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1
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Chandra P, Sacks GD. Contemporary Surgical Management of Colorectal Liver Metastases. Cancers (Basel) 2024; 16:941. [PMID: 38473303 DOI: 10.3390/cancers16050941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
Colorectal cancer is the third most common cancer in the United States and the second most common cause of cancer-related death. Approximately 20-30% of patients will develop hepatic metastasis in the form of synchronous or metachronous disease. The treatment of colorectal liver metastasis (CRLM) has evolved into a multidisciplinary approach, with chemotherapy and a variety of locoregional treatments, such as ablation and portal vein embolization, playing a crucial role. However, resection remains a core tenet of management, serving as the gold standard for a curative-intent therapy. As such, the input of a dedicated hepatobiliary surgeon is paramount for appropriate patient selection and choice of surgical approach, as significant advances in the field have made management decisions extremely nuanced and complex. We herein aim to review the contemporary surgical management of colorectal liver metastasis with respect to both perioperative and operative considerations.
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Affiliation(s)
- Pratik Chandra
- Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Greg D Sacks
- Department of Surgery, NYU Grossman School of Medicine, New York, NY 10016, USA
- VA New York Harbor Healthcare System, New York, NY 10010, USA
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2
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Tatsumi K, Wada H, Hasegawa S, Asukai K, Nagata S, Ekawa T, Akazawa T, Mizote Y, Okumura S, Okamura R, Ohue M, Obama K, Tahara H. Prediction for oxaliplatin-induced liver injury using patient-derived liver organoids. Cancer Med 2024; 13:e7042. [PMID: 38400666 PMCID: PMC10891453 DOI: 10.1002/cam4.7042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 01/22/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND Liver injury associated with oxaliplatin (L-OHP)-based chemotherapy can significantly impact the treatment outcomes of patients with colorectal cancer liver metastases, especially when combined with surgery. To date, no definitive biomarker that can predict the risk of liver injury has been identified. This study aimed to investigate whether organoids can be used as tools to predict the risk of liver injury. METHODS We examined the relationship between the clinical signs of L-OHP-induced liver injury and the responses of patient-derived liver organoids in vitro. Organoids were established from noncancerous liver tissues obtained from 10 patients who underwent L-OHP-based chemotherapy and hepatectomy for colorectal cancer. RESULTS Organoids cultured in a galactose differentiation medium, which can activate the mitochondria of organoids, showed sensitivity to L-OHP cytotoxicity, which was significantly related to clinical liver toxicity induced by L-OHP treatment. Organoids from patients who presented with a high-grade liver injury to the L-OHP regimen showed an obvious increase in mitochondrial superoxide levels and a significant decrease in mitochondrial membrane potential with L-OHP exposure. L-OHP-induced mitochondrial oxidative stress was not observed in the organoids from patients with low-grade liver injury. CONCLUSIONS These results suggested that L-OHP-induced liver injury may be caused by mitochondrial oxidative damage. Furthermore, patient-derived liver organoids may be used to assess susceptibility to L-OHP-induced liver injury in individual patients.
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Affiliation(s)
- Kumiko Tatsumi
- Department of Cancer Drug Discovery and Development, Research CenterOsaka International Cancer InstituteOsakaJapan
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hiroshi Wada
- Department of Gastroenterological SurgeryOsaka International Cancer InstituteOsakaJapan
| | - Shinichiro Hasegawa
- Department of Gastroenterological SurgeryOsaka International Cancer InstituteOsakaJapan
| | - Kei Asukai
- Department of Gastroenterological SurgeryOsaka International Cancer InstituteOsakaJapan
| | - Shigenori Nagata
- Department of Diagnostic Pathology and CytologyOsaka International Cancer InstituteOsakaJapan
| | - Tomoya Ekawa
- Department of Cancer Drug Discovery and Development, Research CenterOsaka International Cancer InstituteOsakaJapan
| | - Takashi Akazawa
- Department of Cancer Drug Discovery and Development, Research CenterOsaka International Cancer InstituteOsakaJapan
| | - Yu Mizote
- Department of Cancer Drug Discovery and Development, Research CenterOsaka International Cancer InstituteOsakaJapan
| | - Shintaro Okumura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Ryosuke Okamura
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Masayuki Ohue
- Department of Gastroenterological SurgeryOsaka International Cancer InstituteOsakaJapan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Hideaki Tahara
- Department of Cancer Drug Discovery and Development, Research CenterOsaka International Cancer InstituteOsakaJapan
- Project Division of Cancer Biomolecular TherapyThe Institute of Medical Science, The University of TokyoTokyoJapan
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3
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Filoni E, Musci V, Di Rito A, Inchingolo R, Memeo R, Mannavola F. Multimodal Management of Colorectal Liver Metastases: State of the Art. Oncol Rev 2024; 17:11799. [PMID: 38239856 PMCID: PMC10794467 DOI: 10.3389/or.2023.11799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024] Open
Abstract
Liver is the most common site of colorectal cancer (CRC) metastases. Treatment of CRC liver metastases (CRLM) includes different strategies, prevalently based on the clinical and oncological intent. Valid approaches in liver-limited or liver-prevalent disease include surgery, percutaneous ablative procedures (radiofrequency ablation, microwave ablation), intra-arterial perfusional techniques (chemo-embolization, radio-embolization) as well as stereotactic radiotherapy. Systemic treatments, including chemotherapy, immunotherapy and other biological agents, are the only options for patients with no chance of locoregional approaches. The use of chemotherapy in other settings, such as neoadjuvant, adjuvant or conversion therapy of CRLM, is commonly accepted in the clinical practice, although data from several clinical trials have been mostly inconclusive. The optimal integration of all these strategies, when applicable and clinically indicated, should be ever considered in patients affected by CRLM based on clinical evidence and multidisciplinary experience. Here we revised in detail all the possible therapeutic approaches of CRLM focusing on the current evidences, the studies still in progress and the often contradictory data.
