1
|
Swaminathan A, Sparrow MP. Perianal Crohn's disease: Still more questions than answers. World J Gastroenterol 2024; 30:4260-4266. [PMID: 39492828 PMCID: PMC11525859 DOI: 10.3748/wjg.v30.i39.4260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/17/2024] [Accepted: 09/23/2024] [Indexed: 10/12/2024] Open
Abstract
In this editorial we comment on the article by Pacheco et al published in a recent issue of the World Journal of Gastroenterology. We focus specifically on the burden of illness associated with perianal fistulizing Crohn's disease (PFCD) and the diagnostic and therapeutic challenges in the management of this condition. Evolving evidence has shifted the diagnostic framework for PFCD from anatomical classification systems, to one that is more nuanced and patient-focused to drive ongoing decision making. This editorial aims to reflect on these aspects to help clinicians face the challenge of PFCD in day-to-day clinical practice.
Collapse
Affiliation(s)
- Akhilesh Swaminathan
- Department of Medicine, University of Otago, Christchurch 8011, Canterbury, New Zealand
- Department of Gastroenterology, Alfred Health, Melbourne 3004, Victoria, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, The Alfred Hospital, Melbourne 3004, Victoria, Australia
- Department of Gastroenterology, Alfred Health and School of Translational Medicine, Monash University, Melbourne 3004, Victoria, Australia
| |
Collapse
|
2
|
Hanna LN, Anandabaskaran S, Iqbal N, Geldof J, LeBlanc JF, Dige A, Lundby L, Vermeire S, D'Hoore A, Verstockt B, Bislenghi G, De Looze D, Lobaton T, Van de Putte D, Spinelli A, Carvello M, Danese S, Buskens CJ, Gecse K, Hompes R, Becker M, van der Bilt J, Bemelman W, Sebastian S, Moran G, Lightner AL, Wong SY, Colombel JF, Cohen BL, Holubar SD, Ding NS, Behrenbruch C, Sahnan K, Misra R, Lung P, Hart A, Tozer P. Perianal Fistulizing Crohn's Disease: Utilizing the TOpClass Classification in Clinical Practice to Provide Targeted Individualized Care. Clin Gastroenterol Hepatol 2024:S1542-3565(24)00692-X. [PMID: 39134293 DOI: 10.1016/j.cgh.2024.06.047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 04/26/2024] [Accepted: 06/11/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND & AIMS Perianal fistulation is a challenging phenotype of Crohn's disease, with significant impact on quality of life. Historically, fistulae have been classified anatomically in relation to the sphincter complex, and management guidelines have been generalized, with lack of attention to the clinical heterogenicity seen. The recent 'TOpClass classification system' for perianal fistulizing Crohn's disease (PFCD) addresses this issue, and classifies patients into defined groups, which provide a focus for fistula management that aligns with disease characteristics and patient goals. In this article, we discuss the clinical applicability of the TOpClass model and provide direction on its use in clinical practice. METHODS An international group of perianal clinicians participated in an expert consensus to define how the TOpClass system can be incorporated into real-life practice. This included gastroenterologists, inflammatory bowel disease surgeons, and radiologists specialized in PFCD. The process was informed by the multi-disciplinary team management of 8 high-volume fistula centres in North America, Europe, and Australia. RESULTS The process produced position statements to accompany the classification system and guide PFCD management. The statements range from the management of patients with quiescent perianal disease to those with severe PFCD requiring diverting-ostomy and/or proctectomy. The optimization of medical therapies, as well as the use of surgery, in fistula closure and symptom management is explored across each classification group. CONCLUSION This article provides an overview of the system's use in clinical practice. It aims to enable clinicians to have a pragmatic and patient goal-centered approach to medical and surgical management options for individual patients with PFCD.
