D, Wang HW, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020; 130 (5): 2620-2629. doi: 10.1172/jci137244.[17] Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, Torralbo A, Shallcross L, et al. Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: A population-based cohor t s tudy. Lancet 2020; 395 (10238): 1715-1725. doi: 10.1016/s0140-6736(20)30854-0.[18] Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow. J Am Coll Cardiol 2020; 75 (23): 2950-2973. doi: 10.1016/j.jacc.2020.04.031.[19] Bhimraj A, Morgan RL, Shumaker AH, Baden L, Cheng VCC, Edwards KM, et al. Infectious diseases society of America guidelines on the treatment and management of patients with coronavirus disease 2019 (COVID-19). Clin Infect Dis 2022; 100. doi: 10.1093/cid/ciac724.[20] Hu DY, Kong Y, Li WG, Han QY, Zhang X, Zhu LX, et al. Frontline nurses' burnout, anxie ty, depress ion , and fear s ta tuses and their associated factors during the COVID-19 outbreak in Wuhan, China: A l a rg e - s c a l e c r o s s - s e c t i o n a l s t u d y. ECl in i ca lMed ic ine 2020 ; 24 10 . do i : 10.1016/j.eclinm.2020.100424.
41Guo Liang ZHANG et al.第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomaAbstractObjective: To determine presenting features, management, and outcome of extranodal Non-Hodgkin’s lymphoma (NHL) of the sinonasal and nasopharyngeal, with a review to optimizing management.Methods:A retrospective study recruited patients with sinonasal and nasopharyngeal extranodal NHL diagnosed and/or treated between January 2015 and December 2023 in the Department of Otorhinolaryngology-Head and Neck Surgery at Huashan Hospital and CHCSJ. Epidemiologic ,diagnostic and prognostic criteria were analyzed. Results: Thirty-seven patients, including 28 men and 9 women, were included in this study. Overall, most B-cell non-Hodgkin lymphomas(B-NHL) originated from the nasopharynx,while the majority of NKT-cell non-Hodgkin lymphomas(NKT-NHL) occurred in the nasal cavity. The most frequent presenting symptoms were unilateral nasal obstruction, mucopurulent rhinorrhea, recurrent epistaxis or diplopia. Systematic symptoms occurred in 38% of patients. A majority (68%) had extensive lesions invading multiple anatomical subsites at diagnosis. Histopathologic classification included B-NHL (n=16), NKT-NHL (n=14), peripheral T cell lymphoma (n=6) and extraosseous plasmacytoma (n=1). Diagnosis was reached through punch biopsy or surgery. Futhermore, radiotherapy was beneficial for survival in patients with sinonasal B-NHL and NKT-NHL.Conclusions: Otolaryngologists may be the first to recognize sinonasal and nasopharyngneal NHL, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential.Keywords: Non-Hodgkin lymphoma; sinonasal; nasopharyngeal; review1Department of Otorhinolaryngology, Affiliated Huashan Hospital, Fudan University, Shanghai 200040, China2Department of Otorhinolaryngology, Conde de São Januário General Hospital, Macau*Corresponding author: Ki Man PAI, E-mail: paikiman@gmail.comDOI : 10.30224/MMJ.202507_12(2).0005Guo Liang ZHANG1, Yi Tan CAO1, Ki Man PAI2*, Wan Pang SAM2, Tin Seak MOK2, Xin Ye CHEN2, Xian Zhong WANG2, Chon Man KAN2, Choeng Un SIO2, Kit Ian LIO2, Ut Man IONG21. IntroductionLymphomas a re nonepi the l ia l mal ignant neoplasms, which are commonly categorized as Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) [1]. Notably, the NHL, which accounts for approximately 90% of all lymphomas, ranks as the sixth most frequent malignancy in the United States [2]. Its incidence and mortality have gradually increased recently. Although most malignant lymphomas are
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal42Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomaderived from the lymph nodes, more than a quarter of NHL cases originate from the extranodal lymph nodes [3]. Extranodal NHL is a common lymphoma subtype that occurs in the head and neck region. and can involve multiple sites, including the nasal cavity, nasopharynx, oral cavity, eye, salivary, and thyroid glands, among which the sinonasal and nasopharynx are the most common sites. However, due to the limited sample sizes and adjacent anatomical characteristics of nasal cavity lymphoma, nasopharyngeal lymphoma, and sinonasal lymphoma , researchers have often categorized them as one sinonasal type for analysis.It is quite a challenging job for otorhinolaryngologists to make a differential diagnosis between malignant lymphoma and other benign inflammatory nasal diseases due to subtleties at presentation with a lack of specific clinical signs, diagnosis can be delayed, which may worsen prognosis. In this study, we reviewed the clinical characteristics of sinonasal and nasopharyngeal NHL which diagnosed at the otorhinolaryngology department of our hospital. The objective of this study is to present a better understanding of the rhinologic features of this subset of NHL. 2. Materials and MethodsWe retrospectively reviewed patient files from the Department of Otorhinolaryngology-Head and Neck Surgery at Huashan Hospital and CHCSJ. The Institutional Review Board at Huashan Hospital approved this study. Patients with histological diagnosed of lymphoma from the external nose, nasal cavity, paranasal sinuses and nasopharynx between January 2015 and December 2023 were identified. Patients were excluded if they did not have pathology reviewed at the authors’respective institutions or i f fol low-up information was unavai lable . Clinical data regarding demographic information, dura t ion to d iagnosis , present ing symptoms, clinical and image findings, Ann Arbor stage, treatment modalities and outcomes were collected through review of patients’charts.Histopathologic classification was determined according to the Wor ld Heal th Organiza t ion c lass i f ica t ion of tumours of haematopoietic and lymphoid tissues [4]. Immunohisto-chemical(IHC) analysis was performed automatically(AutostainnerLink 48, Dako) using a panel of antibodies. In situ hybridization with an EpsteineBarr virus (EBV) encoded RNA-1 (EBER1) probe (Dako, Glostrup, Denmark) was performed to detect possible EBV infection. In our institution, a panel of IHC: CD20, CD3, CD5, CD10, BCL6, MUM1, and cyclin D1, is performed when DLBCL is suspected by morphological examination, and a panel of IHC: CD3, CD20, CD4, CD8, CD56, CD30, and EBER1 ISH, is performed when peripheral T-cell lymphoma is suspected by morphology and clinical presentation. When these markers are negative, other IHC markers are additionally tested. Epstein-Barr virus (EBV) infection status was determined by in-situ hybridization of EBV encoded small RNA (EBER) probes. 3. Results and analysisThirty-seven patients, including 28 men and 9 women, were included in this study. Sex ratio was 3: 1 with a male predominance. Detailed patient demographic and clinical information is summarized in Table 1. The average age at diagnosis was 49.8 years (range, 16-75 years). Age distribution showed different patterns in various histological subtypes: ENKTL occurred predominantly in patients during their fourth decades of life, while B-cell lymphomas occurred more often in patients over 60 years of age (Figure 1). Of 21 patients with known smoking status, 12 had a positive smoking history (57%). The mean time between patients’first symptom onset and final histopathological diagnosis lasted 5.5 months (range, 10 days to 24 months). Presenting symptoms included nasal obstruction (76%), rhinorrhea (41%), diplopia and vision loss (22%), epistaxis (16%), neck mass (11%), facial swelling and numbness (11%) and fever (24%). Two patients showed skin rash or lumps on their upper body and limbs. Physical and endoscopic examinations were performed in all patients. Among these sinonasal or nasopharyngeal neoplasms, 31 presented with an ulcerous appearance,
43Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphoma第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2sugges t ing the poss ib i l i t y o f ma l ignanc ie s , whereas 6 showed a polypoid appearance, leaving a first impression of inflammatory benign lesions. Systematic B symptoms such as fever, weight loss and night sweats are present in 38% of patients in our series, and they occur more often in ENKTL than in B-cell lymphoma patients.Radiographic results were available in 36 patients (21 received CT, 4 received MRI, 11 received both CT and MRI, and 10 received complementary PET-CT scans.). Image findings of CT/MRI revealed: discrete soft tissue mass in the nasal cavity or nasopharynx, mucosal thickening, paranasal sinus fluid accumulation, and/or bone erosion. 10 patients had soft tissue mass in the nasal cavity, 15 had maxillary sinus involvement, 13 had ethmoid sinus involvement, 2 had sphenoid sinus involvement, 2 had frontal sinus involvement, and 12 had nasopharyngeal involvement. 25 presented with extensive lesions affecting more than one subsite. One patient had nasopharyngeal soft tissue mass extending to the oropharyngeal space. 2 had postorbital involvement, and 3 had intracranial infiltration. A total of 2 patients had localized craniofacial tumor, 6 had cervical lymphadenopathy, and 10 had systemic lymphoma. Figure 2 and figure 3 showed endoscopic pictures, image findings and histopathological slides of two patients. Case No.1 was a 64-year-old male, presenting with a two-week history of headache as well as occasional epistaxis. Rhinoscopy revealed a mass in the left nasal cavity and coronal CT and MRI findings showed soft tissue mass in both nasal cavities, ethmoid and sphenoid sinuses. Punch biopsy was performed in the left nasal cavity and pathologic examination revealed diffuse large B cell lymphoma. Case No. 2 was a 44-year-old male, suffering from nasal congestion for over a year. Both of his nasal cavities are filled with ulcerative neoplasms covered by massive necrotic tissue, extending to the nasopharynx and oropharynx. The uvula and part of the soft palate were destroyed. Because previous punch biopsy from the nasal cavity showed only lymphatic tissue with inflammation and necrotic tissue, partial turbinectomy of the right middle turbinate as well as nasopharyneal biopsy were performed. Post-operative histopathology confirmed the diagnosis of extranodal NK/T cell lymphoma, nasal type.Diagnosis was reached through punch biopsy (23 cases) or surgery (14 cases). All nasopharyngeal neoplasms were diagnosed by punch biopsy in the clinic, among which two received biopsies twice until a definite pathologic diagnosis could be reached. One patient also received biopsy of his skin lesion. Surgeries were performed in 14 patients with sinonasal lesions. Surgical approaches included: 3 patients who were diagnosed as rhinosinusitis preoperatively underwent endonasal sinus surgery (ESS), 2 patients with sphenoid sinus lesions received endoscopic sphenoidotomy, 4 patients received Caldwell-Luc surgery for maxillary masses, 5 had partial turbinectomy, and one underwent open frontal sinus surgery. 9 patients received multiple surgical procedures until the diagnosis of lymphoma was confirmed (previous biopsies showed inflammatory tissue). Using the Ann Arbor staging method, Stage I disease was found in 49%, Stage II disease 30%, Stage III 5% and Stage IV disease accounted for 16%.Histological types and tumor location are listed in Table 2. Histologically, the most common type of disease in this group was B-NHL (n=16), followed by NKT-NHL (n=14), peripheral T cell lymphoma (n=6) and extraosseous plasmacytoma (n=1). Among 20 patients who underwent EBER detection, 60% were positive. Two patients carried a history of malignant tumors prior to the diagnosis of nasopharyngeal or sinonasal lymphomas: one patient had chronic lymphocytic leukemia and one patient had received surgery and post-operat ive chemotherapy for lung cancer. The CHOP or R-CHOP regimen ( c y c l o p h o s p h a m i d e , d o x o r u b i c i n , o n c o v i n , prednisone, with or without rituximab) was adopted in patients with B-NHL as first-line treatment, and
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal44Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomanon-anthracycline-based chemotherapy for patients with NKT-NHL [5]. 3 patients with intracranial involvement received additional intrathecal injection of Ara-C with dexamethasone. 2 patients didn’t receive any further treatments. Until December of 2023, 21 patients were alive, 12 patients died and 4 were lost to follow-up.Table 1. Number of patients shown in different age groups.Table 2. Patient characteristics.CharacteristicsNumber of patients(% of total)Age(years) Median(range) 49.8(16-75)≥50 16 (43) <50 21 (57) GenderMale 28 (76) Female 9 (24) Presenting symptomsSinonasal symptomsNasal obstruction 28 (76) Rhinorrhea 15 (41) Epistaxis 6 (16) Facial swelling/numbness 4 (11) Headache/dizziness 3 (8) Ocular symptomsDiplopia/ptosis/vision loss 8 (22)
45Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphoma第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Ear symptomsHearing loss 5 (14) Fullness 7 (19) B symptomsFever 8 (22) Fatigue 6 (16) Weight loss 4 (11) Toothache 2 (5) Neck mass 4 (11) Skin lesion 2 (5) Endoscopic findingsUlcerous neoplasm 31 (84) Polypoid mass 6 (16) Bony erosion of nasal septum 3 (8) Site of involvementNasal cavity 10 (27) Maxilary sinus 15 (41) Ethmoid sinus 13 (35) Sphenoid sinus 2 (5) Frontal sinus 2 (5) Nasopharynx 12 (32) Multiple involvement 19 (51) Ann Arbor stageI 18 (49) II 11 (30) III 2 (5) IV 6 (16) Table 3. Histopathologic subtypes and tumor location.Histopathologic subtypeTumor locationNumber of patients(% of total)Nasal cavities and sinusesNasopharynx BothT 4 0 2 6 (16) NK/T 3 6 5 14 (38) B 6 6 4 16 (43) EP 1 0 0 1 (3) Total 14 12 11 37
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal46Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomaFigure 1.Figure 1 A-C showed endoscopic pictures, coronal CT and MRI images from Case No.1 who had left sinonasal diffuse large B cell lymphoma. D-E showed endoscopic pictures of nasal cavity, oropharynx and CT image from Case No.2 who had ENKTL in the nasopharynx, with extension to both nasal cavities and oropharynx. IT: inferior turbinate; S: nasal septum; SP: soft palate; T: tongue; *: tumor.Figure 2.Figure 2 A-D showed biopsies of Case No. 1, A: low power magnification (100×) of hematoxylin and eosin (H&E) stain of DLBCL; B: high power magnification (400×) of H&E stain; C: immunohistochemistry (IHC) showed strong staining for CD20, a B-cell marker; D: IHC showed positivity for pax5, a B-cell marker. E-H showed biopsies of Case No.2, E: H&E slide (200×) of ENKTL; F: H&E slide (400×); G: IHC showed strong staining for CD56, NK-cell marker; H: in situ hybridization showed positivity of EBER.
47Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphoma第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 24. DiscussionSinonasal and nasopharyngeal neoplasms are a rare group of d iseases , account ing for approximately 3% of all head and neck tumors in the United States [1]. Dissimilar from data in Western countries, nasopharyngeal carcinoma is one of the leading malignancies in southern China and its pathogenesis is known to be associated with Epstein-Barr virus (EBV) infection. Malignant carcinomas locating in these regions are mainly squamous cell carcinomas, while ten percent of these neoplasms a re o f lymphopro l i f e ra t ive o r ig ins [6]. N o n -Hodgkin’s lymphoma encompasses a wide range of histopathologies. In our study, we found that the incidence of NKT-NHL was 38%, which is higher than statistics from the United States and Europe, where the predominant subtype of NHL was of B-cell origin [7-9]. The higher incidence of extranodal NK/T-cell lymphoma, nasal type in certain geographic areas, such as Asia, Africa or South America, can be explained by EBV infection and gene susceptibility [3]. By reviewing histopathological slides of EBER in-situ hybridization, we found widespread EBER positivity in NKT-NHL patients, suggesting the close association between EBV infection and lymphoma pathogenesis. EBV infection not only contributes to the formation of squamous cell carcinoma, but also plays a crucial role in the pathogenesis of lymphoproliferative disorders. On the basis of growing knowledge concerning interactions between EBV and human immune system, many new entities for EBV-positive lymphoproliferative disorders have been added to the 2016 World Health Organization (WHO) classification [10]. While EBV is variably involved in the etiology of systematic lymphoma, localized subtypes of NKT-NHL of the nasal type often harbor EBV and in most cases, EBV can be detected by using in-situ hybridization of EBER with paraffin-embedded tissues [11]. Reports also showed a variable incidence of EBV+ B-NHL worldwide with the highest prevalence occurring in East Asia (13–15%) [3]. Further clinical and experimental researches are needed to clarify the pathogenesis of EBV+ LPDs.Early diagnosis is of paramount importance in improving prognosis for sinonal and nasopharyngeal NHL patients. However, due to the non-specific nature of local symptoms including nasal blockage, rhinorrhea, and epis taxis , the les ion remains oblivious for a long period of time. Early symptoms may disguise as benign inflammation or allergic reactions especially for patients with bilateral lesions. More often than not, patients only begin to seek medical intervention until the appearance of ocular or neural symptoms, which indicates local invasion to the post-ocular space or the skull base. Thus, making an early detection is a quite challenging job for otorhinolaryngologists. In particular, the presence of proptosis, visual loss, and facial palsy should be regarded as red flags and warrant further investigation. In our series, 8 patients (5 had nasopharyngeal lymphomas, 1 had lymphoma in the nasal cavitiy and 2 had sphenoidal lymphomas) demonstrated isolated ocular symptoms of diplopia, restrictive movement of eyeballs and visual loss. Lawson [12] reported that sixth nerve involvement was present in 6% of inflammatory cases and in 50% of neoplastic cases of isolated sphenoid sinus disease. When the lesions extended into the intracranial space and involved suprasellar extension, optic nerve compression might occur to cause visual impairment [13]. E n d o s c o p i c f i n d i n g s r e v e a l e d , i n m o s t cases, mass lesions or enlarged inferior turbinate tha t appea red to be u l ce ra t ive , po lypo id o r granulomatous. While ENKTL appeared more often at the midline with or without bone or cartilage invasion and showed bilateral symptoms, B-NHL presented more with unilateral involvement of nasal cavity or paranasal sinuses. In this study, although CT is often used as the preferred and routine examination method for sinonasal masses, MRI has been shown to be superior to CT for lymphoma workup, which often presents as a mass with soft tissue attenuation. Dong [14] reported in a retrospective study of NKT-NHL patients that
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal48Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphomathose who had eyeball or brain involvement showed significantly lower 2-year overall survival rates than those without orbital or skull base invasion. If eyeball or skull base invasion are present on radiological exams, a suspicion for possible malignancies should be raised and complimentary PET-CT scans would be helpful in determining the nature of disease. In terms of taking biopsies, how to harvest sufficient tissue for histopathological examination is a challenging task for rhinologists. In our study, nasopharyngeal biopsies are successfully carried out in 12 patients (two of them received biopsy twice), whereas sinonasal lymphoma patients underwent 1.9 procedures on average until adequate tissue could be obtained to reach histopathological diagnosis. 8 underwent multiple biopsies and 4 received surgery after unsuccessful biopsy attempts. Sinonasal lymphomas are often accompanied by chronic inflammation, and in some cases, especially NKT-NHL patients, appears as an angiocentric lesion with vascular destruction and extensive necrosis. For these reasons, it is of great difficulty to obtain adequate specimens for histologic exams. NKT-NHL used to be known as lethal midline granuloma with an inclination of necrotizing and destructing adjacent bone or cartilage tissue in the mid-facial area. Sakamoto suggested that for NKT-NHL patients, specimens should optimally be harvested from the lateral plate of the nasal cavity and the inferior turbinate [15]. From our experience, superficial punch biopsies may be not adequate for patients who are suspected of having sinonasal malignancies because they often fail to obtain bulky specimens for a definitive diagnosis. A surgical procedure of endoscopic nasal surgery, partial turbinectomy or a Caldwell-Luc operation can approach deeper submucosal lesions and is more suitable for patients with signs of necrotic lesions within the sinonasal area. 5. ConclusionsDespite playing a limited role in sinonasal and nasopharygenal NHL treatment, the otolaryngologist plays a paramount role in the diagnosis. Sinonasal and nasopharyngeal NHL are rare and present with various rhinological, orbital and neurologic symptoms . Whi le the c l in i ca l p resen ta t ions and image findings are mostly nonspecific, it is imperative to keep a broad differential in the workup, especially when dealing with chronic refractory inflammatory lesions. Early biopsy procedure of deep and bulky tissue is essential for reaching a definitive pathohistological diagnosis. Although there are no posttreatment surveillance protocols specific to sinonasal lymphoma, long‐term follow‐up with otolaryngology and oncology teams, and utilizing multimodal measures is recommended to evaluate for response and recurrence [16].References [1] Siegel, R.L., K.D. MillerA. Jemal. Cancer statistics, 2015. CA: a cancer journal for clinicians. 2015; 65(1): 5-29. DOI: 10.3322/caac.21254[2] Benjamin F Bitner, Nyein Nyein Htun, Edward C Kuan,. Sinonasal lymphoma:A primer for otolaryngologists. Laryngoscope Investig Otolaryngol. 2022 Oct 4; 7(6):1712-1724. DOI:10.1002/lio2.941[3] D o j c i n o v , S . D . , F . F e n d L . Q u i n t a n i l l a - M a r t i n e z . E B V- P o s i t i v e Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts. Pathogens. 2018; 7(1). DOI:10.3390/pathogens7010028[4] Sabattini, E., F. Bacci, C. SagramosoS.A. Pileri. WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview. Pathologica. 2010; 102(3): 83-87. PMID:21171509[5] Kim, S.J., S.E. YoonW.S. Kim. Treatment of localized extranodal NK/T cell lymphoma, nasal type: a systematic review. Journal of hematology & oncology. 2018; 11(1): 140. DOI:10.1186/s13045-018-0687-0
49Rhinologic manifestations of sinonasal and nasopharyngeal extranodal Non-Hodgkin’s lymphoma第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2[6] Das, S.C.F. Kirsch. Imaging of lumps and bumps in the nose: a review of sinonasal tumours. Cancer imaging : the official publication of the International Cancer I m a g i n g S o c i e t y. 2 0 0 5 ; 5 : 1 6 7 - 1 7 7 . DOI:10.1102/1470-7330.2005.0111[7] Dubal, P.M., R. Dutta, A. Vazquez, T.D. Patel, S. BaredesJ.A. Eloy. A comparative population-based analysis of sinonasal diffuse large B-cell and extranodal NK/T-cell lymphomas. The Laryngoscope. 2015; 125(5): 1077-1083. DOI:10.1002/lary.25111[8] A b b o n d a n z o , S . L . B . M . We n i g . N o n -Hodgkin's lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic s t u d y o f 1 2 0 c a s e s . C a n c e r . 1 9 9 5 ; 75(6) : 1281-1291. DOI:10.1002/1097-0 1 4 2 ( 1 9 9 5 0 3 1 5 ) 7 5 : 6 < 1 2 8 1 : : a i d -cncr2820750610>3.0.co;2-i[9] Peng, K.A. , A.E. Kita , J .D. Suh, S.M. BhutaM.B. Wang. Sinonasal lymphoma: case series and review of the literature. International forum of allergy & rhinology. 2014; 4(8): 670-674. DOI:10.1002/alr.21337[10] Kim, H.J., Y.H. Ko, J.E. Kim, S.S. Lee, H. Lee, G. Park, J.H. Paik, H.J. Cha, Y.D. Choi, J.H. Han, J. HuhP. Hematopathology Study Group of the Korean Society of. Epstein-Barr Virus-Associated Lymphoproliferative Disorders: Review and Update on 2016 WHO Classification. Journal of pathology and translational medicine. 2017; 51(4): 352-358. DOI:10.4132/jptm.2017.03.15[11] Kreisel, F.H. Hematolymphoid Lesions of the Sinonasal Tract. Head and neck pathology. 2016; 10(1): 109-117. DOI:10.1007/s12105-016-0698-5[12] Lawson, W.A.J. Reino. Isolated sphenoid sinus disease: an analysis of 132 cases. The Laryngoscope. 1997; 107(12 Pt 1): 1590-1595. DOI:10.1097/00005537-199712000-00003[13] Roth , D.B.R.M. Sia tkowski . Bi la tera l blindness as the init ial presentation of lymphoma of the sphenoid sinus. American journal of ophthalmology. 2000; 129(2): 256-258. DOI:10.1016/s0002-9394(99)00308-6[14] Dong, G.H., Y. Li, J.Y. Dong, X. Li, H.F. Wan, L. Yang, J .W. Wang, L.P. Gong, Y.H. Zhao, H. Zhang, Z.F. GaoH.G. Liu. Prognostic significance of locally invaded sites and tissue types in patients with nasal extranodal natural-killer/T-cell lymphoma: a single-center retrospective analysis. Chinese medical journal. 2019; 132(11): 1305-1313. DOI:10.1097/CM9.0000000000000263[15] Sakamoto, M., Y. Miyair iM. Ishizawa. Optimal specimen site for diagnosis of nasal T/NK cell lymphoma and treatment including bone marrow transplantation. ORL; journal for oto-rhino-laryngology and its related specialties. 2003; 65(5): 275-278. DOI:10.1159/000075225[16] Workman AD, Velasquez N, Khan NI, et al. Rates of symptomatology are lower in recurrent sinonasal malignancy than in other recurrent cancers of the head and neck: a multi‐institutional study. Int Forum Allergy Rhinol. 2019;9(6):688‐694. DOI:10.1002/alr.22310
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal50Io Hong CHOU et al.The Prenatal Testing in Conde de São Januário General HospitalAbstractPrenatal testing is offered to the local residents to detect congenital anomaly in the Department of O&G, Conde de São Januário General Hospital (CHCSJ), Macao. It serves as a complementary and increasingly essential tool in providing anticipatory guidance and genetic counseling for disease risk of inherited disorders. In the past decade, varies fetal anomalies were identified through prenatal testing in CHCSJ. It is a retrospective study to investigate the outcomes of prenatal testing in CHCSJ.Keywords: Prenatal Screening; Prenatal Diagnosis; NIPT; Amniocentesis1Department of O&G, Conde de São Januário General Hospital, Health Bureau, Macao, China2Department of Radiology, Conde de São Januário General Hospital, Health Bureau, Macao, China*Corresponding author: Io Hong CHOU, Email: chouih@hotmail.comDOI : 10.30224/MMJ.202507_12(2).0006Io Hong CHOU1*, Si Man LEONG1, Wai Kuan LAM1, Im Heng WONG1, Xiao Yi YANG1, Lan Heng HOI1, Van Ieng TONG1, Xiao Li XU2, Wai Ieng FONG11. IntroductionP r e n a t a l t e s t i n g i s a m u l t i d i s c i p l i n a r y clinical field aimed at detecting fetal diseases or conditions early and accurately during pregnancy. Chromosomal abnormalities occur in approximately 1 in 150 live births [1]. A wide variety of prenatal screening and diagnostic tests are available. It is offered to women during pregnancy to determine if the fetus has a possibi l i ty to be born with a genetic condition or birth defect. It enables treatment prenatally and postnatally. Chromosome abnormali t ies , genet ic disorder, thalassemia, muscular dystrophy, etc, are detected using different tests. The CHCSJ serves as a public hospital, provides free Obstetrical services to the local residents in Macao, including prenatal testing.2. The Prenatal Testing in Conde de São Januário General HospitalThe CHCSJ offered prenatal testing since 1996. It provides prenatal screening and prenatal diagnostic tests. The One-Step Clinic for Assessment of Risk (OSCAR Test) is offered to pregnant women under 35 years old in first trimester. The detection rate of OSCAR test with nuchal translucency (NT) ultrasonography (USG) for trisomy 21, 18 and 13 is about 90% with false positive rate 5% [2, 3]. Non-invasive prenatal test (NIPT) is provided to women equal to or older than 35 years old. NIPT is considered the screening method with the highest accuracy. It screens fetal chromosomes from cell-free fetal DNA in maternal peripheral blood [4]. The detection rate of NIPT is reported to be 99% for Trisomy 21, 96% for Trisomy 18, and 90% for Trisomy 13 and Monosomy X [5, 6]. The Down syndrome (DS) screening test is allowed for women in second trimester. A combination of fetal NT and DS screening test reported a detection rate of trisomy 21 being 85–90% [2, 3]. They all serve as screening tests. Besides, USG is done between 11~13+6 weeks, between 20~24 weeks, around 32 weeks and accordingly.
51The Prenatal Testing in Conde de São Januário General Hospital第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 22.1 Prenatal Screening TestsFrom 2014 to 2023, there were total 25286 screening tests done in the Department of O&G in CHCSJ, DS screening test and OSCAR test being 20400 and NIPT being 5246 respectively (Table 1). Although the birth rate was decreasing over the past 10 years, the total serum screening number remained in a steady level (Figure 1). Table 1. Total Number and Distribution of Prenatal Screening Tests from 2014~20232014 2015 2016 2017 2018 2019 2020 2021 2022 2023 TotalBirths 7360 7055 7146 6529 5925 5979 5545 5032 4344 3712 58627DS screening & OSCAR test 3314 1997 2236 1832 1598 1614 2209 2127 1655 1458 20040NIPT 0 485 694 609 653 534 583 587 500 601 5246Total screening No 3314 2482 2930 2441 2251 2148 2792 2714 2155 2059 25286Figure 1. Figure 1. Distribution of Serum Screening Tests from 2014~20232.2 Prenatal Diagnostic TestsInvasive procedure, such as amniocentesis (AMC), chorionic villi sampling (CVS), cordocentesis are offered to women with positive NIPT, OSCAR test and DS screening test , or with abnormal ultrasonography findings, or previous pregnancy with chromosomal aneuploidy, or known parental carriers or age over 35. There were total 1090 invasive procedures performed from 2014 to 2023 (Table 2). The invasive procedure was in a decreasing trend (Figure 2), which is compatible with the global change [7, 8], owing to the introduction of cell-free DNA-based (cfDNA) screening.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal52The Prenatal Testing in Conde de São Januário General HospitalTable 2. Total Number and Distribution of Prenatal Diagnostic Test from 2014~20232014 2015 2016 2017 2018 2019 2020 2021 2022 2023 TotalBirths 7360 7055 7146 6529 5925 5979 5545 5032 4344 3712 58627Invasive procedure 243 152 84 80 88 95 98 102 81 67 1090Figure 2. Figure 2. Distribution of Prenatal Diagnostic Tests from 2014~2023There were total 26376 cases of prenatal screening and diagnostic tests over the past 10 years. As a result of decreasing birth rate, the total number showed a decreasing trend also (Figure 3).Figure 3. Figure 3. Distribution of Prenatal Diagnosis from 2014~2023
53The Prenatal Testing in Conde de São Januário General Hospital第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 22.3 UltrasonographyUSG is widely used for the prenatal evaluation of fe ta l growth and anatomy. Effect ive fe ta l structure screening maximizes detection of structural anomalies. In CHCSJ, all pregnant women are offered an NT USG or dating USG, a mid-trimester scan, a third-trimester scan as part of routine pregnancy care. The NT is done between 11~13+6 weeks to measure the nuchal translucency thickness, to assess viability and pregnancy location. It is also for accurate dating of the pregnancy, for assessment of chorionicity in multiple pregnancy, for evaluation of the uterine and adnexal anomalies, to screen for aneuploidies, and to identify major structural anomalies.The mid-trimester USG is performed between 18~22 weeks. It is for anatomical evaluation of the fetus. It is an important examination to discover or exclude the fetal malformation. It includes evaluation of the fetal number; chorionicity and amnionicity in cases of multiple pregnancy; cardiac activity; fetal size; basic fetal anatomy; placental appearance and location; amniotic fluid volume and cord structure. The biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL) are measured routinely for the assessment of fetal size. Mid-trimester USG is used to identify anomalies of fetal size [9]. Estimated fetal weight (EFW) or AC is used as a baseline parameter for the detection of subsequent growth problems [10].Routine third-trimester USG has provided est imates of i ts diagnostic accuracy for fetal anomalies, small-for-gestational age (SGA) and large-for-gestational age (LGA), as well as some adverse perinatal outcomes. It is performed between 32~34 weeks and remains an important fe ta l anomalies scan for detecting those abnormalities that will not be detected at the routine second-trimester anatomy scan. It is to confirm fetal lie and presentation, to detect abnormal placenta location or implantation, to identify abnormal amniotic fluid volume and fetal growth. Whenever it is necessary, further USG examination will be provided. If any malformations or any fetal growth abnormalities are found, a detailed level II USG will be scheduled, which is done by senior USG professionals.There were total 73288 USG examination done in the past 10 years in the Department of O&G in CHCSJ, with NT scan being 19348, 2nd and 3rd trimester being 37718 and level II USG being 16222 respectively (Table 3 and Figure 4).Table 3. Total Number and Distribution of USG from 2014~2023.2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 TotalNT scan 1992 2050 2335 1820 1601 1792 2271 2201 1731 1555 193482nd & 3rd trimester USG 4366 4253 5043 4380 4132 3941 3561 3169 2486 2387 37718Level II USG 1992 1755 1847 1694 1720 1540 1673 1541 1217 1243 16222Total screening No 8350 8058 9225 7894 7453 7273 7505 6911 5434 5185 73288
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal54The Prenatal Testing in Conde de São Januário General HospitalFigure 4. Figure 4. Distribution of Obstetric USG from 2014~2023Table 4. Fetal Chromosomal or Genetic Abnormalities Detected From 2014~2023.Chromosomal or Genetic Abnormalities Total NumberDown Syndrome (T21) 58Edwards Syndrome (T18) 25Turner Syndrome (45X0) 24Thalassemia Major (Alfa/Beta) 13Klinefelter's Syndrome 11Patau Syndrome (T13) 10Microdeletion Syndrome 7Triple X Syndrome 5Chromosomal variation 5A thalassemia (-SEA) deletions 4Swyer Syndrome 2Hemophilia Major 2Trisomy 20 1Jacob Syndrome 13. Fetal Abnormalities Detected From 2014~2023Prena ta l sc reen ing and d iagnos t ic t es t s , combined with USG examination serves as major tools in CHCSJ to identify fetal chromosomal or structural abnormalities. In the past 10 years, there were total 173 fetuses with chromosomal or genetic abnormality (Table 4), and 118 fetuses with fetal structure abnormality (Table 5) were detected respectively. Among the 291 fetuses with chromosomal, genetic or structural abnormalities, 46.7% (136/291) were detected by USG and 53.3% were identified directly by prenatal diagnostic tests. The pregnant women with fetal major malformation detected by USG would undergo invasive procedures, such as CVS, AMC or cordocentesis, to confirm or exclude fetal chromosomal or genetic aberration.
55The Prenatal Testing in Conde de São Januário General Hospital第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2DiGeorge Syndrome 1Hereditary factor IX deficiency disease 1Temple Syndrome 1ATR-16 Syndrome 1Chromosome 5q duplication syndrome 1Total 173Table 5. Fetal Structural Abnormality Detected From 2014~2023.Structural Abnormalities Total NumberFetal heart malformation 25Fetal head/ brain malformation 16Fetal multiple malformation 16Fetal cystic hydroma 10Fetal facial malformation 10Fetal hydrops 10Fetal diaphragmatic hernia 4Fetal omphalocele 4Fetal urinary tract malformation 4Fetal lung malformation/mass 3Fetal ascites 2Fetal dextrocardia 2Fetal gastrointestinal tract malformation 2Fetal limb malformation 2Thanatophoric dysplasia 2Fetal abdominal wall malformation 1Fetal chondrodysplasia 1Fetal neck mass 1Fetal retroperitoneum mass 1Fetal spina bifida 1Fetal spinal tumor 1Total 1184. Detection RateThe average detection rate of abnormal fetus was 0.496%. Due to the increased sensitivity and specificity of screening tests, the detection rate was in an increasing trend (Figure 5).