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Affiliation(s)
- Elisabetta Filoni
- Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Vittoria Musci
- Interdisciplinary Department of Medicine, University of Bari “Aldo Moro”, Bari, Italy
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
| | - Alessia Di Rito
- Radiotherapy Unit, P.O. “Mons A.R. Dimiccoli”, Barletta, Italy
| | - Riccardo Inchingolo
- Unit of Interventional Radiology, “F. Miulli” General Regional Hospital, Acquaviva delle Fonti, Italy
| | - Riccardo Memeo
- Unit of Hepato-Pancreatic-Biliary Surgery, “F. Miulli” General Regional Hospital, Acquaviva delle Fonti, Italy
| | - Francesco Mannavola
- Division of Medical Oncology, A.O.U. Consorziale Policlinico di Bari, Bari, Italy
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4
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Gupta V, Chopde A, Patkar S, Deodhar K, Goel M. Oxaliplatin-Induced Sinusoidal Obstruction Syndrome Masquerading as Colorectal Liver Metastasis: A Case Report. J Gastrointest Cancer 2023; 54:682-686. [PMID: 35666356 DOI: 10.1007/s12029-022-00835-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Oxaliplatin-based chemotherapy is commonly used in adjuvant treatment of colon cancer as well as in neoadjuvant setting in patients with liver metastases. However oxaliplatin can cause damage to non-tumor bearing liver which presents as sinusoidal obstructive syndrome (SOS). These changes are difficult to differentiate from metastasis clinic-radiologically and manifests as sinusoidal dilatation, peliosis and nodular regenerative hyperplasia. CASE The present study reports the case of a patient with oxaliplatin-induced SOS which mimicked colo-rectal liver metastasis on follow up imaging studies after receiving neoadjuvant oxaliplatin based chemotherapy. After multidisciplinary discussion, patient was planned for simultaneous resection of rectal primary and right hepatectomy for metastasis. Final histopathology revealed no tumour in liver but the liver lesions seen radiologically were actually changes of oxaliplatin induced focal SOS and mimicked metastatic nodules. CONCLUSION In patients with colo-rectal cancer having received oxaliplatin-based chemotherapy, SOS may be considered as one of the causes of newly developed liver lesions, and should be subjected to additional radio-pathologic evaluation to prevent overtreatment and avoiding potentially morbid surgeries.
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Affiliation(s)
- Vipul Gupta
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Ernest Borges Road, Parel, Mumbai, 400012, India
| | - Amit Chopde
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Ernest Borges Road, Parel, Mumbai, 400012, India
| | - Shraddha Patkar
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Ernest Borges Road, Parel, Mumbai, 400012, India.
| | - Kedar Deodhar
- Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Mahesh Goel
- Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Ernest Borges Road, Parel, Mumbai, 400012, India
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Baldin P, Carrasco J, Beniuga G, Jouret-Mourin A, Demolin G, Roland S, D’Hondt L, Vergauwe P, Van Daele D, Mailleux M, Sinapi I, De Cuyper A, Blétard N, Massart B, Delos M, Castella ML, van Maanen A, Van den Eynde M. Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial). Cancers (Basel) 2022; 14:cancers14051183. [PMID: 35267491 PMCID: PMC8909786 DOI: 10.3390/cancers14051183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/11/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023] Open
Abstract
Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.
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Affiliation(s)
- Pamela Baldin
- Pathology Department, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium; (P.B.); (A.J.-M.)
| | - Javier Carrasco
- Department of Medical Oncology, GHdC-Grad Hopital de Charleroi-Site Notre Dame, 6000 Charleroi, Belgium; (J.C.); (I.S.)
| | - Gabriela Beniuga
- Pathology Department, Institut de Pathologie et Génétique, 6041 Gosselies, Belgium;
| | - Anne Jouret-Mourin
- Pathology Department, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium; (P.B.); (A.J.-M.)
- Pathology Department, Institut de Pathologie et Génétique, 6041 Gosselies, Belgium;
| | - Gauthier Demolin
- Gastroenterology Department, Clinique CHC MonLégia, 4000 Liège, Belgium;
| | - Sandrine Roland
- Gastroenterology Department, CHIREC-Hôpital Delta, 1160 Auderghem, Belgium;
| | - Lionel D’Hondt
- Oncology Department, CHU-UCL-Namur, Site Godinne, 5530 Yvoir, Belgium;
| | - Philippe Vergauwe
- Gastroenterology Department, AZ Groeninge Hospital, 3220 Kortrijk, Belgium;
| | | | - Marie Mailleux
- Medical Oncology, Clinique Saint-Luc Bouge, 5000 Namur, Belgium;
| | - Isabelle Sinapi
- Department of Medical Oncology, GHdC-Grad Hopital de Charleroi-Site Notre Dame, 6000 Charleroi, Belgium; (J.C.); (I.S.)
| | - Astrid De Cuyper
- Department of Medical Oncology, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium;
| | - Noëlla Blétard
- Pathology Department, Clinique CHC MonLégia, 4000 Liège, Belgium; (N.B.); (B.M.)
| | - Brigitte Massart
- Pathology Department, Clinique CHC MonLégia, 4000 Liège, Belgium; (N.B.); (B.M.)
| | - Monique Delos
- Pathology Department, CHU-UCL-Namur, Site Godinne, 5530 Yvoir, Belgium;
| | - Marie-Laure Castella
- Colorectal Clinical Research Unit, Institut Roi Albert II, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium;
| | - Aline van Maanen
- Support Statistique, Institut Roi Albert II, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium;
| | - Marc Van den Eynde
- Department of Medical Oncology and Gastroenterology, Cliniques Universitaires Saint Luc (UCL)—Université Catholique de Louvain, 1200 Bruxelles, Belgium
- Correspondence:
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Han J, Zhang J, Zhang C. Irinotecan-Induced Steatohepatitis: Current Insights. Front Oncol 2021; 11:754891. [PMID: 34707997 PMCID: PMC8542761 DOI: 10.3389/fonc.2021.754891] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 09/23/2021] [Indexed: 01/14/2023] Open
Abstract
The hepatotoxicity of irinotecan is drawing wide concern nowadays due to the widespread use of this chemotherapeutic against various solid tumors, particularly metastatic colorectal cancer. Irinotecan-induced hepatotoxicity mainly manifests as transaminase increase and steatosis with or without transaminase increase, and is accompanied by vacuolization, and lobular inflammation. Irinotecan-induced steatohepatitis (IIS) increases the risk of morbidity and mortality in patients with colorectal cancer liver metastasis (CRCLM). The major risks and predisposing factors for IIS include high body mass index (BMI) or obesity, diabetes, and high-fat diet. Mitochondrial dysfunction and autophagy impairment may be involved in the pathogenesis of IIS. However, there is currently no effective preventive or therapeutic treatment for this condition. Thus, the precise mechanisms underlying the pathogenesis of IIS should be deciphered for the development of therapeutic drugs. This review summarizes the current knowledge and research progress on IIS.