Collapse
Affiliation(s)
- Luke N Hanna
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom; IBD Unit, St Mark's Hospital, London, United Kingdom.
| | - Sulak Anandabaskaran
- Department of Gastroenterology, School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, University of New South Wales, Sydney, Australia
| | - Nusrat Iqbal
- Department of Colorectal Surgery, St Mark's Hospital, London, United Kingdom
| | - Jeroen Geldof
- Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
| | - Jean-Frédéric LeBlanc
- Department of Gastroenterology, Hôpital du Sacré-Coeur de Montréal, Montreal, Canada
| | - Anders Dige
- Department of Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
| | - Lilli Lundby
- Department of Surgery, Pelvic Floor Unit, Aarhus University Hospital, Aarhus, Denmark
| | - Séverine Vermeire
- Department of Gastroenterology, University Hospitals of Leuven, Leuven, Belgium
| | - André D'Hoore
- Department of Abdominal Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Bram Verstockt
- Department of Gastroenterology, University Hospitals of Leuven, Leuven, Belgium
| | - Gabriele Bislenghi
- Department of Abdominal Surgery, University Hospitals of Leuven, Leuven, Belgium
| | - Danny De Looze
- Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
| | - Triana Lobaton
- Department of Gastroenterology, University Hospital Ghent, Ghent, Belgium
| | - Dirk Van de Putte
- Department of Colorectal Surgery, University Hospital Ghent, Ghent, Belgium
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Michele Carvello
- Department of Biomedical Sciences, Humanitas University, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Silvio Danese
- IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Christianne J Buskens
- Department of Colorectal Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Krisztina Gecse
- Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Roel Hompes
- Department of Colorectal Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Marte Becker
- Department of Gastroenterology, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Jarmila van der Bilt
- Department of Colorectal Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Willem Bemelman
- Department of Colorectal Surgery, Amsterdam University Medical Center, Amsterdam, The Netherlands
| | - Shaji Sebastian
- IBD Unit, Hull University Teaching Hospitals, Hull, United Kingdom
| | - Gordan Moran
- Department of Gastroenterology, Nottingham University Hospitals, Nottingham, United Kingdom
| | - Amy L Lightner
- Department of Colorectal Surgery, Scripps Clinic, San Diego, California
| | - Serre-Yu Wong
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jean-Frédéric Colombel
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Benjamin L Cohen
- Department of Gastroenterology, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Stefan D Holubar
- Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio
| | - Nik S Ding
- Department of Gastroenterology, St Vincent's Hospital, Melbourne, Australia
| | - Corina Behrenbruch
- Department of Colorectal Surgery, St Vincent's Hospital, Melbourne, Australia
| | - Kapil Sahnan
- Department of Colorectal Surgery, St Mark's Hospital, London, United Kingdom
| | - Ravi Misra
- IBD Unit, St Mark's Hospital, London, United Kingdom
| | - Phillip Lung
- Department of Radiology, St Mark's Hospital, London, United Kingdom
| | - Ailsa Hart
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom; IBD Unit, St Mark's Hospital, London, United Kingdom
| | - Phil Tozer
- Department of Colorectal Surgery, St Mark's Hospital, London, United Kingdom
| |
Collapse
|
3
|
Kim ES, Choi S, Choe BH, Park S, Lee YJ, Sohn SJ, Kim SC, Kang KS, Lee K, Shim JO, Kim YB, Hong SJ, Lee YM, Kim HJ, Choi SY, Kim JY, Lee Y, Park JS, Kim JY, Yi DY, Lee JH, Choi KH, Jang HJ, Jeong IS, Kang B. Comparison of endoscopic healing and durability between infliximab originator and CT-P13 in pediatric patients with inflammatory bowel disease. Front Immunol 2024; 15:1284181. [PMID: 38455036 PMCID: PMC10917915 DOI: 10.3389/fimmu.2024.1284181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 01/25/2024] [Indexed: 03/09/2024] Open
Abstract
Background and aims Favourable clinical data were published on the efficacy of CT-P13, the first biosimilar of infliximab (IFX), in pediatric inflammatory bowel disease (IBD); however, few studies have compared the effect on endoscopic healing (EH) and drug retention rate between the IFX originator and CT-P13. Therefore, we aimed to compare EH and the drug retention rate between the IFX originator and CT-P13. Methods Children with Crohn's disease (CD) and ulcerative colitis (UC)/IBD-unclassified (IBD-U) at 22 medical centers were enrolled, with a retrospective review conducted at 1-year and last follow-up. Clinical remission, EH and drug retention rate were evaluated. Results We studied 416 pediatric patients with IBD: 77.4% had CD and 22.6% had UC/IBD-U. Among them, 255 (61.3%) received the IFX originator and 161 (38.7%) received CT-P13. No statistically significant differences were found between the IFX originator and CT-P13 in terms of corticosteroid-free remission and adverse events. At 1-year follow-up, EH rates were comparable between them (CD: P=0.902, UC: P=0.860). The estimated cumulative cessation rates were not significantly different between the two groups. In patients with CD, the drug retention rates were 66.1% in the IFX originator and 71.6% in the CT-P13 group at the maximum follow-up period (P >0.05). In patients with UC, the drug retention rates were 49.8% in the IFX originator and 56.3% in the CT-P13 group at the maximum follow-up period (P >0.05). Conclusions The IFX originator and CT-P13 demonstrated comparable therapeutic response including EH, clinical remission, drug retention rate and safety in pediatric IBD.