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal56The Prenatal Testing in Conde de São Januário General HospitalFigure 5. Figure 5. Detection Rate of Prenatal Testing from 2014~2023The age of the women with fetal chromosomal, genetic or structural abnormalities ranged from 21~47 years old, with a mean of 32.2 years old. Two hundred and nine cases (71.8%) underwent termination of pregnancy (TOP); 55 cases (18.9%) gave birth and 27 cases (9.3%) lost follow up. 5. Conclusion Congenital malformations remain a leading cause of childhood and infant mortality worldwide[11]. Effective risk assessment through prenatal screening or diagnostic tests is critical in pregnancy. However diagnostic tests offer the most accurate information to guide pregnancy management. The American Col lege o f Obs te t r i c ians and Gyneco log is t s (ACOG) recommends that all patients are offered aneuploidy screening or diagnostic testing [12]. Prenatal diagnosis aims to diagnose any anomaly or genet ic d isease before b i r th . I t he lps the Obstetrician and Neonatologist to counsel the family, discuss the prognosis of the fetus, offer available options, including TOP, in-utero therapy, continue pregnancy, and to initiate a neonatal management plan even before delivery. It also helps in reduction of adverse outcomes in pregnancy thus achieving an optimal perinatal outcome. In the past decade, the Department of O&G in CHCSJ has made a tremendous effort in prenatal testing, contributing to improve the quality of life of the local population. However, challenges persist, and further efforts are needed to enhance diagnostic accuracy, accessibility, and patient support. Continued research and clinical innovation will be essential to address these gaps and improve standards of care in fetal medicine. Yet it is a long way to go and we will keep moving forward. References[1] N uss baum RL , M cInnes RR, Wi l l a rd HF. Principles of cl inical cytogenetics and genome analysis. Thompson & Thompson genetics in medicine. 8th ed. Philadelphia, PA: Elsevier; 2016. p.57–74.[2] Nicolaides KH. The 11–13+6 Weeks Scan. Detection Rate of Prenatal Testing
57The Prenatal Testing in Conde de São Januário General Hospital第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Fetal Medicine Foundation; London, 2004. [3] Spencer K, Liao A, Skentou H, Cicero S, et al. Screening for Triploidy by Fetal nuchal translucency and maternal serum free B-hCG and PAPP-A at 10-14 weeks of gestation. Prenatal Diagnosis. 2000;20(6):495-499[4] Hui L, Bianchi DW. Noninvasive prenatal DNA testing: the vanguard of genomic medicine. Annu Rev Med. 2017;68:459–72.[5] Committee Opinion No. 640: Cell-Free DNA Screening For Fetal Aneuploidy. Obstet Gynecol. 2015, 126(3): e31-e37. doi: 10.1097/AOG.0000000000001051.[6] Society for Maternal-Fetal Medicine (SMFM) Publications Committee. #36: Prenatal aneuploidy screening using cell-free DNA. Am J Obstet Gynecol. 2015, 212(6):711-716. doi: 10.1016/j.ajog.2015.03.043.[7] Lisa Hui, Mary Norton. What is the real “price” of more prenatal screening and fewer diagnostic procedures? Costs and trade‐offs in the genomic era. Prenat Diag. 2018; 38:246-249. doi.org/10.1002/pd.5228[8] Okmen F, Ekici H, Hortu I, et al. Comparison of ind ica t ions and resu l t s of prena ta l invasive diagnostic tests before and after the implementation of the use of cell-free fetal DNA: a tertiary referral center experience. J Assist Reprod Genet. 2020;37:2019–24.[9] Hadlock FP, Harrist RB, Sharman RS, Deter RL, Park SK. Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. Am J Obstet Gynecol 1985; 151: 333–337.[10] McCowan LM, Figueras F, Anderson NH. Evidence-based national guidelines for the management of suspected fetal growth restriction: comparison, consensus, and controversy. Am J Obstet Gynecol 2018; 218(2S): S855–S868.[11] Kochanek K, Kirmeyer S, Martin J, et al. Annual summary of vital statistics: 2009. Pediatrics 2012; 129:338–348.[12] Practice bulletin no. 162: prenatal diagnostic testing for genetic disorders. Obstet Gynecol 2016; 127:e108–e122.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal58Ip Pio SAM et al.Review of Clostridioides difficile infectionAbstractClostridioides difficile is the leading cause of diarrhea in hospitalized patient and is life-threatening in high-risk group such as in elderly. Stool sampling is important for diagnosis by toxin polymerase chain reaction detection. Metronidazole failures were commonly reported recently. It is necessary to review the updated treatment and prevention modalities, in order to get a better control of this disease.Keywords: Clostridioides difficile; Colitis; Toxin A; Toxin B; Oral Vancomycin.1Department of Internal Medicine, Conde de São Januário General Hospital, Macau Health Bureau, Macau SAR, China*Corresponding author: Ip Pio SAM, E-mail: samippio@gmail.comDOI : 10.30224/MMJ.202507_12(2).0007Ip Pio SAM1*, Hou NG2, Tak Ming LI2, Yun Ming FAN2, Ya Kun TIAN21. IntroductionIn hospitalized patients within developed countries, there has been a notable rise in the incidence of Clostridioides difficile (C. difficile) infection. There are around 7-17 cases per ten thousand admissions. Colonization was found in 20-40% admitted patient. It is an anaerobic gram-positive bacillus. The “difficile” is named after its difficulty of growing in laboratory setting. However, its spores are highly resistant to high temperatures, UV light, harsh chemical, and antibiotics. It is reclassified from “Clostridium dif f ic i le” to “Clostridioides difficile” in 2016. The virulence factors are the enterotoxin A and cytotoxin B. The toxins invade the intestinal epithelial cells and lead to diarrhea. Another toxin named binary toxin or C. difficile transferase is seen in 5-30% of cases. Although the mechanism is not clear yet, the ribotype 027 with the deletion of toxin C has high mortality in clinical view. NAP1 restrain is thought to be related to higher toxicity. [1]The initial identification of the associated in fec t ion da tes to 1893 when i t was t e rmed pseudomembranous coli t is . In 1935, Hall and O'Toole observed the presence of bacillus difficile under a microscope, marking a significant milestone. Subsequently, as the use of antibiotics became increasingly prevalent over the next four decades, a surge in cases of antibiotic-associated colitis was observed. In 1978, the toxin was found in infected humans and helped in diagnosis. However, even treated with oral Vancomycin and Metronidazole since then, there were still more cases found with even higher severity and virulence in these 3 decades. [2] We notice an increasing trend of Clostridioides difficile infection in medical institutions in Macao.[3]2. PathophysiologyIn the context of an infection, multiple factors come into play, including host factors, environmental factors, and microorganism factors. Host factors encompass various elements such as advanced age, recent antibiotic usage within the past 12 weeks, gastrointestinal mucosal injury resulting from procedures like nasogastric tube insertion or gastrointestinal surgery, chemotherapy, and the presence of multiple comorbidities. [6] Proton pump inhibitors were equivocal because the spore itself can resist the acidic environment. It may not be a
59Review of Clostridioides difficile infection第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2risk factor. Environmental factors include length of staying in hospital or nursing center, food or pets exposure. C. difficile can be found in water supply especially in river. The spores exist in pets, vegetable skins and artificial foods. The environment may induce virulence of C. difficile. Trehalose, for example, can make the food more appealing. It can make fried chicken look juicier. Trehalose increases the C. difficile virulence probably because only highly toxic strains can metabolize trehalose. So, the modern diet may actually enhance the selection of the more virulent strains. [4]From a physiological perspective, there is a classification of bacterial flora into two categories: beneficial or "good" bacteria and potentially harmful or "bad" bacter ia . Bif idobacteia , Escherichia coli and Lactobacilli are with some degree of function, such as vitamin formation. On the other hand, Campylobacter, Enterococcus faecalis and Clostridioides di f f ic i le are more virulent and causes colitis, intra-abdominal abscess, or even other metabolic diseases if overgrowth. [5] For Clostridioides difficile, endotoxin A and B are the main culprits of clinical manifestation. Certain strains exhibit the production of exclusively toxin B, yet possess comparable virulence to those strains that produce both toxins. These toxins disrupt the actin cytoskeleton of enterocytes construction and signal transduction, thus leading to the disruption of tight junctions of colonic epithelial cells, and upregulation the proinflammatory mediators. Severe dysregulation may lead to fulminant coli t is , cardiotoxici ty, abdominal compartment syndrome, respiratory failure, and multiple organs failure. [7]3. ManifestationsWithin the context of colon dysbiosis, there is an observed elevation in the levels of sialic acid and succinate, which in turn facilitate the growth of C. difficile. Watery stool usually started at the second or third day followed, and abdominal cramping may present. In combination with abdomen guarding or ileus, C. difficile-associated colitis should be considered, even without diarrhea. So, the clinical manifestation is diverse, ranging from mild diarrhea to severe fulminant colitis. Stool samples obtained from infected patients may exhibit a distinct odor, and trained nurses have demonstrated an 84% sensitivity and 77% specificity in utilizing their olfactory sensation to detect C. difficile infection based on this odor. [6]4. Diagnostic testsStools sampling should be from type 6 or 7 stool according to Bristol Stool Chart, which is muddy like. Enzyme immunoassay for toxin are old methods with lower sensitivity compared to nucleic acid amplification assay tests of toxin B. Toxigenic culture is accurate but too slow and cumbersome with the isolation of pathogeny. Infectious Diseases Society of America (IDSA) suggested nucleic acid amplification assay tests (PCR) of stool samples can be used for diagnosis, with good sensitivity and specificity (Table 1). However, it cannot differentiate infection from colonization and may persist after treatment. Colonoscopy may be considered if the patient is constipated or ileus, but risk of bowel perforation needs to be balanced. [8]
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal60Review of Clostridioides difficile infectionTable 1. Microbiological diagnostic tests for C. difficile and their accuracy. Test Sensitivity (%) Specificity (%) RemarksEnzyme Immunoassay toxin test 66-85% 95% Detects both toxin A and B, lack of sensitivityGlutamate dehydrogenase assay 86-99% 98-100% Sometimes used as initial step of a 2-step algorithmToxigenic culture 90-100% 98-100% Labor intensive, and needs anaerobic culture and samplingNucleic acid amplification tests of toxin gene95% ~100% Good sensitivity and specificity but may remain positive even after treatment. There are several different ways for scoring severity. The Hospital-specific guidelines were the oldest but with low sensitivity. So, more physicians use IDSA guidelines, by which WBC> 15 thousand per microliter or creatinine over 1.5 times baseline indicating severe cases. [9] Zar’s criteria also indictes severity by pseudomembranous colitis on colonoscopy, or any two presentations of: age > 60 years old, hypoalbuminemia < 2.5mg/dl, leukocytosis >15*109/L and fever over 38.3C. 5. TreatmentThe init ial and crucial step in addressing dysbiosis and C. difficile infection in the colon is the discontinuation of unnecessary antibiotics. This action allows for the spontaneous recovery of the fecal microbiota. Antibiotic usage is determined by severity. In the initial episode with severe type, either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day. This dosage of oral vancomycin has low systemic absorption and does not require serum level monitoring, except for those concomitantly using intravenous vancomycin or larger dose of vancomycin. [17]Since metronidazole was less expensive and it is not regarded as a “big gun”, it is the first choice for mild cases. However, Fred A Zar et al conducted a randomized controlled trial comparing vancomycin and metronidazole for severe infection of C. difficile. It showed better cure rate (97%vs 76%) in vancomycin group for severe C. difficile infection. In mild infection, the use of vancomycin is equivocal. [17] In other words, when facing patients with sepsis, high leukocytes or acute kidney injury, oral vancomycin should be considered.By applying Zar 's cri teria, cl inicians can identify high-risk patients who may benefit from more aggressive treatment strategies, such as prolonged tapering antibiotic therapy. After the regular treatment, we may taper the frequency of administrating Vancomycin. By tapered regimen of vancomycin, the normal flora could be able to regenerate to prevent the next C. di f f ic i le infection. In patients who cannot tolerate oral feeding, Vancomycin could be given through rectum, especially for those with colitis. Rifaximin 400mg twice daily can be used to substitute the vancomycin tapering phase. In case of Vancomycin allergy, teicoplanin can be used especially for the severe ones, although there is no benefit for the teicoplanin over Vancomycin. [13] Another option is Fidaxomicin, which is an antibiotic with narrow spectrum, targeting Gram positive organisms and gastrointestinal normal flora is not affected. It may be the reasons of less recurrence when using Fidaxomicin. [12] However, even af ter t reatment , there are 20-35% of recurrent rate. [10] The recurrence is
61Review of Clostridioides difficile infection第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2thought to be related to elderly (>65 years old), immunosuppression, antibiotic usage at the time of C. difficile infection (CDI) diagnosis, or high virulence strain. We can repeat once previous treatment in the first recurrence episode, with around 50% patients cured. For subsequent recurrent infections, cure is difficult due to the spores. [11] 6. Adjunctive treatmentApart f rom ant ibiot ics , some researchers are studying about monoclonal antibody, acting as passive immunity targeting the toxins, to treat recurrent Clostridioides difficile, but the tolerability and efficacy are still under study. So, the role is still uncertain. Another possible treatment is probiotic. Despite the existence of various types of probiotics commonly employed in clinical practice, clinical trials have not demonstrated any beneficial effects for either treatment or prevention purposes. [14]7. Fecal microbial transplantation Fecal microbiota transfer (FMT) is developed within this decade, for treating patients suffering from recurrent C. difficile infection and refractory to antibiotic treatment. In 1958, doctors in Denver used feces by enema to treat pseudomembranous enterocolitis. FDA already approved fecal microbial transplantation for Clostridioides difficile infection. In 2017, the first Asian fecal bank established in Hong Kong. The successful rate was over 80% and no report of iatrogenic infection. Bacteroidetes and Firmicutes are the main roles in inhibiting pathogenic vegetative growth.[16] The major concerns include way of administration and risk of iatrogenic infection in immunocompromised patients. So, some protocols suggest a retrograde way, by colonoscope infusion ather then by nasoduodenal tube. And this may be performed in multiple times minimal injection to avoid volume-related perforation in case of severe colitis. In Hong Kong SAR of China, a total of 55 patients received FMT for C. difficile infection, showed a significantly higher cumulative survival probability during the follow-up period compared with the control group, without significant difference in new-onset medical side effect between both groups, indicating the safety and effectiveness of FMT. [15] 8. PreventionNovel vaccination may emerge. A Phase 2b C. difficile vaccine trial remains in clinical development, though a previous phase 3 trial terminate due to inefficacy.[20] Given its fecal-oral transmission route, proper hand hygiene practices play a crucial role in preventing the spread of C. difficile. Besides wearing gloves, it is essential to thoroughly wash hands with soap and water to effectively reduce the transmission of C. difficile spores. Besides, the affected patient should be isolated in single room, if possible, especially those with stool incontinence. Contact precautions should last for over 48 hours after diarrhea stops. In area with high C. difficile infection rate, contact precautions may need to be prolonged until discharge. Other strategies include isolation measures, environmental disinfection and antibiotic stewardship.[18] C. difficile spores are highly resistant to alcohol, so the incidence of CDI did not change after alcohol-based hand hygiene. However, handwashing with soap and water has been shown to effectively eliminate 88% C. difficile from hands. Some sporicidal wipes can help in decreasing the transmission eff iciency after the hospital environment surface disinfection.[19]9. SummaryOngoing research and guideline development aim to enhance the management of C. difficile infection; nevertheless, clinically, we continue to encounter cases of this infection. Some of them got high mortality. The toxin B PCR test increase the sensitivity of diagnosis, but clinicians should make a good use of it rather than over-diagnosis. Alert should be raised in case of ileus without stool sample for toxin test. The IDSA guideline suggested
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal62Review of Clostridioides difficile infectiontreatment should be given according to the severity. There is still no clear evidence for the adjuvant therapy including vaccination and the monoclonal antibody to toxin. Further trial may focus on the refractory cases and immunosuppressed patients. Among them, fecal microbial transplantation is more promising and provides benefits. So far, most of the cases are treated with metronidazole or vancomycin, which have already been used for over half century. C. difficile would still be often seen in daily practice under high consumption of antibiotic in the near future. Fecal microbiota transplantation is promising, even for recurrent cases. In prevention of view, C. difficile is resistant to alcohol and sporicidal agents have a role in decreasing the transmission.References[1] K Jin, SX Wang, Zuhu Huang, Shan Lu, et al. Clostridium difficile infections in China. J Biomed Res. 2010 Nov; 24(6): 411–416. doi: 10.1016/S1674-8301(10)60055-3[2] Loo VG, Bourgault AM, Poirier L, Lamothe F, Michaud S, Turgeon N, et al. Host and Pathogen Factors for Clostridium difficile In fec t ion and Coloniza t ion . N Engl J Med 2011; 365:1693-1703. doi: 10.1056/NEJMoa1012413.[3] JW Zhang , XY Zhu , HH Yu. C l in ica l characteristics of Clostridioides difficile-associated diarrhea: analysis of 39 adult inpatients. Macao Medical Journal, Volume 11, number 1, p 25-31.[4] Collins J, Robinson C, Danhof H, Knetsch CW, van Leeuwen HC, Lawley TD, et al. Dietary trehalose enhances virulence of epidemic Clostridium difficile. Nature. 2018 Jan 18;553(7688):291-294. DOI: 10.1111/j.1469-0691.2012.03853. x[5] Zhang YJ, Li S, Gan RY, Zhou T, Xu DP, Li HB.. Impacts of Gut Bacteria on Human Health and Diseases. Int J Mol Sci. 2015 Apr; 16(4) : 7493–7519. doi : 10.3390/ijms16047493.[6] Wang T, Matukas L, Streutker CJ.. Histologic Findings and Clinical Characteristics in Acutely Symptomatic Ulcerative Colitis Patients With Superimposed Clostridium diffi cile Infection . American Journal of Clinical Pathology, Volume 140, Issue 6, December 2013, Pages 831–837. https://doi.org/10.1309/AJCP2LBRTTJBF3KD[7] Koenigsknecht MJ, Theriot CM, Bergin IL, Schumacher CA, Schloss PD, Young VB. . Dynamics and e s t ab l i shmen t o f Clostridium difficile infection in the murine gastrointestinal tract. Infect. Immune. 2015; 83: 934-941. DOI: 10.1128/IAI.02768-14.[8] G u e r y B , G a l p e r i n e T , B a r b u t F . Clostr idioides diff ic i le : diagnosis and t r e a t m e n t s B M J 2 0 1 9 ; 3 6 6 : l 4 6 0 9 . doi:10.1136/bmj.l4609.[9] Mart ínez-Meléndez A, Camacho-Ort iz A, Morf in-Otero R, Maldonado-Garza HJ, Villarreal-Treviño L, Garza-González E. Comparison of 3 Severity Criteria for Clostridium difficile Infection. Infect Control Hosp Epidemiol. 2014 Feb; 35(2): 196–199. doi: 10.1086/674851.[10] Roy J Hopkins and Rober t B Wi lson . Treatment of recurrent Clostridium difficile colitis: a narrative review Gastroenterol Rep (Oxf). 2018 Feb; 6(1): 21–28. DOI: 10.1093/gastro/gox041.[11] Leff le r DA, Lamont JT. Trea tment o f Clostridium difficile-associated disease. Gastroenterology 2009; 136: 1899-912. DOI: 10.1053/j.gastro.2008.12.070[12] Louie TJ , Cannon K, Byrne B, Emery J, Ward L, Eyben M, et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis2012;55(Suppl 2):S132-42. DOI:
63Review of Clostridioides difficile infection第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 210.1093/cid/cis338.[13] Bishop EJ , Tiruvoipat i R, Metcal fe J , Marsha l l C , Botha J , Ke l ley PG. The outcome of patients with severe and severe-complicated Clostridium difficile infection treated with tigecycline combination therapy: a retrospective observational study. Intern Med J2018;48 :651-60 . DOI: 10 .1111/imj.13742.[14] Hempel S, Newberry SJ, Maher AR, Wang Z, Miles JN, Shanman R, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA 2012; 307: 1959-69. DOI: 10.1001/jama.2012.3507.[15] Yau YK, Lau LHS, Lui RNS, Wong SH, Guo CL, Mak JWY, Ching JYL, Ip M, Kamm MA, Rubin DT, Chan PKS, Chan FKL, Ng SC. Long-Term Safety Outcomes of Fecal Microbiota Transplantation: Real-World Data Over 8 Years From the Hong Kong FMT Registry. Clin Gastroenterol Hepatol. 2024 Mar;22(3):611-620.e12. DOI: 10.1016/j.cgh.2023.09.001.[16] Weingarden AR, Dosa PI, DeWinter E, Steer CJ, Shaughnessy MK, Johnson JR, et al. Changes in colonic bile acid composition following fecal microbiota transplantation a re su ff i c i en t t o con t ro l C los t r id ium difficile germination and growth. PLoS One2016;11:e0147210. DOI: 10.1371/journal.pone.0147210.[17] Nelson RL, Kelsey P, Leeman H, Meardon N , Pa t e l H , Pau l K , e t a l . An t ib io t i c t r e a t m e n t f o r C l o s t r i d i u m d i f f i c i l e - associated diarrhea in adults. Cochrane Database Syst Rev2017;3:CD00461 0. doi: 10.1002/14651858.CD004610.pub5[18] Waqar S, Nigh K, Sisler L, Fanning M, Tancin S, Brozik E, et al. Multidisciplinary performance improvement team for reducing health care-associated Clostridium difficile infection. Am J Infect Control 2016; 44:352–4. DOI: 10.1016/j.ajic.2015.09.022.[19] Lawley TD, Clare S, Deakin LJ, Goulding D, Yen JL, Raisen C, et al. Use of Purified Clostridium difficile Spores To Facilitate Evaluation of Health Care Disinfection Regimens. Appl ied and environmental microbiology, Oct. 2010, p. 6895–6900. DOI: 10.1128/AEM.00718-10.[20] E m m a J a n e B i s h o p , R a v i n d r a n a t h Tiruvoipati, Management of Clostridioides difficile infection in adults and challenges in clinical practice: review and comparison of cur rent IDSA/SHEA, ESCMID and ASID guidelines, Journal of Antimicrobial Chemotherapy, Volume 78, Issue 1, January 2023, Pages 21–30, DOI: 10.1093/jac/dkac404.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal64In Ha CHAN et al.AbstractImmune checkpoint inhibitors (ICI) have been widely implemented as a treatment modality for multiple malignancies. Nevertheless, their utilization has been concurrently met with significant adverse effects. In particular, the administration of ICI has been documented to engender hemolytic anemia, although such an occurrence has been encountered less than one percent. The following presents a case report of autoimmune hemolytic anemia (AIHA) that arose consequent to the administration of pembrolizumab. There is a 50-year-old woman with right breast triple negative invasive ductal carcinoma, ensuing her diagnosis six months prior. The patient was hospitalized seven cycles after she received preoperative pembrolizumab. She had been presented to the hospital owing to an episode of severe hemolytic anemia, manifested by a hemoglobin count of 4.0 g/dL. Following extensive examinations, the patient was diagnosed with AIHA that developed consequent to her treatment with pembrolizumab. The patient made a stable recovery after receiving a week of prednisone. The prednisone treatment facilitated a stabilization of hemoglobin levels, and led to an improvement in the hemolytic manifestations, resulting in a reduced requirement to undergo blood transfusion. Albeit a rare side effect, hemolytic anemia may potentially endanger lives; hence, an early identification and prompt commencement of treatment may prove life-saving.Oncological Department, Conde de São Januário General Hospital (CHCSJ) Macau*Corresponding author: In Ha CHAN, E-mail: cihwke@gmail.comDOI : 10.30224/MMJ.202507_12(2).0008Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancerIn Ha CHAN*, Yi LIN 1. IntroductionPembrol izumab, an inh ib i tor o f immune checkpoint protein (ICI), exerts remarkable antitumor activity by targeting PD-1 or PD-L1. A recent clinical study proved that addition of pembrolizumab to neoadjuvant chemotherapy would significantly upscale the proportion of patients afflicted with early triple-negative breast cancer who achieved a pathological complete response [1]. However, several severe adverse events potentially impacting the endocrine system or eliciting an autoimmune disorder instigated by PD-1 inhibitors, encompassing pembrolizumab, have been observed [2]. In this article, we unveil an unparalleled case of breast cancer in a patient who underwent autoimmune hemolytic anemia (AIHA) induced by pembrolizumab.2. CaseA 50-year-old female was diagnosed with triple negative right breast cancer (cT2N0, stage II). Initially, her ECOG performance status was 0, and her laboratory examinations, including CBC, hepatic, and renal function tests, showed normal values (Table1). She underwent two cycles of Paclitaxel + Carboplatin treatment, following which pembrolizumab 200 mg was added for cycles 3 and 4. She was then switched to Doxorubicin + CTX + Pembrolizumab, with four cycles planned, but only three were administered. This was due to septic
65Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancer第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2shock, bacteremia, covid-19 positivity, pneumonia (which could not exclude immunotherapy-induced pneumonitis) after the first 7 cycles of neoadjuvant chemotherapy plus immunotherapy. The patient had mild hyperbilirubinemia and anemia, but LDH levels were still within normal range. After infection control and blood transfusions, the patient's Hb and bilirubin levels were within normal range at the time of discharge.One month after receiving the last dose of pembrolizumab, the patient presented with severe anemia (Hb 4.0g/dL) and increased levels of total bilirubin (51 umol/L),non conjugated bilirubin (41.3umol/L), reticulocytes (31.72 %), and LDH (1549 U/L) (Table1), indicating hemolysis. Her liver function tests showed normal values. Iron and vitamin deficiencies, folate deficiency, and hypothyroidism were ruled out. Further examination revealed that the haptoglobin levels were less than 8 mg/dL, but there was a negative direct and Table 1. Results of laboratory investigations corresponding to hemolytic anemia.lab test pre-pembrolizumab10 days post 5th pembrolizumab(septic shock)50 days post 5th pembrolizumabHemoglobin (g/dL) 12.6 6.9 4.0Reticulocytes (%) N/A N/A 31.72Tbil (umol/L) 5 (<15) 27 51Non conjugated bilirubin( umol/L ) N/A 4.5 ( <10) 41.3LDH (U/L) N/A 189 (135 - 214) 1549 (135 - 214)Iron (umol/L) N/A N/A 10.3 (6.6 - 26.0)Vitamin B12 ( pg/mL ) N/A N/A 609.0 (197.0 - 771.0)Folate (ng/mL) N/A N/A 8.0 (3.9 - 26.8)Haptoglobin (mg/dL) N/A N/A <8 (35.0 - 250.0)Direct antiglobulin test N/A N/A NegativeIgA (g/L) N/A N/A 1.77 (0.65 - 4.21)IgG (g/L) N/A N/A 11.79(5.52 - 16.31)indirect Coombs test, and Hemosiderin in Urine was Positive. Peripheral blood smear revealed the presence of anisopoikilocytosis. Bone marrow examination revealed erythroid hyperplasia with mild hypercellularity for age. Therefore, the patient was diagnosed with AIHA and was admitted. The patient received four blood transfusions, totaling 7 units, before starting prednisolone treatment. One unit of blood transfusion was provided in the first two days after starting prednisolone treatment. The administration of prednisone (60 mg/day) and intravenous IVIG improved the patient's hemoglobin levels gradually, and the patient was discharged after 8 days of prednisone initiation (Fig. 1). After discharge, the patient no longer required blood transfusions, and laboratory tests associated with hemolysis, including LDH, bilirubin, reticulocyte count, and haptoglobin, showed values that were almost normal.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal66Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancerIgM (g/L) N/A N/A 0.91 (0.33 - 2.93)C3 (g/L) N/A N/A 1.57 (0.83 - 1.93)C4 (g/L) N/A N/A 0.300 (0.150-0.570)ANA-Screen (IF) N/A N/A NegativeANCA (IF) N/A N/A NegativeFigure 1. Figure 1. Time course of hemoglobin, non conjugated bilirubin, serum lactate dehydrogenase (LDH), reticulocyte, and treatment.
67Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancer第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 23. DiscussionThe primary etiology of hemolytic anemia is idiopathic, while factors correlated with secondary AIHA include neoplasia, infection, autoimmune diseases, and medication use [3]. Prior investigations have established that the prevalence of immune-mediated hemolytic anemia is approximately 0.6% in patients receiving ICIs [4]. Moreover, numerous case reports recently illustrate ICI-induced AIHA [5-6]. Generally, a positive direct antiglobulin test (DAT) is an important AIHA feature, but some data also revealed not all patients had patient positive DAT, Laboratory factors leading to underdiagnosis include the fact that 5% to 10% of patients with clear clinical evidence of AIHA have a negative DAT [7]. There appears to be a relatively high prevalence of DAT-negative AIHA in patients diagnosed with ir-AIHA compared with non ICI-associated ir-AIHA, reported as high as 27% to 38% in one aggregate cohort review of 31 cases [8]. Mechanisms for this occurrence remain unidentified, but antibody-independent pathways of RBC destruction, such as ICI-generated proinflammatory states that lead to direct macrophage-mediated phagocytosis of RBCs, have been proposed as reasons, similar to hemophagocytic lymphohistiocytosis [9]. Therefore, we conclude that the patient’s AIHA was induced by pembrolizumab, rather than secondary causes such as an earlier infection, antibiotic use, pre-existing malignant cancer, or concomitant chemotherapy.Genera l r ecommenda t ions fo r manag ing AIHA involve steroids and consideration of plasma exchange, and guidelines on the management of ICI-related AIHA are comparable. The European Society of Medical Oncology recommends that high-dose corticosteroids and/or immuno-suppressive drugs be considered, in consultation with a hematologist, as for grade 3 hemolytic anemia, and that ICPi treatment should be permanently discontinued, with prednisone administered orally or intravenously (1-2 mg/kg/day according to symptoms/development speed) [10]. ICI therapy-associated AIHA is rare, but most cases can be life-threatening. The number of reported cases has recently escalated with the increase in ICIs. Early diagnosis is crucial, and we hope this case report reinforces the notion that patients with ICI-related AIHA receive appropriate management, including high-dose steroids and plasma exchange. In our case, the patient responded well to treatment with steroids. She received her radical mastectomy with ypT1aN0 in pathology results, and achieved downstaging through neoadjuvant chemotherapy. In summary, this report highlights an unusual case of the development of AIHA as an adverse effect of pembrolizumab. In AIHA that presented with negative standard DAT and severe drop in Hb that non immune hemolytic anemia is excluded and clinical and paraclinical findings confirm the presence of hemolysis, pay special attention to immune mediated hemolysis and do not be misled by a negative coombs test. Additionally, the report underscores the indispensability for healthcare practitioners to be cognizant of plausible immune-related adverse effects of checkpoint inhibitors and the need for prompt and efficient management. Further research involving immune cell profiling in patients manifesting hematological IRAEs can yield a better comprehension of the mechanism and facilitate apt management.Reference[1] Peter Schmid,, Javier Cortes, Lajos Pusztai, et al . Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 2020; 382:810-821.DOI: 10.1056/NEJMoa1910549[2] Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F,Postel-Vinay S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139–48. DOI: 10.1016/j.ejca.2015.11.016[3] P e t z L D , G a r r a t t y G . 2 0 0 4 . I m m u n e hemolytic Anemias, 2nd edn.Churchil l
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal68Immunotherapy-related autoimmune hemolytic anemia in a patient with breast cancerLivingstone, Philadelphia. DOI:10.1016/j.tmrv.2004.09.002[4] Michot JM, Lazarovici J, Tieu A, et al.. Haematological immune-related adverse events with immune checkpoint inhibitors, how to manage? Eur J Cancer. 2019; 122:72-90. DOI: 10.1016/j.ejca.2019.07.014[5] Delanoy N, Michot J-M, Comont T, et al.. Haematological immune-related adverse events induced by anti-PD-1 or anti-PD-L1 immunotherapy: a descriptive observational study. Lancet Haematol. 2019;6(1):e48-e57. DOI: 10.1016/S2352-3026(18)30175-3[6] Wilson NR, Lockhart JR, Garcia-Predoma H A . O o T H , R o j a s - H e r n a n d e z C M . Management and outcomes of hematological immune-related adverse events: systematic review and meta-analysis. J Immunother. 2 0 2 2 ; 4 5 ( 1 ) : 1 3 - 2 4 . D O I : 1 0 . 1 0 9 7 /CJI.0000000000000390[7] Karafin MS, Denomme GA, Schanen M, et al. Clinical and reference lab characteristics o f p a t i e n t s w i t h s u s p e c t e d d i r e c t antiglobulin test (DAT)-negative immune hemolytic anemia. Immunohematology 2 0 1 5 ; 3 1 ( 3 ) : 1 0 8 – 1 5 . D O I : 1 0 . 2 1 3 0 7 /immunohematology-2019-077[8] Leaf RK, Ferrer i C, Rangachar i D, e t a l . Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors. Am J Hematol 2019;94(5):563–74. DOI: 10.1002/ajh.25448[9] Steven R. Hwang, , Antoine N. Saliba, Alexandra P. Wolanskyj-Spinner, et al . Immunotherapy-associated Autoimmune Hemolytic Anemia. Hematol Oncol Clin N Am 36 (2022) 365–380. DOI: 10.1016/j.hoc.2021.11.002[10] Haanen JB, Carbonnel F, Robert C, Kerr KM, Peters S, Larkin J,et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, t r e a t m e n t a n d f o l l o w - u p . A n n O n c o l 2017;28(Suppl 4):IV119–42. DOI: 10.1093/annonc/mdx225
Chon Man IEONG et al.69第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Unveiling the mystery: A toddler’s recurrent intussusception caused by a hidden cecal duplication cystAbstractIntussusception is a common cause of intestinal obstruction in children, with duplication cysts being a rare lead point. We report a case of a 1-year-and-5-month-old female with recurrent intussusception caused by a cecal duplication cyst. The patient presented with vomiting and excessive crying, and ultrasound revealed an intussusception. An attempted air enema reduction was unsuccessful. Diagnostic laparoscopy found a luminal mass at the ileocecal junction, and a submucosal lesion was discovered upon opening the cecum wall. The lesion was completely excised, and pathology confirmed it as a submucosal duplication cyst. Postoperatively, the patient recovered well and was discharged with follow-up. This case highlights the importance of considering rare etiologies, such as duplication cysts, in the differential diagnosis of intussusception in children. Prompt recognition and surgical intervention are crucial to prevent complications and ensure a favorable outcome.Keywords: Intestinal Duplication; Intussusception; Cecum; Infant 1Department of Radiology, Conde de São Januário General Hospital, Macao SAR, China2Department of General Surgery, Conde de São Januário General Hospital, Macao SAR, China*Corresponding author: Soi Chau KONG, E-mail: 14714943407@163.comDOI : 10.30224/MMJ.202507_12(2).0009Chon Man IEONG1, Man Pan TAM1, Wai Lon NG2, Chi Ian KUOK2, Soi Chau KONG1*1. IntroductionIntussusception is a common cause of intestinal obstruction in the pediatric population, accounting for approximately 1-4 cases per 1000 live births [1]. In children, intussusception is usually idiopathic, but a pathologic lead point is found in about 2-12% of cases [2]. Among the pathologic lead points, intestinal duplication cyst is a rare etiology.Enteric duplication cysts can occur anywhere along the gastrointestinal tract, with the ileum being the most frequent location. Cecal duplication cysts are especially rare, representing only 0.4% of all enteric duplications [3]. To date, very few cases of cecal duplication cysts causing intussusception in children have been reported in the literature.Here, we present a case of a 1-year-and-5-month-old female with a history of intussusception who was found to have a cecal duplication cyst as the pathological lead point causing recurrent intussusception.2. Case PresentationA 1-year-and-5-month-old female presented with vomiting, excessive crying, and a history of intussusception reduction 9 months prior.The patient was born at 38 weeks gestation via cesarean section due to fetal distress, with a birth weight of 2.37kg. At 7 months old, she had an episode of intussusception that failed enema
Unveiling the mystery: A toddler’s recurrent intussusception caused by a hidden cecal duplication cyst澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal70reduction and required diagnostic laparoscopy.On the current admission, physical examination was unremarkable. Ultrasonographic f indings demons t r a t e i l eoceca l wa l l t h i cken ing wi th intussusception of ileum into ascending colon, measur ing 5 .2 x 4 .0 x 3 .1cm, an in t ramura l cystic lesion visualized within the bowel wall. suggestive of enteric duplication cyst complicated by intussusception. (Figure 3). Attempted air enema reduction was unsuccessful( Figure 3).Diagnostic laparoscopy showed cecal, ileal, and appendiceal swelling, with a 3-4 cm hard mass at the ileocecal junction. Upon opening the cecum, a submucosal lesion was found, and 5 ml of clear fluid was aspirated (Figure 4). The cyst was excised, and an incidental appendectomy was performed.Pathology revealed a 3.5 x 3 x 1 cm submucosal duplication cyst lined by columnar epithelium with focal mucinous metaplasia, with a wall of smooth muscle layers.Post-operatively, the patient was managed with nasogastric decompression, empirical antibiotics, and gradual feeding. She developed low-grade fever on post-operative days 1-2 but remained clinically stable and was discharged with outpatient follow-up.3. DiscussionThis case report underscores the crucial role of considering rare etiologies, such as duplication cysts, in the differential diagnosis of intussusception in children. Duplication cysts can occur anywhere along the gastrointestinal tract, with an incidence of 1 in 4,500 to 10,000 live births [4]. Cecal duplication cysts, as seen in our patient, are exceptionally rare. Failure to consider rare causes like duplication cysts may lead to delayed diagnosis, recurrent intussusception, and potential complications such as bowel ischemia or perforation.The clinical presentation of intussusception caused by a duplication cyst can be challenging to differentiate from other etiologies [6]. Although ultrasound is the primary imaging modality for diagnosing intussusception, typically demonstrating a "target" or "pseudokidney" sign [7], these classic findings may be absent when a duplication cyst serves as the lead point. In such cases, the ultrasound may reveal an atypical multi-layered mass-like lesion, raising suspicion for a pathologic lead point. Identifying the specific etiology often requires additional imaging, such as contrast enema or computed tomography [8]. In this case, the initial ultrasound showed an unusual multi-layered lesion instead of the characteristic intussusception signs, prompting further investigation. The duplication cyst was later confirmed as the pathologic lead point during surgery, explaining the absence of the typical "target" or "pseudokidney" sign on the ultrasound images.Timely identification of the underlying etiology is crucial for appropriate management and prevention of complications. A high index of suspicion for pathologic lead points is warranted in cases of recurrent intussusception or those that fail to respond to conservative management. The treatment of choice for symptomatic enteric duplication cysts is complete surgical excision [9]. In the setting of intussusception, resection of the affected bowel segment may also be necessary [10].In this case, several features raised suspicion for a cecal duplication cyst as the pathologic lead point. First, the patient presented with recurrent intussusception, which is more commonly associated with a pathologic etiology compared to idiopathic intussusception. Second, the presence of a palpable mass at the ileocecal junction during laparoscopy strongly suggested an anatomic abnormality in that region. Third, the initial ultrasound demonstrated a multi-layered, mass-like lesion in the right lower quadrant, which, although not specific, is consistent with the appearance of an enteric duplication cyst. Finally, the failure of conservative management with air enema reduction pointed towards the likelihood of a persistent lead point necessitating surgical intervention. The combination of these clinical, imaging, and surgical findings ultimately led to the diagnosis of a cecal duplication cyst as the underlying cause of the patient's recurrent intussusception.
Unveiling the mystery: A toddler’s recurrent intussusception caused by a hidden cecal duplication cyst71第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Figure 1. Figure 1. Ultrasonographic findings demonstrate ileocecal wall thickening with intussusception of ileum into ascending colon. The imaging features are consistent with ileocolic intussusception.Figure 3. Figure 3. Fluoroscopic image during an at-tempted air enema re-duction of the intus-susception. The image demonstrates the ina-bility to successfully reduce the intussus-ception, as evidenced by the persistent filling defect within the con-trast-filled bowel lu-men. Figure 2. Figure 2. Ultrasonographic examination demonstrates mural thickening of the terminal ileum with an intramural cystic lesion visualized within the bowel wall. The sonographic features are suggestive of enteric duplication cyst complicated by intussusception.Figure 4. Figure 4. Intraoperative image of the cecal region revealing a submucosal lesion, likely representing a duplication cyst. The lesion appears to be well-circumscribed and located within the submucosal layer of the cecal wall. Fine needle aspiration of the lesion yielded approximately 5 mL of clear fluid, suggesting a cystic nature.