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Affiliation(s)
- Jun Han
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Department of Pharmacy, Affiliated Hospital of Jianghan University, Wuhan, China
| | | | - Chengliang Zhang
- Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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8
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Vigano L, Sollini M, Ieva F, Fiz F, Torzilli G. Chemotherapy-Associated Liver Injuries: Unmet Needs and New Insights for Surgical Oncologists. Ann Surg Oncol 2021; 28:4074-4079. [PMID: 33929618 DOI: 10.1245/s10434-021-10069-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 04/14/2021] [Indexed: 12/15/2022]
Affiliation(s)
- Luca Vigano
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. .,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.
| | - Martina Sollini
- Department of Nuclear Medicine, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Francesca Ieva
- MOX laboratory, Department of Mathematics, Politecnico di Milano, Milan, Italy.,CADS - Center for Analysis, Decisions and Society, Human Technopole, Milan, Italy
| | - Francesco Fiz
- Department of Nuclear Medicine, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Guido Torzilli
- Division of Hepatobiliary and General Surgery, Department of Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
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9
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Lemos BB, Motta KPD, Paltian JJ, Reis AS, Blödorn GB, Soares MP, Alves D, Luchese C, Wilhelm EA. Role of 7-chloro-4-(phenylselanyl) quinoline in the treatment of oxaliplatin-induced hepatic toxicity in mice. Can J Physiol Pharmacol 2021; 99:378-388. [PMID: 32810410 DOI: 10.1139/cjpp-2020-0134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
There is an increasing incidence of hepatotoxicity induced by oxaliplatin (OXA); therefore, researchers' attention has been drawn to therapeutic alternatives that may decrease OXA-induced hepatotoxicity. Studies indicate that oxidative stress plays a major role in OXA-induced liver injury. As several pharmacological effects of 7-chloro-4-(phenylselanyl) quinole (4-PSQ) involve its antioxidant action, the hypothesis that this organoselenium compound could be promising for the treatment or prevention of hepatotoxicity induced by treatment with OXA was investigated. To test this hypothesis, male Swiss mice received OXA (10 mg·kg-1) on days 0 and 2, followed by oral administration of 4-PSQ (1 mg·kg-1) on days 2 to 14. 4-PSQ reduced the plasma aspartate, and alanine aminotransferase activity increased by exposure to OXA. The histopathological examination of the liver showed that 4-PSQ markedly improved OXA-induced hepatic injury. In addition, treatment with 4-PSQ reduced the oxidation of lipids and proteins (thiobarbituric acid reactive species levels and protein carbonyl content) and attenuated the increase of hepatic catalase and glutathione peroxidase activity caused by OXA. The inhibition of hepatic δ-aminolevulinic dehydratase activity induced by OXA was reverted by 4-PSQ. In conclusion, results indicate that 4-PSQ may be a good therapeutic strategy for attenuating OXA-induced liver damage.
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Affiliation(s)
- Briana B Lemos
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
- Curso de Bacharelado em Química Forense, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Pelotas, 96010-900, RS, Brazil
| | - Ketlyn P da Motta
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
- Curso de Bacharelado em Química Forense, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Pelotas, 96010-900, RS, Brazil
| | - Jaini J Paltian
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
| | - Angélica S Reis
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
| | - Gustavo B Blödorn
- Laboratório de Síntese Orgânica Limpa (LASOL), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
| | - Mauro P Soares
- Laboratório Regional de Diagnóstico Faculdade de Veterinária, Universidade Federal de Pelotas (UFPel), Pelotas, 96010-900, RS, Brazil
| | - Diego Alves
- Laboratório de Síntese Orgânica Limpa (LASOL), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
| | - Cristiane Luchese
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
| | - Ethel A Wilhelm
- Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), P.O. Box 354, Pelotas, 96010-900, RS, Brazil
- Curso de Bacharelado em Química Forense, Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), Pelotas, 96010-900, RS, Brazil
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10
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Baldin P, Van den Eynde M, Mlecnik B, Bindea G, Beniuga G, Carrasco J, Haicheur N, Marliot F, Lafontaine L, Fredriksen T, Lanthier N, Hubert C, Navez B, Huyghe N, Pagès F, Jouret‐Mourin A, Galon J, Komuta M. Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore. J Pathol Clin Res 2021; 7:27-41. [PMID: 32902189 PMCID: PMC7737782 DOI: 10.1002/cjp2.178] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 05/24/2020] [Accepted: 07/10/2020] [Indexed: 12/11/2022]
Abstract
Surgical resection of colorectal liver metastases combined with systemic treatment aims to maximize patient survival. However, recurrence rates are very high postsurgery. In order to assess patient prognosis after metastasis resection, we evaluated the main patho-molecular and immune parameters of all surgical specimens. Two hundred twenty-one patients who underwent, after different preoperative treatment, curative resection of 582 metastases were analyzed. Clinicopathological parameters, RAS tumor mutation, and the consensus Immunoscore (I) were assessed for all patients. Overall survival (OS) and time to relapse (TTR) were estimated using the Kaplan-Meier method and compared by log-rank tests. Cox proportional hazard models were used for uni- and multivariate analysis. Immunoscore and clinicopathological parameters (number of metastases, surgical margin, histopathological growth pattern, and steatohepatitis) were associated with relapse in multivariate analysis. Overall, pathological score (PS) that combines relevant clinicopathological factors for relapse, and I, were prognostic for TTR (2-year TTR rate PS 0-1: 49.8.% (95% CI: 42.2-58.8) versus PS 2-4: 20.9% (95% CI: 13.4-32.8), hazard ratio (HR) = 2.54 (95% CI: 1.82-3.53), p < 0.0000; and 2-year TTR rate I 0: 25.7% (95% CI: 16.3-40.5) versus I 3-4: 60% (95% CI: 47.2-76.3), HR = 2.87 (95% CI: 1.73-4.75), p = 0.0000). Immunoscore was also prognostic for OS (HR [I 3-4 versus I 0] = 4.25, 95% CI: 1.95-9.23; p = 0.0001). Immunoscore (HR [I 3-4 versus I 0] = 0.27, 95% CI: 0.12-0.58; p = 0.0009) and RAS mutation (HR [mutated versus WT] = 1.66, 95% CI: 1.06-2.58; p = 0.0265) were significant for OS. In conclusion, PS including relevant clinicopathological parameters and Immunoscore permit stratification of stage IV colorectal cancer patient prognosis in terms of TTR and identify patients with higher risk of recurrence. Immunoscore remains the major prognostic factor for OS.