Collapse
Affiliation(s)
- Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sujin Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
| | - Sowon Park
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Yonsei University College of Medicine, Severance Children’s Hospital, Seoul, Republic of Korea
| | - Yeoun Joo Lee
- Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Sang Jun Sohn
- Department of Pediatrics, Pusan National University Children’s Hospital, Pusan National University School of Medicine, Yangsan, Republic of Korea
| | - Soon Chul Kim
- Department of Pediatrics, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Ki Soo Kang
- Department of Pediatrics, Jeju National University Hospital, Jeju, Republic of Korea
| | - Kunsong Lee
- Department of Pediatrics, Dankook University College of Medicine, Cheonan, Republic of Korea
| | - Jung Ok Shim
- Department of Pediatrics, Korea University College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea
| | - Yu Bin Kim
- Department of Pediatrics, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Suk Jin Hong
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
- Department of Pediatrics, Daegu Catholic University School of Medicine, Daegu, Republic of Korea
| | - Yoo Min Lee
- Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea
| | - Hyun Jin Kim
- Department of Pediatrics, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - So Yoon Choi
- Department of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Republic of Korea
| | - Ju Young Kim
- Department of Pediatrics, Daejeon Eulji Medical Center, Eulji University, Daejeon, Republic of Korea
| | - Yoon Lee
- Department of Pediatrics, Korea University Medical Center Anam Hospital, Seoul, Republic of Korea
| | - Ji-Sook Park
- Department of Pediatrics, Gyeongsang National University College of Medicine, Jinju, Republic of Korea
- Institute of Medical Science, Gyeongsang National University, Jinju, Republic of Korea
| | - Jae Young Kim
- Department of Pediatrics, Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea
| | - Dae Yong Yi
- Department of Pediatrics, Chung-Ang University Hospital, Chung-Ang University, College of Medicine, Seoul, Republic of Korea
| | - Ji Hyuk Lee
- Department of Pediatrics, Chungbuk National University College of Medicine, Chungju, Republic of Korea
| | - Kwang-Hae Choi
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
- Department of Pediatrics, Yeungnam University School of Medicine, Daegu, Republic of Korea
| | - Hyo-Jeong Jang
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
- Department of Pediatrics, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - In Sook Jeong
- Department of Pediatrics, Chung-Ang University, Gwangmyeong Hospital, Gwangmyeong, Republic of Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Republic of Korea
| |
Collapse
|
4
|
Cao D, Qian K, Zhao Y, Hong J, Chen H, Wang X, Yang N, Zhang C, Cao J, Jia K, Wu G, Zhu M, Shen J, Zhang Y, Cui Z, Wang Z. Association of neutrophil extracellular traps with fistula healing in patients with complex perianal fistulising Crohn's disease. J Crohns Colitis 2022; 17:580-592. [PMID: 36322703 DOI: 10.1093/ecco-jcc/jjac171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Perianal fistulising Crohn's disease (pfCD) is a disabling phenotype of Crohn's disease (CD) with suboptimal outcomes. We assessed neutrophil extracellular traps (NETs) in perianal fistulas and implicated their roles in pfCD healing. METHODS Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy, and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NETs components, including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3), were identified using immunofluorescence. Serum infliximab (IFX), anti-IFX antibodies, and tissue levels of IFX, adalimumab (ADA), MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV (PAD4), tumour necrosis factor (TNF)-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with qPCR. RESULTS Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-seq revealed difference in neutrophil associated pathways between unhealed and healed fistulas. NETs components (MPO/NE/CitH3) were detectable in the fistulas and were parallel with the PAD4 levels. Eleven of 21 (52%) patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. CONCLUSIONS NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.