Unveiling the mystery: A toddler’s recurrent intussusception caused by a hidden cecal duplication cyst澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal724. ConclusionT h i s c a s e h i g h l i g h t s t h e i m p o r t a n c e o f considering duplication cysts as a rare cause of intussusception in the pediatric population. Prompt diagnosis and surgical intervention are crucial in preventing complications such as bowel ischemia and necrosis. Close follow-up and monitoring for recurrence are essential in the management of these patients.Reference[1] J iang J , J iang B, Parashar U, Nguyen T, B i n e s J , P a t e l M M . C h i l d h o o d intussusception: a literature review[J]. PLoS One, 2013, 8(7):e68482. doi: 10.1371/journal.pone.0068482.[2] B l a k e l o c k R T , B e a s l e y S W. T h e clinical implications of non-idiopathic intussusception[J]. Pediatr Surg Int, 1998, 14(3):163-167. doi: 10.1007/s003830050473.[3] Macpherson RI . Gast rointes t inal t rac t d u p l i c a t i o n s : c l i n i c a l , p a t h o l o g i c , etiologic, and radiologic considerations[J]. Radiographics, 1993, 13(5):1063-1080. doi: 10.1148/radiographics.13.5.8210590.[4] Pul igand la PS , Nguyen LT, S t -Vi l D , Flageole H, Bensoussan AL, Nguyen VH, et al. Gastrointestinal duplications. J Pediatr Surg 2003 ;38 :740-744 . do i : 10 .1016 /jpsu.2003.50197.7.[5] Liu R , Ad le r DG. Dup l i ca t i on cys t s : Diagnosis, management, and the role of endoscopic ultrasound. Endosc Ultrasound 2 0 1 4 ; 3 : 1 5 2 - 1 6 0 . d o i : 1 0 . 4 1 0 3 / 2 3 0 3 -9027.138783.[6] Cheng J , Gao F, Zhang X, Wu X, Lu Y, Zeng Q. Sonographic pitfalls in the diagnosis of enteric duplication cysts. J Clin Ultrasound 2012;40:224-229. doi: 10.2214/ajr.184.2.01840521.[7] M o n i e r A , Aw a d A , S z m i g i e l s k i W, Muneer M, Alrashid A, Darweesh A, et a l . Heterotopic pancreas: a rare cause o f i l e o - i l e a l i n t u s s u s c e p t i o n . P o l J Radiol 2014;79:349-351. doi: 10.12659/PJR.890913.[8] Arslan MS, Basuguy E, Okur MH. A Rare Cause of Intestinal Obstruction in Infants: I leum Duplicat ion Cyst and Literature Review. J Neonatal Surg 2015;4:35. doi: 10.1155/2015/362478.[9] Gupta A, Chakaravarthi K, Pattnaik B, Kaman L. Duplication cyst of ileum presenting as acute intestinal obstruction in an adult. BMJ Case Rep 2016;2016:bcr2016214775. doi: 10.1136/bcr-2016-214775.[10] Kim SM, Lee SH, Park GY, Kim SS, Lee CG, Jin SJ. Cecal duplication cyst in an infant presenting as shock: A case report. World J Clin Cases 2023;11:6931-6937. doi: 10.12998/wjcc.v11.i28.6931.
Kin Sing WONG et al.73第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptomsAbstractPanayiotopoulos Syndrome (PS), also known as self-limited epilepsy with autonomic seizures (SeLEAS) or early-onset benign occipital epilepsy, is a childhood epileptic syndrome accounting for approximately 5% of childhood epilepsies. It typically manifests between ages 1 and 14 years with characteristic autonomic seizures featuring symptoms such as nausea, vomiting, unresponsiveness, flaccidity, and ocular deviation. This report presents two illustrative cases from Macau Kiang Wu Hospital in 2023–2024. PS is frequently misdiagnosed as gastrointestinal disorders, migraine, or syncope. Recognizing this epileptic syndrome can facilitate early diagnosis and provide appropriate parent education and evidence-based treatment.Keywords: Panayiotopoulos syndrome; Self-limited epilepsy with autonomic seizures; Early-onset benign occipital epilepsyDepartment of Pediatrics, Kiang Wu Hospital, Macau.*Corresponding author: Kin Sing WONG, E-mail: kswong311@gmail.comDOI : 10.30224/MMJ.202507_12(2).0010Kin Sing WONG*1. IntroductionPanayiotopoulos syndrome (PS), also known as self-limited epilepsy with autonomic seizures (SeLEAS) or early-onset benign occipital epilepsy. It is an epileptic syndrome that appears in early ch i ldhood. I t i s charac te r ized by au tonomic symptoms such as emetics, unresponsiveness, flaccid and ocular deviation. Prolonged seizures are common. We report 2 cases of PS admitted to Macau Kiang Wu Hospital in 2023 to 2024.2. Case presentationThe first patient was a female aged 5 years 11 months. She had normal development and good school performance. Her past medical history was unremarkable. She experienced sudden nausea and vomiting lasting for 5 minutes during sleep. The level of consciousness was not completely decreased at the beginning, but gradually became unresponsiveness and flaccid. Her eyes were deviated to one side. On arrival at the emergency department, her oxygen saturation (SPO2) decreased to 81%. She had shallow and irregular breathing. There were no tonic or clonic convulsions. Intravenous administration of 5 mg diazepam resulted in gradual awakening. The attack lasted for a total of 1 hour. No fever or respiratory symptoms were noted. EEG showed some δ activity in the right posterior temporal and occipital regions during wakefulness. Right posterior temporal and occipital spikes and slow complexes can be seen (Figure 1-2). They were increased obviously during sleep. Some of which occurred continuously for 10 seconds. Brain Magnetic Resonance Imaging (MRI) was unremarkable. Blood cell count, C reactive protein, renal function, liver function, electrolyte, lactate and ammonia were all within normal range. No regular anti-epileptic drugs (AED) treatment was
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal74Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptomsreceived. Rectal diazepam was given to the parent for use in case of a prolonged seizure.The second patient was a gir l who had 3 episodes at the ages of 2 years 9 months, 3 years 3 months and 3 years 4 months. She had normal developmental milestones. Three episodes had similar symptoms. She vomited suddenly during sleep and was responsive at the time. Then she gradually lost consciousness, became flaccid and her eyes were deviated to one side. The first 2 episodes lasted about 15-30 minutes. After the second seizure, valproic acid was administered, but the dose was not increased to reach the therapeutic concentration, and a third seizure occurred and it lasted about 40 minutes. She was cyanotic with an oxygen saturation (SPO2) of 80%. Her heart rate and blood pressure were normal. Status epilepticus was diagnosed and intravenous levetiracetam was given to stop the seizure. The EEG showed a small number of δ activity paroxysms during wakefulness, located at O2 and T6, lasting approximately 2-5 seconds, and a small number of spikes or spikes-slows complex waves during sleep, located at O2 (Figure3-4). Brain MRI was normal. Valproic acid was increased to 25mg/kg/day after the third episode.Figure 1.Figure 1. EEG showed δ activity in the right posterior temporal and occipital regions during wakefulness in the first patientFigure 2.Figure 2. A lot of spikes and slow complexes can be seen over the right posterior temporal and occipital region during sleep in the first patient.
75Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptoms第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Figure 3.Figure 3. A small number of δ activity paroxysms during wakefulness, located at O2 and T6, lasting approximately 3 seconds in the second patient.Figure 4.Figure 4. Small number of spikes or spikes-slows complex waves during sleep, located at O2, in the second patient.3. DiscussionPanayiotopoulos syndrome (PS), also known as self-limited epilepsy with autonomic seizures (SeLEAS) or early-onset benign occipital epilepsy. It is an epileptic syndrome of childhood. It accounts for 5% of childhood epilepsies between the ages of 1 and 14 years. There is no apparent gender or racial preference. The first seizure occurs between the ages of 1 and 14 years, particularly between the ages of 3 and 6 years [1]. A minority of patients have a history of febrile seizures. Developmental milestones and neurological examination are normal. Autonomic seizures are the hallmark of PS. To summarize the above cases, the clinical presentation includes sudden onset of nausea or vomiting, syncope-like manifestations, eye deviation, prolonged seizures or nonconvulsive status epilepticus, changes in respiratory rhythm and cyanosis . The most common symptom in PS is emetics. Emetics include nausea, retching o r vomi t ing . I t i s eas i ly misd iagnosed a s a gastrointestinal disease or cyclic vomiting syndrome if the patient’s consciousness is preserved. If the
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal76Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptomsmain manifestation is unresponsive and flaccid without convulsion, it may be similar to syncope [2]. Other autonomic symptoms such as pallor, cyanosis or flushing, abdominal pain, headache, pupillary dilation or constriction had been reported. The patient may experience cardiorespiratory abnormalities such as apnea, irregular breathing and bradycardia. Potentially life-threatening cardiorespiratory arrest has been reported [3].Seizure often presents as eye or head deviation, generalized hypotonia, focal clonic or focal to tonic-clonic seizure. Consciousness is typically preserved at the onset but may be decreased as the seizure continues. More than 70% of seizures in PS occur during sleep. They are always prolonged and lasting more than 30 minutes [4]. EEG is the most important investigation for the diagnosis of PS. The interictal EEG has normal background with high amplitude sharp and slow wave complexes. Their location is highly variable. 68% have epileptic discharge in the occipital region and some may involve other regions such as the frontal, central or temporal regions. 21% have epileptic discharge in other regionsbut without occipital region. 2% have generalized discharge only. 9% have a normal EEG, even if there is a series of EEGs.EEG abnormali t ies are often seen during sleep. Patients do not exhibit photosensitivity. EEG abnormalities often persist after the clinical seizures have resolved. These abnormalities are expected to decrease over time and usually disappear eventually [5]. MRI should be done to rule out brain abnormalities. No evidence of brain damage was reported in the nonconvulsive status epilepticus of PS. Patient with low seizure frequency or severity and nocturnal seizure predominant are not routinely treated with AEDs. Regular AED treatment should be considered if the attacks are frequent and interfere the life quality of patient. The first-line AED for treating PS is Carbamazepine, Lamotrigine, Levetiracetam, Oxcarbazepine or Sodium valproate. AED should be used as short duration and considered to stop 1-2year if seizure-free. Prolonged seizure or nonconvulsive s tatus epi lept icus can be treated by rectal or intravenous diazepam [6]. 4. ConclusionPS is an epileptic syndrome that appears in early childhood. Autonomic seizures are the hallmark of PS. PS can be mimicked by gastrointestinal disease, migraine, or syncope if the patient does not have convulsive seizures. Recognizing this epileptic syndrome can facilitate early diagnosis and provide appropriate parent education and evidence-based treatment. Reference[1] Specchio N, Wir re l l EC, Scheffer IE , Nabbout R, Riney K, Samia P, Guerreiro M, Gwer S, Zuberi SM, Wilmshurst JM, Yozawitz E, Pressler R, Hirsch E, Wiebe S, Cross HJ, Perucca E, Moshé SL, Tinuper P, Auvin S. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022 ;63(6):1398-1442. doi: 10.1111/epi.17241.[2] Covanis A. Panayiotopoulos syndrome: a benign childhood autonomic epilepsy frequently imitating encephalitis, syncope, migraine, sleep disorder, or gastroenteritis. Pediatr ics. 2006;118(4):e1237-43. doi: 10.1542/peds.2006-0623. [3] F e r r i e C , C a r a b a l l o R , C o v a n i s A , Demirbilek V, Dervent A. Panayiotopoulos syndrome: a consensus view. Dev Med Child Neurol. 2006;48(3):236-40. doi: 10.1017/S0012162206000508.[4] Capovilla G, Striano P, Beccaria F. Changes in Panayiotopoulos syndrome over time. Epi lepsia . 2009;50 Suppl 5 :45-8. doi : 10.1111/j.1528-1167.2009.02120.x.[5] Oguni H. A reappraisal of interictal EEG
77Panayiotopoulos syndrome: A childhood epilepsy with gastrointestinal and autonomic symptoms第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2characteristics in self-limited epilepsy with autonomic seizures, formerly known as Panayiotopoulos syndrome or early-onset benign occipital epilepsy. Eur J Paediatr Neurol . 2023;47:18-24 . doi : 10 .1016/j.ejpn.2023.08.004. [6] Panay io topou los CP. The Ep i l eps i e s : Seizures, Syndromes and Management. Bladon Medical Publishing, Oxfordshire (UK); 2005.
Ian Ian KOU et al.澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal78Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature reviewAbstractDiffuse large B-cell lymphoma (DLBCL) is categorized as an aggressive lymphoma due to its poor prognosis and high relapse rate of the disease regardless of the treatment. The standard treatment of DLBCL is rituximab-combination chemotherapy, but spontaneous regression without any treatment rarely occurs. The mechanism of spontaneous regression remains unclear. We present a case of a 77-year-old male presented with a large erythematous mass on the abdominal wall. Biopsy was performed, and a diagnosis of DLBCL was confirmed by histopathologic examination and immunohistochemical study. Two months after the biopsy, the abdominal mass regressed spontaneously without any treatment. The second excisional biopsy of the skin lesion was done and revealed no tumor cell. Instead, dense cytotoxic small T lymphocytes and histiocytes infiltrating are noted. Thus, we assume the cytotoxic T cells activate the host immune response against tumor cells and cause complete regression. In addition, the administration of antibiotics, traumatic event (biopsies), tumor microenvironment and apoptosis may be the mechanism of spontaneous regression in diffuse large B cell lymphoma. Keywords: Diffuse large B-cell lymphoma; Spontaneous regression; Cytotoxic T-cell reaction; PD-L1/PD-11Anatomical Pathology, Conde de São Januário General Hospital2Dermatology, Conde de São Januário General Hospital*Corresponding author: Ian Ian KOU, E-mail: starrykou229@gmail.comDOI : 10.30224/MMJ.202507_12(2).0011Ian Ian KOU1*, Lai Fong KOK1, Si Leong CHEONG2, Sio In WONG1, Isabel LOURENCO1, Thazin HLAING1.1. IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoproliferative disorder. The standard treatment is rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)[1], but the prognosis is poor due to the high relapse rate of the disease. Spontaneous regression (SR) is defined as the complete or partial resolution of the tumor cells without receiving chemotherapy or other treatment[2]. SR occasionally occurs in different types of tumor, such as lung cancer[3], breast cancer[4], and melanoma[5]. SR in low grade lymphoma also have been reported[6], but in aggressive DLBCL rarely occurs[2,7,8]. We usually start treatment for lymphoma as soon as possible after diagnosis in clinical practice. However, further investigation and clarifying the mechanism of SR may provide new treatment strategies.2. Case presentationA 7 7 - y e a r - o l d m a l e w i t h a h i s t o r y o f hypertension and diabetes mellitus, on amlodipine, insulin subcutaneous injection and oral hypoglycemic medication. He consulted to our hospital with a painless erythematous mass (size: 2.5 x 2 cm) on
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review79第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2the abdominal wall in November 2021. The lesion gradually increased in size to 6.5 x 4.3 cm by June 2022. Weight loss 3-4 kg was noted in the past 6 months. No fever or other systemic symptoms were observed. Physical examination showed a large erythematous mass measuring 6.5 x 4.3 cm on the right abdominal wall near the umbilical region (Fig. 1 A). No tenderness or discharge was noted. Skin biopsy was performed in August 2022, and histological examination revealed dense sheets and infiltrative growth of large neoplastic lymphoid cells in the mid and deep dermis. The tumor cells possessed large irregular nuclei, vesicular chromatin and prominent nucleoli. No epidermal involvement was seen (Fig. 1B). Immunohistochemical study: the tumor cells were positive for CD20, negative for CD3, BCL2, BCL6, CD10, MUM1, ALK and EBER, with a high proliferative index (Ki-67 >90%) (Fig. 1 C, D, E, F). Kappa and Lambda study on the plasma cells showed no light chain restriction. Thus, the overall features were consistent with diffuse large B-cell lymphoma. Additionally, the tumor cells were negative for PD-L1(Fig. 2 A, which was done in the Department of Anatomical Pathology, Kiang Wu Hospital, Macau). There were many CD8+ cells surrounding the tumor and the T cells are also positive for PD-1 (Fig. 2 B, C). Figure 1.Figure 1. First skin biopsy specimen. (A) There is a large erythematous mass in right abdominal wall. (B) There are dense sheets and infiltrative growth of large neoplastic lymphoid cells in the mid and deep dermis. (C) The atypical lymphoid cells possess large irregular nuclei, vesicular chromatin and prominent nucleoli. (D) These atypical cells express CD20. (E) CD3 is negative. (F) The Ki-67 proliferative index is high. A BC D E F
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal80Figure 2.Figure 2. First skin biopsy specimen. (A) The tumor cells are negative for PD-L1. (B) Many CD8 + cells are found around the tumor. (C) CD8+ cells around the tumor are positive for PD-1. Figure 3.Figure 3. Second excisional biopsy specimen. (A) Dense reactive small lymphocytes. (B) Large sheets of foamy histiocytes. (C) Most of the small lymphoid cells are T cells that are CD3+. (D) The vast majority of these T cells express CD8. (E) Small amount of these T cells expresses CD4. (F) The Ki-67 proliferative index is low. A A B CBC D E F
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review81第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2The further laboratory study including: LDH, immunoglobulin, light chains were negative. The PET-CT (from Kiang Wu Hospital, Macau) showed local patchy soft tissue thickening with mild FDG activity in the subcutaneous region or right middle abdominal wall, consistent with lymphoma. No FDG active and bulky lymph node evoked in above or below diaphragm. A p a r t f r o m t h e r e g u l a r m e d i c i n e f o r hypertension and diabetes mellitus, he also took antibiotic (cefuroxime for 7 days) for the dental abscess in September 2022 after the first skin biopsy. Later, the tumor decreased in size spontaneously, leaving a small subcutaneous nodule (size: 1cm in diameter) with erythema in October 2022. Excisional biopsy was performed and revealed large sheets of foamy histiocytes with dense reactive small lymphocytes, predominantly CD8+ T cells. Granulomatous reaction - foreign body type was seen (Fig. 3 A, B). No residual large B cell lymphoma was noted despite extensive tissue sampling.Immunohistochemistry study: Most lymphocytes were T cells highlighted by CD3, and most of them were cytotoxic T lymphocytes CD8+ (Fig. 3 C, D, E). A few small lymphocytes are highlighted by CD20. BCL2, CD10, BCL6, CD30, c-Myc, MUM1, Kappa, Lambda, and Ki-67 were done, presenting a negative result. In situ-hybridization for EBER (Epstein-BarrVirus) was negative. The pa t i en t r ema ins a symptomat i c pos t excisional biopsy after 10 months follow-up. 3. DiscussionWe report a case of spontaneous regression of diffuse large B-cell lymphoma (DLBCL) after a skin biopsy diagnosis. DLBCL is the most common non-Hodgkin lymphoma, which accounts for approximately 30% of all non-Hodgkin lymphoma cases. Spontaneous regression has been described in various malignancies [9]. Although spontaneous regression in low-grade lymphoma has been reported, aggressive diffuse large B-cell lymphoma rarely occurs. The mechanism of spontaneous regression in high grade lymphomas remains unclear. Immune-mediated response to tumor cells has been proposed as the most l ikely mechanism of spontaneous regression in malignant tumor [9]. A probable reaction of the host’s immune system to bacterial or viral infections, and traumatic events (biopsies) in patients with spontaneous regression of diffuse large B-cell lymphoma have been described [10]. There are various causes related to spontaneous regression, including host immune system, tumor microenvironment and apoptosis, considering CD8+ T lymphocytes infiltrate as an important part because of its cytolytic action [9].A common phenomenon observed in reported cases is that SR developed in all cases of DLBCL after biopsy. The relationship between traumatic events (biopsies) and SR remains uncharacterized. The biopsy raises the possibi l i ty of physical disruption of the tumor microenvironment, and activates the immune system. Moreover, abundant cytotoxic T cells infiltration reinforced the immune recognit ion a potent ial mechanism for tumor regression [11], and suggests that pro-inflammatory state within the tumor after biopsy may be one of the factors of complete regression [2].Several reported cases describe that the tumor regression is associated with viral or bacterial infections. Whether each host’s immunologic response to these various infections triggered an antitumor response is not clear. The cross-reaction between pathogen-specif ic T cel ls and tumor antigens is postulated [12,13]. In addition, literature reports that antibiotic administration or the use of immunomodulatory herbal medicine (such as LingZhi) can result in SR of DLBCL [14,15]. The authors postulate that the abundant cytotoxic T cells infiltration may represent a host immune-mediated response that induced complete regression of tumor. In our case, the patient has received 7 days antibiotic treatment for dental abscess after the first skin biopsy. Thus, infection and administration of antibiotics may be playing a role in tumor regression. Recently, several immune escape mechanisms have been proposed [16]. One such mechanism is the