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Affiliation(s)
- Pamela Baldin
- Department of PathologyCliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Marc Van den Eynde
- Department of Medical Oncology and Hepato‐GastroenterologyCliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Bernhard Mlecnik
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
- InovarionParisFrance
| | - Gabriela Bindea
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Gabriela Beniuga
- Department of PathologyInstitute of Pathology and Genetics (IPG)CharleroiBelgium
| | - Javier Carrasco
- Department of Medical OncologyGrand Hzal de Charleroi (GHdC)CharleroiBelgium
| | - Nacilla Haicheur
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Florence Marliot
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Lucie Lafontaine
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Tessa Fredriksen
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Nicolas Lanthier
- Department of Hepato‐GastroenterologyInstitut Roi Albert II, Cliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Catherine Hubert
- Hepatobiliary Surgery Unit, Department of Abdominal Surgery and TransplantationInstitut Roi Albert II, Cliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Benoît Navez
- Hepatobiliary Surgery Unit, Department of Abdominal Surgery and TransplantationInstitut Roi Albert II, Cliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Nicolas Huyghe
- Institut de Recherche Clinique et Expérimentale (Pole MIRO)Institut Roi Albert II, Cliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Franck Pagès
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
- InovarionParisFrance
| | - Anne Jouret‐Mourin
- Department of PathologyCliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
| | - Jérôme Galon
- INSERM, Laboratory of Integrative Cancer ImmunologySorbonne Université, Université de Paris, Equipe labellisée Ligue Contre le Cancer, Centre de Recherche des CordeliersParisFrance
| | - Mina Komuta
- Department of PathologyCliniques Universitaires Saint‐Luc/Université Catholique de Louvain (UCLouvain)BrusselsBelgium
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11
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Shaikh S. Editorial for "T1 Mapping on Gd-EOB-DTPA-Enhanced MRI for the Prediction of Oxaliplatin-Induced Liver Injury in a Mouse Model". J Magn Reson Imaging 2020; 53:903-904. [PMID: 33314447 DOI: 10.1002/jmri.27465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 11/09/2022] Open
Affiliation(s)
- Sikandar Shaikh
- Consultant PET-CT and Radiology, Yashoda Hospitals, Somajiguda, Hyderabad, India.,Assistant Professor, Department of Radiology, Shadan Institute of Medical Sciences, Hyderabad, India.,Adjunct Assistant Professor. Department of Biomedical Engineering, Indian Institute of Technology, Hyderabad, India
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12
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Parmar KL, O'Reilly D, Valle JW, Braun M, Naish JH, Williams SR, Lloyd WK, Malcomson L, Cresswell K, Bamford C, Renehan AG. Prospective study of change in liver function and fat in patients with colorectal liver metastases undergoing preoperative chemotherapy: protocol for the CLiFF Study. BMJ Open 2020; 10:e027630. [PMID: 32967864 PMCID: PMC7513559 DOI: 10.1136/bmjopen-2018-027630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Preoperative chemotherapy in patients undergoing resection for colorectal liver metastases (CLM) improves oncological outcomes. However, chemotherapy-associated liver injury (occurring in two patterns: vascular and fat deposition) is a real clinical concern prior to hepatic resection. After major liver resection, regeneration of the residual liver is a prerequisite for recovery and avoidance of liver failure, but this regenerative capacity may be hindered by chemotherapy. Thus, there is a need to predict for this serious complication. Over the past two decades, several tests and derived indices have been developed, which have failed to achieve clinical utility, mainly as they were indirect measurements of liver function. Here, we will use a novel test of liver function (the liver maximum capacity (LiMAx) test), and measure liver fat using MRI. METHODS AND ANALYSIS This prospective study will assess changes in liver function longitudinally, measured by the LiMAx test, and liver fat, measured by advanced MRI using both MR spectroscopy and the modified Dixon method, in up to 35 patients undergoing preoperative chemotherapy for CLM. The primary outcomes will be the changes in liver function and fat compared with baseline prechemotherapy measurements. Secondary outcome measures include: routinely measured liver function blood tests, anthropometric measurements, postoperative histology and digital quantification of fat, postoperative complications and mortality and quality of life. ETHICS AND DISSEMINATION The study was approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences and the National Institute for Health Research network. Manuscripts will be published. TRIAL REGISTRATION NUMBER This study is registered online at www.clinicaltrials.gov (registration number NCT03562234).
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Affiliation(s)
- Kat L Parmar
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester Cancer Research Centre, Manchester, UK
| | - Derek O'Reilly
- Hepatobiliary Surgery, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Juan W Valle
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Oncology, Christie NHS Foundation Trust, Manchester, UK
| | - Michael Braun
- Oncology, Christie NHS Foundation Trust, Manchester, UK
| | - Jo H Naish
- Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | - Steve R Williams
- Centre for Imaging Sciences, University of Manchester, Manchester, UK
| | - William K Lloyd
- Centre for Imaging Sciences, University of Manchester, Manchester, UK
| | - Lee Malcomson
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Surgery, Christie NHS Foundation Trust, Manchester, UK
| | - Katharine Cresswell
- Public Programmes Team, Research and Innovation Division, Manchester University NHS Foundation Trust, Manchester, UK
| | - Colin Bamford
- Cancer Patient and Public Advisory Group, NIHR Manchester Biomedical Research Centre, Manchester, UK
| | - Andrew G Renehan
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Surgery, Christie NHS Foundation Trust, Manchester, UK
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13
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Larrey D, Meunier L, Valla D, Hillaire S, Hernandez-Gea V, Dutheil D, Plessier A, Bureau C. Drug induced liver injury and vascular liver disease. Clin Res Hepatol Gastroenterol 2020; 44:471-479. [PMID: 32371005 DOI: 10.1016/j.clinre.2020.03.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Accepted: 03/03/2020] [Indexed: 02/04/2023]
Affiliation(s)
- Dominique Larrey
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France.