Collapse
Affiliation(s)
- Dongxing Cao
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Keyu Qian
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Ying Zhao
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive Disease; Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200001, China
| | - Jie Hong
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive Disease; Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200001, China
| | - Haoyan Chen
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology; Shanghai Cancer Institute; Shanghai Institute of Digestive Disease; Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine. Shanghai 200001, China
| | - Xiaohui Wang
- Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Nailin Yang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Cheng Zhang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jingkai Cao
- Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Keyu Jia
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Guangyu Wu
- Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Mingming Zhu
- Division of Gastroenterology and Hepatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jun Shen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, Ren Ji Hospital, School of Medicine, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University, Shanghai, China
| | - Ye Zhang
- Laboratory of Medicine, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200444, China
| | - Zhe Cui
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China; Department of General Surgery, Baoshan Branch, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.1058, Huan Zhen Bei Rd, Baoshan District, Shanghai 200444, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| |
Collapse
|
5
|
Wetwittayakhlang P, Al Khoury A, Hahn GD, Lakatos PL. The Optimal Management of Fistulizing Crohn's Disease: Evidence beyond Randomized Clinical Trials. J Clin Med 2022; 11:3045. [PMID: 35683433 PMCID: PMC9181669 DOI: 10.3390/jcm11113045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 05/21/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Fistulizing Crohn's disease (FCD) remains the most challenging aspect of treating patients with CD. FCD can occur in up to 30% of patients with CD and may lead to significant disability and impaired quality of life. The optimal treatment strategies for FCD require a multidisciplinary approach, including a combined medical and surgical approach. The therapeutic options for FCD are limited due to sparse evidence from randomized clinical trials (RCTs). The current recommendations are mainly based on post hoc analysis from RCTs, real-world clinical studies and expert opinion. There is variation in everyday clinical practice amongst gastroenterologists and surgeons. The evidence for anti-tumor necrosis factor therapy is the strongest in the treatment of FCD. However, long-term fistula healing can be achieved in only 30-50% of patients. In recent years, emerging data in the advent of therapeutic modalities, including the use of new biologic agents, therapeutic drug monitoring, novel surgical methods and mesenchymal stem cell therapy, have been shown to improve outcomes in achieving fistula healing. This review summarizes the existing literature on current and emerging therapies to provide guidance beyond RCTs in managing FCD.
Collapse
Affiliation(s)
- Panu Wetwittayakhlang
- Division of Gastroenterology, McGill University Health Center, Montreal, QC H3G 1A4, Canada or (P.W.); (G.D.H.)
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla 90110, Thailand
| | - Alex Al Khoury
- Division of Gastroenterology, University of Florida, Jacksonville, FL 32209, USA;
| | - Gustavo Drügg Hahn
- Division of Gastroenterology, McGill University Health Center, Montreal, QC H3G 1A4, Canada or (P.W.); (G.D.H.)
- Graduate Course Sciences in Gastroenterology and Hepatology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre 90035-002, Brazil
| | - Peter Laszlo Lakatos
- Division of Gastroenterology, McGill University Health Center, Montreal, QC H3G 1A4, Canada or (P.W.); (G.D.H.)
- First Department of Medicine, Semmelweis University, 1085 Budapest, Hungary
| |
Collapse
|