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal82expression of inhibitory signal molecules, such as CD80, PD-L1 on tumor cells [8]. There are about 90% of DLBCL cases expressing CD80 by the tumor cells. It is believed that the CD80 expressing lymphoma cells active anti-lymphoma T cells leading to the anti-tumor immune response [17]. The study of CD80 was omitted from our study because the antibody is not available in our laboratory. Thus we focus on PD-L1/PD-1 axis because the expression of PD-L1 on tumor cells is supposed to be one of the most powerful and frequent immune escape mechanisms [8]. Programmed Cell Death Protein 1 (PD-1) is an inhibitor of both adaptive and innate immune responses, and it is highly expressed on tumor-specific T cells. Programmed Cell Death Ligand 1 (PD-L1) is a ligand of PD-1. It usually expressed by macrophages and some activated T cells and B cells. In addition, PD-L1 is expressed on tumor cells which act as a pro-tumorigenic factor and results in an immune escape mechanism [18]. PD-L1/PD1 axis is a negative modulatory signaling pathway. When tumor cells express PD-L1, PD-1/CD8 double-positive T lymphocytes do not attack them. Thus, antitumor effect would not be occurred. In contrast, when tumor cells do not express PD-L1, PD-1/CD8 double-positive T lymphocytes will attack them and prompt the apoptosis of tumor cells. This is one of the mechanisms of immune escape in cancer. Therefore, we focused on the mechanism of PD-L1/PD-1 axis in our case. In our patient, lymphoma cells did not express PD-L1, whereas the surrounding lymphocytes, including CD4 and CD8 positive T cells, expressed PD1. This PD-L1/PD-1 axis may play an important role of SR in our case. Furthermore, it is known that the expression of PD-L1 in tumor cells is associated with a poor prognosis in DLBCL [19]. In addition, most of the reported cases with SR have had disease in extranodal sites. Thus, the tumor microenvironment may be different in the extranodal and nodal tumors. However, there is no definitive conclusion can be made based on the limited reported cases currently[7]. The microenvironment of B-cell lymphoma demonstrates a complex network composed of multiple cells type and signals mediated, which formed a physical barrier surrounding the tumor cells. The tumor microenvironment plays a critical role in treatment, drug resistance and prognosis of B-cell lymphoma. Therefore, the challenge of tumor microenvironment of B-cell lymphoma is actively investigated [20].SR in aggressive high grade lymphoma after biopsy is a rare phenomenon. Although treatment for lymphoma should be started soon after diagnosis, clinicians should be closely monitoring the alteration of the biopsy site, patient’s general condition, and radiological findings before chemotherapy. If any significant change happens, we should pay attention to it and adjust the treatment plan in time. As in our case, the skin lesion was found spontaneously decreased in size after the first skin biopsy in the out-patient department. In this situation, the clinician adjusted the treatment plan immediately, replacing it by close monitoring, arranging further investigations and excisional biopsy.The single case is not enough to approve the clear mechanism of SR in DLBCL, because the reported cases of SR in DLBCL are limited and the various mechanisms of spontaneous regression of tumor are postulated and explored. Therefore, it is a challenge for clinicians and pathologists. Clinicians would struggle with starting treatment or temporary observation because aggressive lymphoma can progress rapidly. For pathologists, extensive sampling of the specimen and immunohistochemical studies are significant for making a diagnosis.4. ConclusionWe report the rare phenomenon of spontaneous regress ion of d i ffuse large B-cel l lymphoma p r e s u m a b l y m e d i a t e d b y c y t o t o x i c T- c e l l reaction, which may be related to the traumatic mechanism after biopsy which impaired the tumor microenvironment and act ivated the immune response. The incidental use of antibiotics for dental abscess after the first skin biopsy as well as the PD-
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review83第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2L1/PD-1 axis may also play a role in the spontaneous regression of aggressive lymphoma in our case. Although the mechanism for the SR in our case remains uncertain, we emphasize that SR in DLBCL after any disruption of tumor microenvironment, such as biopsy, does happen. Therefore, before the chemotherapy treatment, additional biopsy is needed in particular if there are any alterations of the cutaneous lesion. Keep close monitoring of the patient after SR is remaining essential. On the other hand, most reported cases with SR are extranodal sites. The tumor microenvironment between the nodal site and extranodal site is different and complicated. Thus, further investigation for the tumor microenvironment is benefit for treatment, drug resistance and prognosis. Reference:[1] Sehn, L. H. & Gascoyne, R. D. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 125, 22–32 (2015). DOI: 10.1182/blood-2014-05-577189.[2] Snijder, J., Mihyawi, N., Frolov, A., Ewton, A. & Rivero, G. Spontaneous remission in diffuse large cell lymphoma: a case report. J. Med. Case Reports 13, 28 (2019). DOI: 10.1186/s13256-018-1937-z.[3] Hwang, E. D. et al. Spontaneous Regression of Non-Small Cell Lung Cancer in a Patient with Idiopathic Pulmonary Fibrosis: A Case Report. Tuberc. Respir. Dis. 75, 214 (2013). DOI: 10.4046/trd.2013.75.5.214.[4] Iwatani, T., Kawabata, H., Miura, D., Ota, Y. & Ohashi, K. Complete Spontaneous Regression of Primary Diffuse Large B-Cell Lymphoma of the Breast. J. Clin. Oncol. 29 , e113–e115 (2011) . DOI: 10 .1200/JCO.2010.31.2801.[5] Tran, T., Burt, D., Eapen, L. & Keller, O. R. Spontaneous Regression of Metastatic Melanoma after Inoculation with Tetanus–D i p h t h e r i a – P e r t u s s i s Va c c i n e . C u r r. Oncol. 20, 270–273 (2013). DOI: 10.3747/co.20.1212.[6] Morigi, A., Casadei, B., Argnani, L., Cavo, M. & Zinzani, P. L. Spontaneous remission of follicular lymphoma. Hematol. Oncol. 37, 626–627 (2019). DOI: 10.1002/hon.2653.[7] Buckner, T. W. et al. Complete Spontaneous R e m i s s i o n o f D i f f u s e L a r g e B - C e l l Lymphoma of the Maxillary Sinus After Concurrent Infections. Clin. Lymphoma Myeloma Leuk. 12, 455–458 (2012). DOI: 10.1016/j.clml.2012.06.007.[8] Tanaka, Y. et al. Spontaneous regression of diffuse large B-cell lymphoma in the small intestine with multiple lymphadenopathy. J. Clin. Exp. Hematop. 59, 17–21 (2019). DOI: 10.3960/jslrt.18020.[9] Ricci, S. B. & Cerchiari, U. Spontaneous regression of malignant tumors: Importance of the immune system and other factors (Review). Oncol. Lett. 1, 941–945 (2010). DOI: 10.3892/ol.2010.176.[10] A b e , R . , O g a w a , K . , M a r u y a m a , Y. , Nakamura, N. & Abe, M. Spontaneous R e g r e s s i o n o f D i f f u s e L a rg e B - C e l l Lymphoma Harbouring Epstein-Barr Virus: A Case Report and Review of the Literature. J. Clin. Exp. Hematop. 47, 23–26 (2007). DOI: 10.3960/jslrt.47.23.[11] S a i s , G . , A d m e l l a , C . & S o l e r , T. Spontaneous regression in primary cutaneous neuroendocrine (Merkel cell) carcinoma: a rare immune phenomenon? J. Eur. Acad. Dermatol. Venereol. 16, 82–83 (2002). DOI: 10.1046/j.1468-3083.2002.374_2.x.[12] Burrows, S. R. et al. Cross-reactive memory T cells for Epstein-Barr virus augment the alloresponse to common human leukocyte antigens: degenerate recognition of major histocompatibility complex-bound peptide by T cells and its role in alloreactivity. Eur.
Spontaneous regression of diffuse large B-cell lymphoma after biopsy: A case report and literature review澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal84J. Immunol. 27, 1726–1736 (1997). DOI: 10.1002/eji.1830270720.[13] D’Orsogna , L . J . e t a l . New tools to monitor the impact of viral infection on the alloreactive T-cell repertoire. Tissue Antigens 74, 290–297 (2009). DOI: 10.1111/j.1399-0039.2009.01311.x.[14] Hofbauer, G. F. L. et al . Multi lesional Primary Cutaneous Diffuse Large B-Cell Ly m p h o m a R e s p o n s i v e t o A n t i b i o t i c Treatment. Dermatology 203, 168–170 (2001). DOI: 10.1159/000051735.[15] Cheuk, W., Chan, J. K. C., Nuovo, G., Chan, M. K. M. & Fok, M. Regression o f G a s t r i c L a r g e B - C e l l Ly m p h o m a Accompanied by a Florid Lymphoma-like T-Cell Reaction: Immunomodulatory Effect of Ganoderma lucidum (Lingzhi)? Int. J. Surg. Pathol . 15, 180–186 (2007). DOI: 10.1177/1066896906295890.[16] Okazaki, T. & Okazaki, I.-M. [Regulation of autoimmunity and tumor immunity by immunoinhibi tory co-receptor, PD-1] . Seikagaku 87, 693–704 (2015). [17] Komohara , Y. & Harada, M. Potent ia l mechanisms of spontaneous regression in pat ients with B-cel l lymphoma; the significance of co-stimulatory molecules in lymphoma cells. J. Clin. Exp. Hematop. 59, 207–210 (2019). DOI: 10.3960/jslrt.19026.[18] Ohaegbulam, K. C. , Assal , A. , Lazar-Molnar, E., Yao, Y. & Zang, X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol. Med . 21, 24–33 (2015). DOI: 10.1016/j.molmed.2014.10.009.[19] Kiyasu, J. et al. Expression of programmed cel l death l igand 1 i s associa ted wi th poor overa l l survival in pat ients wi th diffuse large B-cel l lymphoma. Blood 126, 2193–2201 (2015). DOI: 10.1182/blood-2015-02-629600.[20] Coupland, S . E . The cha l lenge of the microenvironment in B-cell lymphomas: Chal lenge of the microenvironment in B-cell lymphomas. Histopathology 58, 6 9 – 8 0 ( 2 0 11 ) . D O I : 1 0 . 1111 / j . 1 3 6 5 -2559.2010.03706.x.
Ingrid Karmane SUMOU et al.85第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Abstract Immune checkpoint inhibitors (ICIs) therapy is a form of cancer treatment that uses the power of the body’s immune system to prevent, control, and eliminate cancer. It is a promising option for various types of advanced solid tumors, alone or in combination with treatments like chemotherapy or surgery. Being a potent treatment, we need to properly address the potential adverse effects, some of which if not intervened adequately might evolve severe enough to interrupt or halt the cancer treatment. We report a case of a young patient with two synchronous primary cancers on a course of immunochemotherapy, with pathologic complete response (pCR) after resection of one of the two tumors but developing refractory pancytopenia, and despite all supportive measures, failed to thrive.1Department of Oncology, Conde de São Januário General Hospital, Macau SAR2Intensive Care Unit, Conde de São Januário General Hospital, Macau SAR *Corresponding Author: Ingrid Karmane SUMOU, E-mail: ingridsumou@gmail.com DOI : 10.30224/MMJ.202507_12(2).0012Immune checkpoint inhibitors induced haematological toxicity: A double-edged swordIngrid Karmane SUMOU1*, Sok Cheng LAI2, Kan Fat LEONG21. Case presentationIn October 2023, a 36-year old female Chinese patient presented with a self-palpated lump in her left breast for 5 years, which she disregarded until it grew bulky and compounded with ulceration. She was premenopausal, nulliparous, with no family history of breast or ovarian malignancy. Physical examination revealed multiple fixed nodules in the left axilla, and a 10x11cm mass over her left breast with skin invasion. Core biopsy of the left breast mass revealed an invasive ductal carcinoma, grade II by the Bloom-Richardson system. Immunohistochemical staining was positive for E-cadherin, negative for estrogen and progesterone receptors both with an Allred score of 0, human epithelial growth factor receptor-2 with IHC score 1+, and a proliferative index Ki-67 65%, corroborating with triple negative breast carcinoma. Positron emission tomography–computed tomography (PET-CT) showed a left breast mass measured 74x81x80mm with SUVmax 18.4, left axillary lymphadenopathies up to 16x6mm with SUVmax 5.0 considered nodal metastasis, as well as ascending colon wall thickening spanning 3cm in length with SUVmax 23.6. Colonoscopy revealed a cecum mass 4cm in dimension spanning one-third circumference, it was biopsied and the pathology revealed moderately differentiated adenocarcinoma, with mucinous component . Molecular test ing imparted immunoreact ivi ty intact for MLH1, MSH2, MSH6, PMS2. Genetic testing revealed no identifiable germline pathogenic variants in BRCA1, BRCA2. Under the impression of synchronous primary malignancies including left-sided triple nega t ive breas t cancer wi th c l in ica l s tag ing cT4N2M0 stage IIIB, and cecum adenocarcinoma cTxNxM0 mismatch repair proficient, neoadjuvant systemic therapy was considered with judicious se lec t ion of a regimen that would s t r ive for maximized cure to both malignancies. In view
Immune checkpoint inhibitors induced haematological toxicity: A double-edged sword澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal86of adequate organ function with a good Eastern Cooperative Oncology Group performance score of 1, she received anthracycline-based chemotherapy with epirubicin 90mg/m2 intravenously (IV) day 1 and cyclophosphamide 600mg/m2 IV day 1 triweekly for 3 cycles in a private clinic. She sought referral to our center for further treatment. A full blood count and metabolic panel were conducted by day 12 of cycle 3, and revealed neutropenia grade 4 based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [1]. Granulocyte colony-stimulating factor (G-CSF) 300mcg subcutaneously daily for 3 days was administered, with recovery of the neutropenia to grade 2 [1]. Baseline assessment for thyroid function was normal. She received chemotherapy cycle 4 in our center with the same regimen and dose, added with pembrolizumab 200mg IV day 1, then proceeded to sequential platinum-based chemotherapy with carboplatin dosing by area under curve of 5 IV day 1 and paclitaxel 80mg/m2 IV on days 1, 8 and 15, along with pembrolizumab 200mg IV day 1 triweekly, intended for 4 cycles. The patient reported evident breast tumor size reduction. Surveillance biochemical tests revealed grade 2 hypothyroidism [1]. Thyroid hormone replacement with levothyroxine 100mcg orally daily was supplemented. Red blood cell transfusions and G-CSF support were required, alongside treatment in te r rupt ions and dose modi f ica t ions due to hematologic toxicities including grade 3 neutropenia, grade 3 anemia and grade 3 thrombocytopenia [1]. Treatment was eventually brought to a halt after three cycles due to life-threatening myelosuppression. She received salvage G-CSF, blood component transfusions and empirical antibiotics. However, she developed abdominal distension and passed bloody stool. Computed tomography (CT) of the abdomen and pelvis suggested ileocecal intussusception with perforation. Urgent exploratory laparotomy revealed a necrotic tumoral mass in the cecum, with intussusception of the small intestine and segmental bowel ischemia. Right hemicolectomy was performed. Pathology confirmed segmental ischemia, necrosis, hemorrhage and serositis in the small intestine, appendix and colon. The tumoral mass in the cecum showed total necrosis. There was no viable tumor tissue present, no lymphovascular permeation was identified. The viable small intestinal and colonic tissue showed preserved architecture. No vascular thrombosis or vasculitis was noted. The proximal resection margin was viable. The distal margin showed focal ischemic changes. All resection margins were free of malignancy or dysplasia. A total of eleven pericolic lymph nodes were identified, all of them were negative for malignancy. The staging for the known cecum carcinoma was ypTxN0, based on the American Joint Committee on Cancer 8th edition, with the pT staging precluded by the total necrosis of the cecal tumor.She was transferred to the Intensive Care Unit for postoperative care. Stable hemodynamics was achieved within five days postoperatively, inotropes and vasopressors were weaned off. Inflammatory markers including serum procalcitonin and C-reactive protein significantly downtrend within one week along with empirical use of antibiotics. She remained on mechanical ventilation with borderline oxygen saturation. Chest CT showed left breast carcinoma 4.4x7.3cm in dimension (previously 7.4x8.1cm by PET-CT), and bilateral pleural effusion with partial pulmonary atelectasis. There was no intrapulmonary nodule or mass. There was no mediastinal, hilar or axillary lymphadenopathy. Thoracentesis was performed, with drainage of about 600ml turbid yellowish pleural effusion. Cytology of the pleural effusion showed no evidence of malignant cells. She suffered persistent myelosuppression despite receiving PEGylated G-CSF and intermittent blood component transfusions (Table 1). Bone marrow aspiration was performed with a rich harvest in marrow spicules. Smear revealed hypocellularity, completely devoid of hematopoietic tissue among the presence of fat cells (Figure 1), consistent with severe marrow hypoplasia (Figure 2). After discussion with our Hematologist, romiplostim 250mcg was given as a single dose subcutaneously
Immune checkpoint inhibitors induced haematological toxicity: A double-edged sword87第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2in hope of stimulating thrombopoietin production, as well as methylprednisolone succinate 100mg IV twice daily for 3 days, with illusory response in monocytes thus decided for an extension of methylprednisolone therapy up to 6 days. In view of thrombocytopenia refractory to multiple platelet t ransfusions, phenotyped-platelet t ransfusion was ordered to correct coagulopathy. Intravenous immunoglobulin (IVIG) at 1g/kg was also given. Despite supportive measures, the patient turned hemodynamically unstable, requiring vasopressor IV infusion. Endotracheal aspirate culture yielded meth ic i l l in - res i s tan t s taphylococcus aureus , vancomycin IV was implemented. Notwithstanding, her condition deteriorated. She passed away three weeks after the surgical operation.2. DiscussionImmune-mediated hematologic toxicity could vary from anemia, thrombocytopenia, and leukopenia to ra re ly pancytopenia [2]. Severe pro longed pancytopenia associated with ICIs are not well represented in literature because of both its rarity and subsequent poor recognition. This is further complicated by increasing combinations of ICIs with myelosuppressive cytotoxic agents. With increased use of ICIs and improved recognition of hematologic toxicities, cases of hematologic toxicities are expected to rise, establishing a need for clinical management guidelines. The pharmacovigilance database from WHO identified hemolytic anemia and immune thrombocytopenia as among the most common hematologic toxicities with a median time to onset of 40 days [3]. A meta-analysis from Italy reported the pooled incidence for any-grade and grade 3-5 anemia of 9.8% and 5% respectively [4]. If multiple cell lines are affected, evaluation for aplastic anemia, pure red cell aplasia and myelodysplasia should be implemented [5-6]. Most complications could be resolved with drug withholding +/- addition of corticosteroids, IVIG, and hematopoietic growth factors. Thrombocytopenia is uncommon, with a pooled incidence of 2.8% for any-grade and 1.8% for grade 3-5 [4]. Judicious evaluation for the underlying causes must be undertaken. Corticosteroids have been shown to be effective with transfusion support as required.In the current case, the patient suffered from refractory pancytopenia, and despite all supportive measures, failed to thrive. Surgical resection of the ileocolic intussusception brought about a revelation of the most favorable therapeutic effect of pCR of the cecum primary tumor, with pathological proven total necrosis of the cecal tumor. Such anti-tumor therapy has worked so evidently for this patient for her synchronous second primary. It was reasonably anticipated that a favorable response would be ascertained in the breast primary, deliberately for which the neoadjuvant immunochemotherapy has been carefully chartered, earmarked on purpose. The reporter had wished to chaperone the patient across the highway to where the patient could otherwise have received surgical resection of the primary breast tumor, to prove if tumor regression was achieved, with an ambition for another pCR which was already proven in the cecum tumor, which could rescript her survival. Immunotherapy has become more prevalent in cancer treatments. Physicians need to navigate themselves to be more familiarized with potential adverse effects, and to provide timely management. Precautions should be taken to pave the way for adequate organ function and bone marrow reserve. Grade 3-4 hematological toxicities should warrant judicious suspension of the treatment and where necessary start early intervention with high-dose corticosteroids and IVIG.