| | - Lucy Meunier
- Department of Gastroenterology and Hepatology, Saint-Éloi Hospital, University Hospital of Montpellier, 80, avenue Augustin-Fliche, 34090 Montpellier, France; French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France
| | - Dominique Valla
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Sophie Hillaire
- Department of Internal Medicine, Foch Hospital, 40, rue Worth, 92150 Suresnes, France
| | - Virginia Hernandez-Gea
- Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd). Health Care Provider of the European Reference Network onRare Liver Disorders (ERN-Liver), Spain
| | - Danielle Dutheil
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Association of patients with vascular liver diseases (AMVF), Department of Hepatology, Beaujon Hospital, 100, boulevard du Général Leclerc, 92118 Clichy, France
| | - Aurélie Plessier
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Hepatology, Beaujon Hospital, AP-HP, 100, boulevard du Général Leclerc, 92118 Clichy, France; Reference center of vascular liver diseases, European Reference Network (ERN) Rare-Liver, Clichy, France
| | - Christophe Bureau
- French Network for Rare Liver Diseases FILFOIE, Saint-Antoine Hospital, AP-HP, 184, rue du Faubourg Saint-Antoine, 75012 Paris, France; Department of Gastroenterology and Hepatology, Rangueil Hospital, University Hospital of Toulouse, 1, avenue du Professeur Jean-Poulhès, 31400 Toulouse, France
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14
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Nicoară-Farcău O, Rusu I, Stefănescu H, Tanțău M, Badea RI, Procopeț B. Diagnostic challenges in non-cirrhotic portal hypertension - porto sinusoidal vascular disease. World J Gastroenterol 2020; 26:3000-3011. [PMID: 32587444 PMCID: PMC7304099 DOI: 10.3748/wjg.v26.i22.3000] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/31/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Non-cirrhotic portal hypertension consists of a group of diseases characterized by signs and complications of portal hypertension, which differ from cirrhosis through histological alterations, hemodynamic characterization and, clinical outcome. Because of the similarities in clinical presentation and imaging signs, frequently these patients, and particularly those with porto-sinusoidal vascular disease (PSVD), are misdiagnosed as having liver cirrhosis and thus raising difficulties in their diagnosis. The most challenging differentiation to be considered is between PSVD and cirrhosis and, although not pathognomonic, liver biopsy is still the standard of diagnosis. Although they still require extended validation before being broadly used, new non-invasive methods for the diagnosis of porto-sinusoidal vascular disease, like transient elastography, contrast-enhanced ultrasound or metabolomic profiling, have shown promising results. Another issue is the differentiation between PSVD and chronic extrahepatic portal vein obstruction, especially now when it is known that 40% of patients suffering from PSVD develop portal vein thrombosis. In this particular case, once the portal vein thrombosis occurred, the diagnosis of PSVD is impossible according to the current guidelines. Moreover, so far, the differentiation between PSVD and sinusoidal obstruction syndrome has not been clear so far in particular circumstances. In this review we highlighted the diagnostic challenges regarding the PSVD, as well as the current techniques used in the evaluation of these patients.
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Affiliation(s)
- Oana Nicoară-Farcău
- University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, Romania
- Gastroenterology Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
| | - Ioana Rusu
- University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, Romania
- Pathology Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
| | - Horia Stefănescu
- Gastroenterology Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
| | - Marcel Tanțău
- University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, Romania
- Gastroenterology Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
| | - Radu Ion Badea
- University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, Romania
- Imagistic Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
| | - Bogdan Procopeț
- University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca 400000, Romania
- Gastroenterology Department, Regional Institute of Gastroenterology and Hepatology “O. Fodor”, Cluj-Napoca 400000, Romania
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15
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Gangi A, Lu SC. Chemotherapy-associated liver injury in colorectal cancer. Therap Adv Gastroenterol 2020; 13:1756284820924194. [PMID: 32547639 PMCID: PMC7249601 DOI: 10.1177/1756284820924194] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 04/15/2020] [Indexed: 02/04/2023] Open
Abstract
Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.
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Affiliation(s)
- Alexandra Gangi
- Division of Surgical Oncology, Department of Surgery, Cedars Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048, USA
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16
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Hepatic Resection Following Selective Internal Radiation Therapy for Colorectal Cancer Metastases in the FOXFIRE Clinical Trial: Clinical Outcomes and Distribution of Microspheres. Cancers (Basel) 2019; 11:cancers11081155. [PMID: 31408970 PMCID: PMC6721483 DOI: 10.3390/cancers11081155] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 07/30/2019] [Accepted: 08/01/2019] [Indexed: 12/18/2022] Open
Abstract
The FOXFIRE (5-Fluorouracil, OXaliplatin and Folinic acid ± Interventional Radio-Embolisation) clinical trial combined systemic chemotherapy (OxMdG: Oxaliplatin, 5-fluorouracil and folic acid) with Selective Internal Radiation Therapy (SIRT or radio-embolisation) using yttrium-90 resin microspheres in the first-line management for liver-dominant metastatic colorectal cancer (CRC). We report clinical outcomes for patients having hepatic resection after this novel combination therapy and an exploratory analysis of histopathology. Multi-Disciplinary Teams deemed all patients inoperable before trial registration and reassessed them during protocol therapy. Proportions were compared using Chi-squared tests and survival using Cox models. FOXFIRE randomised 182 participants to chemotherapy alone and 182 to chemotherapy with SIRT. There was no statistically significant difference in the resection rate between groups: Chemotherapy alone was 18%, (n = 33); SIRT combination was 21% (n = 38) (p = 0.508). There was no statistically significant difference between groups in the rate of liver surgery, nor in survival from time of resection (hazard ratio (HR) = 1.55; 95% confidence interval (CI) = 0.83-2.89). In the subgroup studied for histopathology, microsphere density was highest at the tumour periphery. Patients treated with SIRT plus chemotherapy displayed lower values of viable tumour in comparison to those treated with chemotherapy alone (p < 0.05). This study promotes the feasibility of hepatic resection following SIRT. Resin microspheres appear to preferentially distribute at the tumour periphery and may enhance tumour regression.