Immune checkpoint inhibitors induced haematological toxicity: A double-edged sword澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal88Figure 1. Figure 1. Bone marrow smear completely devoid of hematopoietic tissue among the presence of fat cells (hematoxylin-eosin stain, 10x)Figure 2. Figure 2. Bone marrow smear consistent with severe marrow hypoplasia (hematoxylin-eosin stain, 20x)
Immune checkpoint inhibitors induced haematological toxicity: A double-edged sword89第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Table 1. Complete blood count monitoring throughout treatment.Complete Blood Count Monitoring Throughout Treatment Date 17-Jan 24-Jan 31-Jan 7-Feb 21-Feb 28-Feb 7-Mar 15-Mar 22-Mar 15-Apr 22-Apr 29-Apr 20-MayNeoadjuvant TherapyC3 EC C4Pembro + ECC5Pembro + TC C6Pembro + TCC7Pembro + TCJan 05 Feb 01 Feb 22 Apr 02 May 02Hgb (g/dL) 8.7 9.6 9.2 9.2 9 8.6 † 9.1 7.6 † 9.2 5.6 † 11.6 11.1 3.8 †WBC ( ×10^9/L) 0.6 3.2 3.3 2.2 2 1.4 7.4 2.1 12.9 3 2.1 3.6 2ANC 0.0* 1.4* 2.2 1.3* 1.2* 0.9* 6.3 0.8* 9.9 2.1 1.0* 1.8* 1.0*PLT ( ×10^9/L) 109 161 242 209 219 126 89 41 97 19 32 68 18Date 21-May 22-May 23-May 24-May 25-May 26-May 27-May 28-May 29-May 30-May 31-May 1-Jun 2-JunEvent Exploratory Laparotomy (May 23)Hgb (g/dL) 4.5 † 11.8 13.1 13.8 12.4 11.3 8.3 † 10.5 8.8 † 9.4 6.5 † 8.9 10.8WBC ( ×10^9/L) 0.4 0.7 0.3 0.5 1.3 1.7 0.9 1.1 0.9 1 0.8 1.8 1.7ANC 0.2* 0.5* 0.3* 0.4* 1.1* 1.3* 0.7* 0.8* 0.8* 0.8* 0.6* 1.58* 1.4*PLT ( ×10^9/L) 16 35 89 26 46 6 ‡ 26 6 ‡ 17 3 ‡ 35 3 ‡ 9Date 3-Jun 4-Jun 5-Jun 6-Jun 7-Jun 8-Jun 9-Jun 10-Jun 11-Jun 12-Jun 13-Jun Hgb (g/dL) 9.9 7.0 † 8.8 7.4 6.8 † 10.9 8.9 5.5 † 8.8 7.3 † 4WBC ( ×10^9/L) 1.4 1.2 2 1.8 1.6 3.6 4.3 1.8 2.9 2.6 2.6ANC 1.1 0.42* 1.5 1.5 1.3* 3.1 3.7 1.5* 2.4 2.3 2.3PLT ( ×10^9/L) 3 ‡ 3 ‡ 15 3 ‡ 2 ‡ 6 3 ‡ 4 ‡ 2 ‡ 14 4 Legend:† RBC transfusion; * G-CSF support given; ‡ Platelet transfusionTreatment and Monitoring Summary:• Neoadjuvant therapy: EC (extramural, cycles 1-3) → Pembrolizumab + EC (cycle 4) → Pembrolizumab + TC (cycles 5-7) (Jan-May 2024)• Surgery: Exploratory Laparotomy (May 23, 2024)• Multiple blood component transfusions and salvage G-CSF required throughout treatmentReference[1] Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National Institutes of Health, National Cancer Institute.[2] Atwa l D , Josh i KP, Rav i l l a R , e t a l . Pembrolizumab-Induced Pancytopenia: A Case Report. Perm J. 2017;21:17-004. DOI: 10.7812/TPP/17-004[3] Dav i s EJ , Sa l em JE , Young A , e t a l . Hematologic complications of immune checkpoint inhibitors. Oncologist 24:584-588, 2019. DOI: 10.1634/theoncologist.2018-0574[4] P e t r e l l i F, A r d i t o R , B o r g o n o v o K , e t a l . Haemato log ica l tox ic i t i e s wi th immunotherapy in patients with cancer: A systematic review and meta-analysis. Eur J Cancer 103:7-16, 2018. DOI: 10.1016/
Immune checkpoint inhibitors induced haematological toxicity: A double-edged sword澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal90j.ejca.2018.07.129[5] Cool ing LL, Sherbeck J , Mowers JC, e t a l . Deve lopment o f r ed b lood ce l l autoantibodies following treatment with checkpoint inhibitors: A new class of anti-neoplas t ic , immunotherapeut ic agents associated with immune dysregulation. Immunohematology 33:15-21, 2017. PMID: 28425751.[6] Nair R, Gheith S, Nair SG. Immunotherapy-associated hemolytic anemia with pure red-cell aplasia. N Engl J Med 374:1096-1097, 2016. DOI: 10.1056/NEJMc1509362
91 Zhi Xiong XIANG et al.第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: A retrospective case seriesAbstractBackground: Spinal dural arteriovenous fistulas (DAVFs) are the predominant subtype of spinal vascular malformations, often requiring precise intraoperative localization for successful microsurgical obliteration. Objective: To assess the efficacy and safety of intraoperative indocyanine green (ICG) video angiography as an adjunct in the microsurgical treatment of spinal DAVFs.Methods: A retrospective analysis was performed on five consecutive patients with spinal DAVFs treated between January 2020 and April 2023. Diagnosis was established via magnetic resonance imaging (MRI) and confirmed by digital subtraction angiography (DSA). Microsurgical interruption involved laminectomy guided by DSA, with ICG video angiography used to delineate fistula anatomy and verify occlusion post-clipping. Outcomes were evaluated through neurological recovery and follow-up imaging. Results: Successful fistula obliteration was achieved in all 5 cases using ICG guidance. Postoperative neurological function improved significantly, with resolution of abnormal vasculature and cord edema confirmed by MRI or DSA at 1–3 months. No adverse events related to ICG were noted. Conclusions: Intraoperative ICG video angiography is a safe, effective, and repeatable tool that enhances precision in microsurgical DAVF resection by providing real-time hemodynamic assessment. Keywords: Indocyanine green, microsurgery, spinal dural arteriovenous fistula, intraoperative angiography, spinal vascular malformation1Department Of Neurosurgery, Kiang Wu Hospita, Macau2Department of Diagnostic Imaging Center, Kiang Wu Hospital, Macau*Corresponding author: Zhi Xiong XIANG, E-mail: doctorxiang@gmail.comDOI : 10.30224/MMJ.202507_12(2).0013Zhi Xiong XIANG1*, Mei Ha LEONG1, Ting LIAO1, Chun Lin MA21. IntroductionS p i n a l d u r a l a r t e r i o v e n o u s f i s t u l a s (DAVFs) account for 70–80% of spinal vascular malformations, comprising approximately 2–4% of all spinal cord pathologies [1]. These lesions feature an aberrant arteriovenous shunt within the dura mater, typically at the intervertebral foramen, resulting in venous hypertension, impaired drainage, and subsequent myelopathy characterized by spinal cord edema or infarction [2]. Untreated, DAVFs may progress to irreversible paraplegia [3]. Definitive therapy entails shunt interruption, achievable via endovascular embolization or microsurgical ligation[4]. The latter, while curative, demands accurate intraoperative identification of the fistulous point―a challenge historically addressed using preoperative digital subtraction angiography (DSA) or intraoperative catheter angiography [5–7].
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal92Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case seriesIndocyanine green (ICG) video angiography, a near-infrared fluorescence technique, has gained traction in neurosurgery for real-time visualization of vascular patency and aneurysm clipping efficacy. Its application in spinal arteriovenous malformations (AVMs) and fistulas has shown promise [8], yet evidence specific to DAVFs remains limited to case reports, lacking comprehensive evaluation of its utility and limitations. This study presents a retrospective case series of five patients undergoing ICG-assisted microsurgical resection of spinal DAVFs, aiming to elucidate its intraoperative value.2. Materials and MethodsThis retrospective case series included five consecutive patients with spinal DAVFs treated at Kiang Wu Hospital, Macau, between January 2020 and April 2023. Institutional ethical approval was obtained, and informed consent was secured for surgical intervention and ICG administration Inclusion criteria comprise (1) clinical suspicion of DAVF based on myelopathic symptoms (e.g., lower limb muscle weakness, sensory deficits, sphincter dysfunction); (2) MRI evidence of spinal cord edema and abnormal vasculature; (3) DSA confirmation of DAVF; and (4) microsurgical treatment with intraoperative ICG angiography. Exclusion criteria are prior embolization or contraindications to ICG (e.g., iodine allergy). All participants were assessed by neurological e x a m i n a t i o n a n d A m e r i c a n S p i n a l I n j u r y Association(ASIA) impairment scale to localize the lesion level and evaluate neurological deficits. Spinal MRI was performed with T1-weighted (T1W), T2-weighted (T2W), and fat-suppressed T2W (fs-T2W) sequences to detect cord edema and flow voids. DSA involved selective catheterization of bilateral intercostal, lumbar, and radiculomedullary arteries with low-pressure contrast injection to map the feeding arteries fistulous points and draining veins. Surgical procedure is as follows: Patients underwent surgery under general anesthesia in the prone position. A targeted laminectomy was performed based on DSA localization. The dura was incised, and a 5-mg bolus of ICG (Akorn, Inc., .Lake Forest, IL) was administered intravenously. Fluorescence was visualized using an operating microscope with integrated near-infrared imaging (Leica Microsystems , Germany). ICG angiography delineated the fistula pre-clipping; after the ligation of the of the draining vein near the fistulous point with a titanium clip or bipolar coagulation, a second ICG injection confirmed shunt obliteration and restoration of physiological flow. Primary endpoints included complete fistula occlusion (assessed intraoperatively by ICG and postoperatively by MRI/DSA) and neurological improvement (graded by the Medical Research Council [MRC] muscle strength scale and ASIA sensory scores). Secondary endpoints included ICG-related complications, and recurrence at 1–3 months image follow-up.3. ResultsIn total, five patients (four male, one female; mean age 69 ± 8.2 years, range 58–77) were included and analyzed (Table 1). Lesions spanned thoracic (T5–T9, n=3) and lumbar (L1/2–L3/4, n=2) segments, Presenting symptoms included paraparesis (100%), sensory deficits (100%), sphincter dysfunction (60%), and sexual dysfunction (20%). ICG angiography successfully identified the fistulous connection in all cases, revealing early venous filling prior to clipping. Post-clipping ICG confirmed absence of shunt flow and normalization of venous drainage. Fistula occlusion was achieved in 100% of cases, verified intraoperatively and on follow-up imaging (MRI, n=4; DSA, n=1) at 1–3 months, showing resolution of flow voids and cord edema. Mean MRC strength improved from 2.8 ± 1.1 preoperatively to 4.2 ± 0.8 postoperatively (p not calculated due to sample size). Following surgery, all five DAVF patients experienced varying degrees of recovery from their spinal neurological deficits. (Table 1). In all cases, no ICG-related adverse events (e.g., anaphylaxis, hypotension) or recurrences were observed.
93Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case series第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Table 1. Patient Demographics, Lesion Characteristics, and Outcomes.CaseSex &age(yr)Level &sidePresenting symptomsPre-op MRC gradePost-op MCR gradePost-op conditionFollow-up imageFollow-up duration(months)1 M77L3/4leftParaparesis, sensory loss, sphincter dysfunction3 4+ Persistent foot hypoesthesiaMRI resolved 242 M70L1/2leftParaparesis, sensory loss, sphincter dysfunction4 4+Sphincter recovery,mild calf numbnessMRI resolved 223 M58T7leftParaparesis, sensory loss, urinary retention4 5Persistent erectile dysfunctionMRI resolved 174 M77T5leftParaparesis, sensory loss, sphincter dysfunction2 3Improved to ambulation with frame,continued catheterizationDSA resolved. 145 F63T8/T9left/rightParaparesis, sensory loss, back pain3 5 Full recovery MRI resolved 9Abbreviations: yr, year; MRC, Medical Research Council; MRI, magnetic resonance imaging; DSA, digital subtraction angiography.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal94Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case seriesFigure 1. Fig 1: A-B: Lumbar MRI shows extensive edema from thoracic level to conus medullaris(arrow), C: Arrow indicates tortuous vessels on the dorsal spinal cord. D: Preoperative spinal angiography reveals left radiculomedullary artery at L1/2 abnormally draining into perimedullary vein(arrow). E: Open the dura of the spinal canal to expose the target vessel.F: The arterialized vein(arrow) near spinal nerve root and the connecting tortuous peirmedullary vein brightened up immediately after ICG injection. G:After clipping of the arterialized vein, the tortuous perimedullary vein was not enhanced after ICG injection indicating fistula disconnection. H: The fistula was coagulated and transected.
95Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case series第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2Figure 2. Fig 2 A：Thoracic spine MRI scan shows extensive abnormal signals from below the T6 vertebral level to the L1 vertebral level, with abnormal dorsal spinal cord vessels in the corresponding segments. ,B-C: DSA shows the left radiculomedullary artery draining at the T7 level, with tortuous and dilated spinal veins in the T5-T12 segmentsD：Intra-operative image shows the arterialized radiculomedullary vein(arrow) connecting to tortuous perimedullary vein(Orange arrow). E ：Visualization of the DAVF after ICG injection(arrow).F-G: Bipolar electrocoagulation and severance of the fistula vein(arrow).H-I：Postoperative follow-up MRI shows no abnormally dilated veins within the spinal canal.Fig 3:A, B: MRI sagittal scans showing abnormally thickened vascular shadows within the thoracic spinal canal(arrow)., along with spinal cord edema(arrow).C, D: DSA images confirming the presence of a dural
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal96Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case seriesarteriovenous fistula (DAVF). left radiculomedullary artery at T9 abnormally draining into perimedullary vein(arrow). Figure 3. Fig 3:A, B: MRI sagittal scans showing abnormally thickened vascular shadows within the thoracic spinal canal(arrow)., along with spinal cord edema(arrow).C, D: DSA images confirming the presence of a dural arteriovenous fistula (DAVF). left radiculomedullary artery at T9 abnormally draining into perimedullary vein(arrow). Figure 4.
97Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case series第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 24. Illustrative CaseA 63-year-old female presented with a chief complaint of thoracic and back pain, accompanied by sensory numbness and weakness in the lower extremities for 2 years, with progressive worsening over the past month. MRI examination(Fig 3A-B) revealed multiple dilated veins within the thoracic spinal canal, along with swelling of the thoracic spinal cord, suggesting a dural arteriovenous fistula (DAVF). DSA examination(Fig 3C-D) showed visualization of the left radiculomedullary artery at the T9 level, draining into the dorsal veins of the spinal canal, resulting in venous dilation and tortuosity. Following C-arm localization, a posterior midline incision was made at the T8-T10 level. Upon opening the dura, dilated and tortuous veins were observed on the dorsal surface of the spinal cord(Fig 4A-B) Exploration was performed upward and downward along both sides of the spinal cord, but no clear fistula vessel traversing the dura was identified. However, suspected fistulas were noted at the following locations: the left side of the lower edge of the T8 (Fig 4 F,G,H) vertebral body, the right side at the T9 vertebral level (Fig 4 I,G,K), and the lower left side at the T9 vertebral level. (Fig 4 C,D,E,) Temporary occlusion was performed using an aneurysm clip or forceps at each site (Fig 4 D,J). After intravenous injection of ICG, observation under a fluorescence filter microscope showed a reduction in ICG visualization following vascular occlusion. The fistulas were sequentially severed, and subsequent ICG angiography confirmed no visualization of dilated veins on the spinal cord surface (Fig 4 E,H,K).5. DiscussionSpinal DAVFs are the most prevalent spinal vascular anomaly, with a propensity for progressive m y e l o p a t h y i f u n t r e a t e d [ 4 ] . M i c r o s u rg i c a l disconnection of the draining vein offers a high cure rate but hinges on precise localization of the fistulous point [5–7]. ICG video angiography, utilizing a fluorescent dye with peak absorption (805 nm) and emission (835 nm) in the near-infrared spectrum, enables intraoperative visualization of vascular dynamics within seconds of injection [8]. Its pharmacokinetics―intravascular retention, hepatic clearance (half-life 3–4 minutes), and dosing at 0.2–0.5 mg/kg (maximum 5 mg/kg/day)―support repeated administration without radiation exposure, distinguishing it from traditional DSA [9]. In this series, ICG consistently delineated the fistula and confirmed occlusion, correlating with radiographic and clinical success. Advantages include its simplicity, real-time feedback, and ability to reduce spinal cord ischemia risk by expediting intervention [10–11]. Notably, Case 5 required identification of multiple feeding vessels, where repeated ICG injections facilitated precise coagulation, highlighting its adaptability. Limitations include reliance on fluorescence-capable microscopes, potential obscuration by blood or calcifications, and a 15–20-minute interval Fig 4 A: Opening of the dura mater and dilated veins can be seen on the surface of the spinal cord（Arrow）. B: Injection of ICG, Dilated veins on the surface of the spinal cord under a fluorescence filter（Arrow）. C: A suspected fistula is observed on the left side of the spinal cord surface（Arrow）. D: Temporary occlusion the fistula using an aneurysm clip（Arrow）. E: After ICG injection, dilated veins on the spinal cord surface are visualized, but the extent is reduced（Arrow）. F: On the right side of the spinal cord, a suspected fistula is identified（Arrow）. G: After ICG injection, it can be confirmed that the contrast flows from the fistula into the dilated veins（Arrow）. H: After the fistula is severed, the ICG contrast in the dilated veins further decreases（Arrow）. I: A suspected fistula is observed on the lower right side of the spinal cord. （Arrow） N: After ICG injection, the fistula is visualized first. O: The fistula is severed.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal98Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case seriesbetween injections to avoid dye overlap, which may prolong surgery . In complex dural arteriovenous fistulas (DAVFs), lesions often involve multiple feeding arteries (feeders), resulting in highly intricate hemodynamic abnormalities. Both indocyanine green (ICG) and digital subtraction angiography (DSA) offer distinct advantages in managing such lesions, yet each has its limitations. Killory et al.[12] demonstrated that ICG can rapidly identify abnormal vasculature during spinal arteriovenous fistula surgery. In Case 5 of our study, we effectively utilized dynamic ICG changes to identify the culprit vessel, reducing reliance on intraoperative DSA. However, ICG’s resolution is constrained by its imaging depth and fluorescence signal intensity. Particularly in cases with multiple feeders, ICG may fail to clearly distinguish deep vessels or overlapping blood flow pathways. In Case 5, we repeatedly confirmed the sequence of visualization of dilated veins on the spinal cord surface following ICG injection to determine the responsible vessel, which proved to be highly beneficial. Nevertheless, Hoh et al. [13] noted that ICG’s field of view is l imited by the microscope’s exposure range, potentially leading to missed detection of deep or concealed feeding arteries. In contrast, DSA, as the gold standard for preoperative diagnosis and intraoperative assessment, provides high-resolution vascular anatomy and hemodynamic information. Chen et al. [14]reported that DSA can precisely map the feeding arteries, fistula site, and draining veins in complex fistulas, allowing selective angiography to analyze the contribution of each feeder―a capability beyond ICG’s reach. However, DSA’s invasiveness (requiring arterial puncture) and the technical challenge of superselective catheterization during surgery significantly increase operative time and risk. Therefore, in complex fistulas with multiple feeders, ICG is better suited as an intraoperative adjunctive tool, while DSA remains the preferred method for preoperative planning and postoperative verification.Emerging hybrid techniques, such as intra-arterial ICG delivery via DSA catheters, mitigate these drawbacks by enhancing specificity and reducing dye volume. While our findings align with prior reports [3, 8, 11], the small cohort precludes statistical power. Larger, prospective studies are warranted to validate ICG’s role and compare it directly with DSA or embolization.6. Conclusions Intraoperative ICG video angiography is a robust adjunct in the microsurgical management of spinal DAVFs, offering real-time visualization of fistula anatomy and confirmation of shunt obliteration. Its safety, repeatability, and efficacy position it as a valuable tool in spinal vascular surgery, potentially complementing traditional angiography in hybrid settings.Acknowledgments The authors thank the surgical and imaging teams at Kiang Wu Hospital for their support.Disclosures The authors report no conflicts of interest or funding related to this study.References[1] Kr ings T, Geibpraser t S . Spinal dura l a r t e r i o v e n o u s f i s t u l a s . A J N R A m J N e u r o r a d i o l . 2 0 0 9 ; 3 0 ( 4 ) : 6 3 9 – 6 4 8 . doi:10.3174/ajnr.A1485[2] C h i b b a r o S , G o r y B , M a r s e l l a M , e t a l . S u r g i c a l m a n a g e m e n t o f s p i n a l d u r a l a r t e r i o v e n o u s f i s t u l a s . J C l i n Neurosci.2015;22(1):180–183. doi: 10.1016/j.jocn. 2014.07.017[3] Ta k a g i K , K u r i t a H , K a w a g u c h i K , e t a l . Inf luence of indocyanine green angiography on microsurgical treatment of spinal per imedul lary ar ter iovenous fistulas. J Neurosurg Focus. 2016;40(3):E9. doi:10.3171/2015.12.FOCUS15567 [4] Rangel-Castilla A, Benjamin Y, Rosenwasser
99Intraoperative indocyanine green video angiography in the microsurgical management of spinal Dural Arteriovenous Fistulas: a retrospective case series第 12 卷第 2 期 Volume 12 Número 2 Volume 12 Number 2RH, et al. Spinal dural arteriovenous fistula: diagnosis, outcomes, and prognostic factors. World Neurosurg. 2020;144:e306–e315. doi:10.1016/j.wneu.2020.08.155 [5] Dammers R, terBrugge KG, Lasjaunias P, et al. Spinal cord arteriovenous shunts: a review of terminology, classification, and surgical treatment. Acta Neurochir (Wien). 2002;144(8):789–808. doi:10.1007/s00701-002-0973-8 [6] Yang C, Ma Y, Tian A, et al. Long-term outcomes and prognostic factors in patients with t reated spinal dural ar ter iovenous fistulas: a prospective cohort study. BMJ Open. 2022;12(1):e047390. doi:10.1136/bmjopen-2020-047390 [7] Narvid J, Hetts SW, Larsen D, et al. Spinal dural arteriovenous fistulae: clinical features and long- te rm resu l t s . Neurosurge ry. 2 0 0 8 ; 6 2 ( 1 ) : 1 5 9 – 1 6 6 . d o i : 1 0 . 1 2 2 7 / 01.NEU.0000311072.98194.15 [8] Sasak i K , Endo H, Ni izuma K, e t a l . Efficacy of intra-arterial indocyanine green angiography for the microsurgical treatment of dural arteriovenous fistula: a case report. Surg Neurol Int. 2020;11:46. doi:10.25259/SNI_36_2020 [9] Hardesty DA, Thind H, Zabramski JM, et al. Safety, efficacy, and cost of intraoperative indocyanine green angiography compared to intraoperative catheter angiography in cerebral aneurysm surgery. J Clin Neurosci. 2014 ;21 (8 ) :1377–1382 . do i : 10 .1016 /j.jocn.2014.02.006 [10] Chen SF, Kato Y, Oda J, et al. The application of intraoperative near-infrared indocyanine green videoangiography and analysis of fluorescence intensity in cerebrovascular surgery. Surg Neurol Int. 2011;2:42. doi: 10.4103/2152-7806.78261. [11] Colby GP, Coon AL, Sc iubba DM, e t a l . I n t r aope ra t i ve i ndocyan ine g r een v ideoang iog raphy fo r ob l i t e r a t ion o f sp ina l dura l a r t e r iovenous f i s tu las . J Neurosurg Spine. 2009;11(6):705–709. doi:10.3171/2009.7.SPINE09206 [12] Killory BD, Nakaji P, Maughan PH, et al. Evaluation of angiographically occult spinal dural arteriovenous fistulae with surgical microscope-integrated indocyanine green angiography: The role of ICG in spinal DAVF surgery. Journal of Neurosurgery: S p i n e , 2 0 0 9， 1 0 ( 3 ) , 2 4 5 - 2 5 0 . d o i：10.3171/2008.11.SPI08648[13] Hoh BL, Choudhr i TF, Conno l ly ES , e t a l . T h e r o l e o f i n d o c y a n i n e g r e e n v ideoangiography in the management o f s p i n a l v a s c u l a r m a l f o r m a t i o n s . Neurosurgery.2011, 68(2), 436-443.doi：10.1227/NEU.0b013e31820215c2.[14] Chen CJ, Hsu HT, Chen YL. The role o f d ig i t a l sub t rac t ion ang iography in the d iagnos is and t rea tment of sp ina l d u r a l a r t e r i o v e n o u s f i s t u l a s . Wo r l d N e u r o s u r g , 2 0 1 2 , 7 8 ( 5 ) , 5 0 4 - 5 0 9 . doi:10.1016/j.wneu.2011.12.001.
澳門醫學雜誌 Revista Médica de Macau Macao Medical Journal100審 稿 人Revisão de TextoReviewers方慧瑩 王惠儀 丘熹彬 朱依諄朱家康 朱海珊 何衍宙 吳庭輝李慧博 周羨梅 林嘉兒 洪順家胡 皓 徐威傑 翁家權 馬春林高永儉 區德偉 張曉戰 曹亞兵曹美芳 曹曉航 梁逸倫 梁溢貞陳丹梅 陳勝炬 陳嘉明 陳耀華陸美娟 麥秀芝 曾紀寧 游健生湯家耀 馮浩明 黃子秉 黃健星楊金桃 楊曉蔚 葉蔭霆 劉水明劉雁華 劉繼勇 潘 慧 鄭煥勤鄭霆鋒 繆智豐 鍾慶佳 譚文斌譚 蕾排名按中文姓氏筆劃及拉丁字母順序a ordem é feita de acordo com o número dos traços dos apelidos em caracteres chineses e as letras do alfabeto latinoIn the order of the number of strokes of Chinese surnames and alphabetical order
The Macao Medical Journal (MMJ) (ISSN 1608-7801) is a comprehensive medical academic journal organized by the Health Bureau of the Macao SAR Government and published semi-annually, usually in January and July, by the Macao Academy of Medicine. Targeted primarily at medical professionals, all articles and manuscripts published in MMJ have been peer-reviewed to report on scientific research outcomes and clinical experience in the fields of medicine and health. The Journal is available for free access and is downloadable from the websites of the Health Bureau and the Macao Academy of Medicine to facilitate extensive academic exchange. 1. Categories of manuscripts The Journal publishes the following categories of manuscripts: Original clinical studies / researches, review articles / lectures, and short articles / case reports. 2. Guide for submission: (references from “Chinese Medical Journal”) 2.1. Manuscripts. The word count of submitted original clinical studies, discussion and review articles should generally be limited to 5000 (including legends of tables/graphs and references). Short articles and case reviews should not exceed 1500 words (including legends of tables/graphs and references). The process of submission will be entirely by electronic means. Authors are required to send their manuscript (in .doc or .docx format) by e-mail to mmj@ssm.gov.mo, with “Submission_Name of First Author_Manuscript Title” as the subject of the email. For blind review purposes, please do not include any author identification information (e.g. name, affiliations, or contact details) in the manuscript. While image captions may be included in the manuscript, it is recommended not to embed the images in the document, as this may compromise the alignment and resolution of the images. 2.2. Language. To align with international standards and academic purposes, authors are encouraged to produce the full text in English; manuscripts presented in Chinese or Portuguese must have an English abstract (400 words). Traditional Chinese characters should be used if the manuscript is in Chinese. The abstract of an original article must consist of the following four parts: “Objective”, “Methods”, “Results” and “Conclusion”, with each bearing their respective heading; these four parts are not required for abstracts of review articles and case reports. 2.3. Authorship. Authors’ names should be written with the surname capitalized―for example, LIU ZhengQian or Zheng Qian LIU. 2.4. Keywords. Each original article should have 2-5 English keywords, which should be selected as much as possible from the Medical Subject Headings (MeSH) database of the United States National Library of Medicine (NLM). Keywords should be separated by a semicolon (;). The first letter of each English keyword should be capitalized. 2.5. Referencing. References should be cited according to the requirements of "Chinese Medical Journal" GB/T7714-2005 "Regulations for Bibliographic References" and GB 3469-1983 "Document Types and Document Carrier Codes". Articles with Digital Object Identifier (DOI) must list DOI at the end of the reference. Regarding the number of references, monographs, reviews, and lectures are generally limited to 20 or less, and 10 or less for short articles and case reviews. The following are examples of reference format: [1] Lam UP, Lopes Lao EP, Lam KC, Evora M, Wu NQ. Trans-brachial artery access for coronary artery procedures is feasible and safe: data from a single-center in Macau. Chin Med J 2019;132:1478-1481. doi: 10.1097/ CM9.0000000000000274. [ 2 ] 黎旭, 刘兴鹏, 刘⼩慧, 等. 早期他汀药物治疗与非缺⾎性扩张性⼼肌病患者病死 率关系的研究[ J]. 中华医学杂志,2010,90(28):1974-1977. doi: 10.3760/ cma.j.issn.0376-2491.2010.28.009. 3. Declaration A declaration letter should be submitted together with the manuscript to express: 3.1. On the cover/title page: Title of the manuscript, name(s) of all authors (with specification of the corresponding author), as well as their type and no. of identification document, name(s) of affiliation(s), contact telephone number and email address. The order of authorship should be settled prior to the submission of the manuscript, and should not be changed during the editorial process; 3.2. The author(s)’s supervisor(s)/superior(s) is/are aware of the content of the manuscript; 3.3. There is no issue on confidentiality; 3.4. The submission is approved by all authors, and there is no issue on controversy about the name order of authors; 3.5. The manuscript submitted must be original and has not been submitted to any other journals. At the time of submission, authors must disclose details if related papers have been published (including presentations in other languages), or if similar and translated papers are in the process of being published; Macao Medical JournalGuide for Authors 2025
3.6. If the manuscript covers research or work involving human subjects, or if it involves the use of institutional data (such as clinical studies and case reports), it must be accompanied by the approval of the regional/national/institutional ethics committee. 4. Instructions for Submission Authors are responsible for all material presented in the journal. If authors do not receive any feedback one month after receiving an acknowledgement of receipt, it means the manuscript is still under review. Authors should avoid multiple submissions to other journals, and should contact the Editorial Office if they wish to do so. Authors can write to appeal if the manuscript is rejected for publication. Accepted manuscripts may be edited or abridged by the Editorial Office prior to publication. Edited content involving change of the original idea would be referred to the authors for consideration. Authors who fail to return the corrected proof within 14 days will be regarded as having withdrawn the manuscript. The copyright to all published materials is owned by the Macao Medical Journal, whose copyright is owned by the Health Bureau of the Macao SAR Government.5. Contact of Editorial Office Postal address: Editorial Office of “Macao Medical Journal”, 5/F, Administration Building of the Health Bureau, Rua Nova à Guia no. 339, Macao.Tel.: (853)-8390 3253 / (853)-6252 0657E-mail: mmj@ssm.gov.mo
A “Revista Médica de Macau” (ISSN1608-7801) é uma revista académica de medicina abrangente, editada pelos Serviços de Saúde do Governo da RAEM e publicada oficialmente e semestralmente pela Academia Médica de Macau, em geral, em Janeiro e Julho, tendo como principais leitores os profissionais da área de medicina. Todos os artigos publicados na Revista Médica de Macau foram revisados por pares para relatar os resultados da investigação científica e a experiência clínica no âmbito da medicina e da saúde. A Revista está disponível para acesso gratuito e pode ser descarregada na página electrónica dos Serviços de Saúde e da Academia Médica de Macau para facilitar o intercâmbio académico. 1. Categorias dos artigos A Revista publica as seguintes categorias de artigos: Monografias e Estudos, Síntese e Palestras, Artigos Curtos e Relatórios de Casos. 2. Requisitos para submissão (Vide “National Medical Journal of China”e“Chinese Medical Journal”)2.1. Artigos. As monografias, sínteses, etc., geralmente não devem exceder 5000 palavras (incluindo figuras, tabelas e documentos de referência); enquanto os relatórios de casos clínicos, etc., não devem exceder 1500 palavras (incluindo figuras, tabelas e documentos de referência). O processo de submissão é feito de forma electrónica, os autores devem enivar os seus artigos (em formato .doc ou .docx) por e-mail para mmj@ssm.gov.mo, com “Submissão_Nome do Primeiro Autor_Título do Artigo” como assunto do e-mail. A fim de facilitar o processo de revisão anónima, no texto devem ser eliminados os dados de identificação do autor, tais como o nome, a entidade de trabalho ou a forma de contacto; a descrição das imagens pode ser incluída no texto, mas propõe-se que as próprias imagens não sejam incorporadas no documento, no sentido de evitar a confusão ou diminuição de resolução destas imagens.2.2. Linguagem. Para satisfazer as necessidades académicas a nível internacional, propõe-se que o texto seja redigido em língua inglesa. Caso seja publicado em língua chinesa ou portuguesa, o resumo deve ser redigido em língua inglesa (400 palavras). O texto em chinês deve ser redigido em chinês tradicional. O resumo de um artigo original deve ser composto pelas quatro partes: Objectivo, Métodos, Resultados e Conclusão, cada uma com os respectivos títulos. As sínteses e relatórios de casos clínicos não precisam incluir as quatro partes acima. 2.3. Autor. O apelido na romanização do autor deve ser todo escrito em letras maiúsculas, por exemplo: LIU ZhengQian ou Zheng Qian LIU. 2.4. Palavras-chave. Devem ser indicadas 2 a 5 palavras-chave em inglês para a monografia. As palavras-chave devem ser seleccionadas na base de dados de Medical Subject Headings (MeSH) da Biblioteca Nacional de Medicina dos Estados Unidos (The United States National Library of Medicine, NLM) tanto quanto possível, e ser separadas por ponto e vírgula (;). A primeira letra de cada palavra-chave em inglês deve ser maiúscula. 2.5. Referências. As referências devem ser listadas de acordo com GB/T7714-2005 “Descriptive rules for bibliographic references” e GB 3469-1983 “Codes for documentary types and documentary carriers”, exigidos pelo “National Medical Journal of China” , e os artigos com Digital Object Identifier (DOI) devem identificar DOI no final de referência. Em relação ao número de referências das monografias, sínteses e palestras, é limitado a vinte ou menos. Para os relatórios de casos, as referências são limitadas a dez ou menos. O seguinte formato é para referência: [1] Lam UP, Lopes Lao EP, Lam KC, Evora M, Wu NQ. Trans-brachial artery access for coronary artery procedures is feasible and safe: data from a single-center in Macau. Chin Med J 2019;132:1478-1481. doi: 10.1097/ CM9.0000000000000274. [ 2 ] 黎旭, 刘兴鹏, 刘⼩慧, 等. 早期他汀药物治疗与非缺⾎性扩张性⼼肌病患者病死 率关系的研究[ J]. 中华医学杂志,2010,90(28):1974-1977. doi: 10.3760/ cma.j.issn.0376-2491.2010.28.009. 3. Carta de declaraçãoA carta de declaração deve ser enviada juntamente com o artigo, a qual deve incluir:3.1. A primeira página desta carta deve conter as seguintes informações: título do artigo, nomes de todos os autores (com indicação do autor correspondente), tipo e n.º do documento de identificação, nome da instituição onde presta funções, número de telefone e e-mail. A ordem dos autores deve ser determinada antes da submissão do artigo, e não deve ser alterada durante o processo editorial; 3.2. Ter dado conhecimento prévio do conteúdo do artigo aos superiores hierárquicos do autor; 3.3. O artigo não contém matéria confidencial; 3.4. A submissão do artigo deve ter aprovação de todos os autores, e não existe divergência relativamente à ordem dos autores; 3.5. O artigo submetido deve ser original, e nunca ter sido publicado em outras revistas. Se o respectivo artigo já tiver sido publicado (incluindo o mesmo artigo em diferentes línguas), ou se houver algum artigo semelhante em elaboração ou tradução, o autor em causa deve fornecer informações detalhadas no acto de submissão; Normas para Publicação na “Revista Médica de Macau” 2025
3.6. Caso o conteúdo dos artigos envolva o uso de seres humanos como alvo de investigação, ou uso dos dados de instituição (por exemplo, estudos clínicos e relatórios de casos), deve ser acompanhado dos pareceres de aprovação da Comissão de Ética da respectiva instituição, região ou país relacionado. A carta de declaração deve ser enviada juntamente com o artigo, a qual deve incluir: 4. Instruções para submissão Os autores são responsáveis por todos os artigos apresentados na presente revista. Se os autores não receberem nenhuma notificação do processamento do artigo dentro de um mês após o recebimento do recibo, isso significa que o artigo ainda está em revisão. Os autores devem evitar submissões múltiplas para outras publicações periódicas. Se desejarem submeter os artigos para outras publicações periódicas, os autores devem previamente entrar em contacto com a secção editorial. Para os artigos rejeitados, os autores podem apresentar opiniões de forma escrita para efeitos de impugnação. Além disso, os artigos aceitos podem ser editados ou abreviados pela secção editorial antes da publicação. Sempre que o conteúdo editado envolva a mudança da ideia original, é encaminhado aos autores para consideração. Se o artigo revisado não for devolvido no prazo de 14 dias, será considerado como desistência. O direito de autor de todos os artigos publicados pertence à “Revista Médica de Macau”, cujos direitos de autor pertencem aos Serviços de Saúde do Governo da RAEM. 5. Contacto Endereço: Rua Nova à Guia, n.º 339, Edifício da Administração dos Serviços de Saúde, 5.º andar, secção editorial da “Revista Médica de Macau”.Tel: (853) 8390 3253 / (853) 6252 0657 E-mail: mmj@ssm.gov.mo