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17
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Hodgson A, Almansouri Z, Adeyi O, Fischer SE. Gross and microscopic changes of liver neoplasms and background hepatic structures following neoadjuvant therapy. J Clin Pathol 2019; 72:112-119. [PMID: 30670563 DOI: 10.1136/jclinpath-2018-205596] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Accepted: 11/26/2018] [Indexed: 01/03/2023]
Abstract
Liver transplantation is a surgical option with curative intent used in the management of some cases of hepatocellular carcinoma and cholangiocarcinoma (hilar, rarely intrahepatic). A number of different therapeutic modalities including ablative techniques, arterially directed therapies, radiation and chemotherapy are used in the neoadjuvant setting prior to liver transplantation with the goals of preventing tumour progression, decreasing post-transplant recurrence and possibly downstaging patients with tumour burden beyond what is acceptable by current transplant criteria. Pathologists evaluating hepatic explants must be aware of these neoadjuvant therapies and the alterations induced by them in both tumourous and non-tumourous tissue. In this review, we discuss common neoadjuvant therapies used in in this setting, as well as the gross and microscopic changes induced by these presurgical treatments within hepatic neoplasms as well as the background hepatic parenchyma and nearby structures. Select secondary tumours involving the liver which are pretreated will also be discussed. Finally, proper reporting of these changes will be mentioned.
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Affiliation(s)
- Anjelica Hodgson
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Zuhoor Almansouri
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Oyedele Adeyi
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada.,Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Sandra E Fischer
- Department of Pathobiology and Laboratory Medicine, The University of Toronto, Toronto, Ontario, Canada .,Department of Pathology, University Health Network, Toronto, Ontario, Canada
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18
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Desjardin M, Bonhomme B, Le Bail B, Evrard S, Brouste V, Desolneux G, Fonck M, Bécouarn Y, Béchade D. Hepatotoxicities Induced by Neoadjuvant Chemotherapy in Colorectal Cancer Liver Metastases: Distinguishing the True From the False. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2019; 13:1179554918825450. [PMID: 30718969 PMCID: PMC6348554 DOI: 10.1177/1179554918825450] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 12/25/2018] [Indexed: 02/06/2023]
Abstract
Background: Pre-operative chemotherapy for colorectal liver metastasis (CRLM) is thought to be the cause of hepatotoxicity of non-tumoural parenchyma. Studies on hepatotoxicity are contradictory. We investigated the impact of a single-line pre-operative chemotherapy on non-tumoural liver analysed by an expert hepatico-pancreatico-biliary pathologist, and the consequences on surgical outcomes. Patients and methods: Patients operated for CRLM, after a pure first-line pre-operative chemotherapy, were retrospectively included. Two comparative histopathological analyses were performed for vascular toxicity and steatohepatitis. Results: Between 2003 and 2015, 147 patients were included. Chemotherapy was based on oxaliplatin (40.1%), irinotecan (55.8%), or both (4.1%). The expert pathologist described 38.8% of vascular lesions including dilation, nodular regeneration, and peliosis. In multivariate analysis, vascular lesions correlated to male sex (P = .01), pre-operative platelets <150 g/L (P = .04), and aspartate aminotransferase to platelet ratio index (APRI) score >0.36 (P = .02). Steatohepatitis was observed in 15 patients (10.2%), more frequently after irinotecan (14.8% vs 3.4%, P = .01; odds ratio [OR] = 7.3; 95% confidence interval [CI] = [1.5-34.7]), and for patients with body mass index (BMI) >25 kg/m2 (P = .004; OR = 10.0; 95% CI = [2.1-47.5]). A total of 29 patients (19.7%) developed major complications with 2 risk factors: portal vein obstruction (PVO) and septic surgery. Reproducibility assessment of steatohepatitis and dilated lesions by 2 pathologists showed moderate agreement (Kappa score 0.53 and 0.54, respectively). Conclusions: There is a probable association between non-alcoholic steatohepatitis (NASH) and irinotecan. Oxaliplatin seems to lead to higher vascular lesions. Except in the presence of pre-existent comorbidities, liver toxicities should not restrain the use of pre-operative chemotherapy prior to parenchymal-sparing surgery.
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Affiliation(s)
| | | | - Brigitte Le Bail
- Department of Anatomopathology, University Hospital, Bordeaux, France
| | - Serge Evrard
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - Véronique Brouste
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | | | - Marianne Fonck
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - Yves Bécouarn
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
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19
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Waters KM, Cottrell TR, Besharati S, Zhu Q, Anders RA. Evaluation of Peritumoral Fibrosis in Metastatic Colorectal Adenocarcinoma to the Liver Using Digital Image Analysis. Am J Clin Pathol 2019; 151:226-230. [PMID: 30339201 DOI: 10.1093/ajcp/aqy134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Objectives It is challenging to separate peritumoral fibrosis from fibrosis due to chronic liver disease in mass-directed liver biopsies. We evaluated the distance that peritumoral fibrosis extends from metastatic colorectal adenocarcinoma in liver. Methods Peritumoral and distant uninvolved liver trichrome stains from 25 cases were analyzed using digital image analysis. Fibrosis was quantitated at concentric intervals from each tumor and in uninvolved liver. Results There was a 3.9 fold (range 0.9-18.6) median increase in fibrosis in the first 0.5 mm of peritumoral liver compared to distant liver. Fibrosis levels returned to baseline at median 2.5 mm (interquartile range 1.5-5.0 mm) from tumor. Conclusions Fibrosis is markedly increased in peritumoral liver. Fibrosis levels returned to baseline by 5 mm from tumor in approximately 75% of cases. Pathologists should be cautious of fibrosis in mass-directed liver biopsies without at least 5 mm of liver tissue distal to the mass.
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Affiliation(s)
- Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | | | - Qingfeng Zhu
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD
| | - Robert A Anders
- Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD
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20
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Hubert C, Lucidi V, Weerts J, Dili A, Demetter P, Massart B, Komuta M, Navez J, Reding R, Gigot JF, Sempoux C. Impact of biological agents on the prevalence of chemotherapy associated liver injury (CALI): Multicentric study of patients operated for colorectal liver metastases. Eur J Surg Oncol 2018; 44:1532-1538. [DOI: 10.1016/j.ejso.2018.07.050] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 06/27/2018] [Accepted: 07/18/2018] [Indexed: 01/10/2023] Open
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21
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22
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Walcott-Sapp S, Billingsley KG. Preoperative optimization for major hepatic resection. Langenbecks Arch Surg 2017; 403:23-35. [PMID: 29150719 DOI: 10.1007/s00423-017-1638-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Accepted: 11/06/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE Major hepatic resections are performed for primary hepatobiliary malignancies, metastatic disease, and benign lesions. Patients with chronic liver disease, including cirrhosis and steatosis, are at an elevated risk of malnutrition and impaired strength and exercise capacity, deficits which cause increased risk of postoperative complications and mortality. The aims of this report are to discuss the pathophysiology of changes in nutrition, exercise capacity, and muscle strength in patient populations likely to require major hepatectomy, and review recommendations for preoperative evaluation and optimization. METHODS Nutritional and functional impairment in preoperative hepatectomy patients, especially those with underlying liver disease, have a complex and multifactorial physiologic basis that is not completely understood. RESULTS Recognition of malnutrition and compromised strength and exercise tolerance preoperatively can be difficult, but is critical in providing the opportunity to intervene prior to major hepatic resection and potentially improve postoperative outcomes. There is promising data on a variety of nutritional strategies to ensure adequate intake of calories, proteins, vitamins, and minerals in patients with cirrhosis and reduce liver size and degree of fatty infiltration in patients with hepatic steatosis. Emerging evidence supports structured exercise programs to improve exercise tolerance and counteract muscle wasting. CONCLUSIONS The importance of nutrition and functional status in patients indicated for major liver resection is apparent, and emerging evidence supports structured preoperative preparation programs involving nutritional intervention and exercise training. Further research is needed in this field to develop optimal protocols to evaluate and treat this heterogeneous cohort of patients.
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Affiliation(s)
- Sarah Walcott-Sapp
- Division of Surgical Oncology, Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Code: L223, Portland, OR, 97239, USA.
| | - Kevin G Billingsley
- Division of Surgical Oncology, Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd., Mail Code: L223, Portland, OR, 97239, USA
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23
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Kim HB, Park SG. Arterioportal shunt incidental to treatment with oxaliplatin that mimics recurrent gastric cancer. World J Gastroenterol 2017; 23:6187-6193. [PMID: 28970735 PMCID: PMC5597511 DOI: 10.3748/wjg.v23.i33.6187] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 07/04/2017] [Accepted: 07/12/2017] [Indexed: 02/07/2023] Open
Abstract
Arterioportal shunt (APS) is an organic communication between the hepatic arterial system and the portal venous system. The APS is one of the major causes of transient hepatic attenuation differences on dynamic computed tomography (CT) or magnetic resonance imaging (MRI). This condition is usually associated with trauma, liver cirrhosis, and malignancies of the liver. However, there has been no report about oxaliplatin-induced APS. A 41-year-old male was diagnosed with Stage IIIB gastric cancer. The patient initially underwent neoadjuvant chemotherapy with capecitabine and oxaliplatin After 3 cycles of therapy, the mass had markedly decreased, and a total gastrectomy with splenectomy was performed. Since the malignancy was locally invasive, the patient was continued on the same regimen of the adjuvant chemotherapy. After 3 more cycles, a computed tomography revealed a 1 cm sized arterial-enhancing nodule in the right lobe of the liver. An MRI revealed an arterial enhancing lesion, and a positron emission tomography CT scan showed a hypermetabolic lesion in the same portion of the liver. We tried to perform a liver biopsy; however, an ultrasonography could not detect any mass. A presumptive diagnosis of an APS due to a recurred cancer was made. We found a similar but slightly different case report of an oxaliplatin-induced liver injury, mimicking a metastatic tumor on an MRI. Based on a prior report, the patient was continued on treatment with adjuvant chemotherapy following discontinuation of oxaliplatin. After 2 cycles, the arterial enhancing liver mass resolved, supporting the final diagnosis of an APS, related to oxaliplatin-induced sinusoidal injury. The patient has not experienced any a relapse after two years of additional follow up recurrent gastric cancer upon interpretation of multiple imaging modalities.
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Affiliation(s)
- Hong-Beum Kim
- Department of Premedical Course, Chosun University School of Medicine, Gwangju 501-717, South Korea
| | - Sang-Gon Park
- Department of Internal Medicine, Hemato-oncology, Chosun University Hospital, Gwangju 501-717, South Korea
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Adeyi OA. Pathology primer: Common liver biopsy findings in patients who have recently undergone liver transplant or resection. Clin Liver Dis (Hoboken) 2017; 10:42-48. [PMID: 30992758 PMCID: PMC6467110 DOI: 10.1002/cld.652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 05/27/2017] [Accepted: 06/12/2017] [Indexed: 02/04/2023] Open
Affiliation(s)
- Oyedele A. Adeyi
- Department of Laboratory Medicine & PathobiologyUniversity of Toronto; and University Health NetworkTorontoONCanada
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Amptoulach S, Gross G, Sturesson C, Rissler P, Kalaitzakis E. Preoperative Aspartate Aminotransferase-to-Platelet Ratio Index Predicts Perioperative Liver-Related Complications Following Liver Resection for Colorectal Cancer Metastases. Scand J Surg 2017; 106:311-317. [PMID: 28737112 DOI: 10.1177/1457496916683094] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND AND AIMS There are limited data on the potential role of preoperative non-invasive markers, specifically the aspartate-to-alanine aminotransferase ratio and the aspartate aminotransferase-to-platelet ratio index, in predicting perioperative liver-related complications after hepatectomy for colorectal cancer metastases. METHODS Patients undergoing liver resection for colorectal cancer metastases in a European institution during 2003-2010 were retrospectively enrolled. Relevant data, such as neoadjuvant chemotherapy, preoperative liver function tests, and perioperative complications, were collected from medical records. The nontumorous liver parenchyma in the surgical specimens of 31 patients was re-evaluated. RESULTS Overall, 215 patients were included. In total, 40% underwent neoadjuvant chemotherapy and 47% major resection, while 47% had perioperative complications (6% liver-related). In multivariate regression analysis, the aspartate aminotransferase-to-platelet ratio index was independently associated with liver-related complications (odds ratio: 1.149, p = 0.003) and perioperative liver failure (odds ratio: 1.155, p = 0.012). The latter was also true in the subcohort of patients with neoadjuvant chemotherapy (odds ratio: 1.157, p = 0.004) but not in those without such therapy (p = 0.062). The aspartate-to-alanine aminotransferase ratio was not related to liver-related complications (p = 0.929). The area under the receiver operating characteristics curve for the aspartate aminotransferase-to-platelet ratio index as a predictor of liver-related complications was 0.857 (p = 0.008) in patients with neoadjuvant chemotherapy. Increasing aspartate aminotransferase-to-platelet ratio index was observed with an increase in degrees of sinusoidal obstruction syndrome (p = 0.01) but not for fibrosis (p = 0.175) or steatosis (p = 0.173) in the nontumorous liver in surgical specimens. CONCLUSION The preoperative aspartate aminotransferase-to-platelet ratio index, but not the aspartate-to-alanine aminotransferase ratio, predicts perioperative liver-related complications following hepatectomy due to colorectal cancer metastases, in particular after neoadjuvant chemotherapy. The aspartate aminotransferase-to-platelet ratio index is related to sinusoidal obstruction syndrome in the nontumorous liver.
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Affiliation(s)
- S Amptoulach
- 1 Department of Oncology, Skåne University Hospital, Lund University, Lund, Sweden
| | - G Gross
- 2 Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden
| | - C Sturesson
- 2 Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.,3 Department of Surgery, Skåne University Hospital, Lund University, Lund, Sweden
| | - P Rissler
- 4 Department of Pathology, Skåne University Hospital, Lund University, Lund, Sweden
| | - E Kalaitzakis
- 2 Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.,5 Digestive Disease Center, Copenhagen University Hospital/Herlev, Copenhagen, Denmark
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Sato T, Arita J, Inoue Y, Koga R, Takahashi Y, Saiura A. Index of convexity: A novel method for assessing liver functional reserve using technetium-99m-galactosyl human serum albumin liver scintigraphy. Biosci Trends 2017; 11:333-339. [PMID: 28484186 DOI: 10.5582/bst.2017.01014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Preoperative evaluation of liver functional reserve is important in hepatobiliary surgery. Although the indocyanine green retention rate at 15 minutes (ICG-R15) is the gold standard for this purpose, a new method without technical complexity would be preferable. We assessed the usefulness of the previously established index of convexity (IOC). In total, 159 consecutive patients who underwent both technetium-99m-galactosyl human serum albumin (99mTc-GSA) scintigraphy and the ICG-R15 were included. Correlation coefficients between indices from 99mTc-GSA scintigraphy and blood examinations including ICG-R15 were evaluated, and a conversion formula from the IOC to the ICG-R15 was established. The IOC was calculated as [L(15) × 2 - L(3) - L(27)] / [L(27) - L(3)], where L(t) indicates the radiation counts within the whole liver at t minutes after 99mTc-GSA injection. The IOC showed a significantly stronger correlation with the ICG-R15 (r = -0.532, p < 0.001) than the index of blood clearance (HH15) and the receptor index (LHL15). A formula for estimating ICG-R15 from IOC was "ICG-R15 = -31.0 × IOC + 30.1". In conclusion, the IOC is a better index for evaluating preoperative liver functional reserve than the conventional indices. A formula for estimating ICG-R15 from the IOC will be useful.
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Affiliation(s)
- Takafumi Sato
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Division, Department of Surgery, The University of Tokyo
| | - Yosuke Inoue
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research
| | - Rintaro Koga
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research
| | - Yu Takahashi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research
| | - Akio Saiura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research
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Vigano L, De Rosa G, Toso C, Andres A, Ferrero A, Roth A, Sperti E, Majno P, Rubbia-Brandt L. Reversibility of chemotherapy-related liver injury. J Hepatol 2017; 67:84-91. [PMID: 28284915 DOI: 10.1016/j.jhep.2017.02.031] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 02/18/2017] [Accepted: 02/20/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Chemotherapy-associated liver injury (CALI) increases the risk of liver resection and may prejudice further surgery and chemotherapy. The reversibility of CALI is therefore important; however, no data concerning this are available. This study aimed to retrospectively analyze the reversibility of CALI in patients undergoing liver resection for colorectal metastases. METHODS All resections of colorectal liver metastases after oxaliplatin and/or irinotecan-based chemotherapy were included. First, liver resections were stratified by time between end of chemotherapy and hepatectomy and several possible cut-off values tested. CALI prevalence in various groups was compared. Second, CALI in the two specimens from each patient who had undergone repeat liver resections without interval chemotherapy were compared. RESULTS Overall, 524 liver resections in 429 patients were analyzed. The median interval chemotherapy-surgery was 56days (15-1264). CALI prevalence did not differ significantly between groups with a chemotherapy-surgery interval <270days. Grade 2-3 sinusoidal dilatation (SOS, 19.4% vs. 40.0%, p=0.022) and nodular regenerative hyperplasia (NRH, 6.5% vs. 20.1%, p=0.063) occurred less frequently in patients with an interval >270days (n=31); prevalence of steatosis and steatohepatitis was similar in all groups. A chemotherapy-surgery interval >270days was an independent protector against Grade 2-3 SOS (p=0.009). Forty-seven patients had repeat liver resection without interval chemotherapy. CALI differed between surgeries only for a chemotherapy-surgery interval >270days (n=15), Grade 2-3 SOS having regressed in 4/5 patients and NRH in 7/8; whereas steatosis and steatohepatitis had persisted. CONCLUSIONS CALI persists for a long time after chemotherapy. SOS and NRH regress only after nine months without chemotherapy, whereas steatosis and steatohepatitis persist. LAY SUMMARY The patients affected by colorectal liver metastases often receive chemotherapy before liver resection, but chemotherapy causes liver injuries that may increase operative risks and reduce tolerance to further chemotherapy. The authors analyzed the reversibility of the liver injuries after the chemotherapy interruption. Liver injuries persist for a long time after chemotherapy. Sinusoidal dilatation and nodular regenerative hyperplasia regress only nine months after the end of chemotherapy, whereas steatosis and steatohepatitis persist even after this long interval.
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Affiliation(s)
- Luca Vigano
- Dept. of Hepatobiliary and General Surgery, Humanitas Clinical and Research Center, Rozzano (MI), Italy.
| | - Giovanni De Rosa
- Dept. of Pathology, Ospedale Mauriziano Umberto I, Torino, Italy
| | - Christian Toso
- Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
| | - Axel Andres
- Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
| | - Alessandro Ferrero
- Dept. of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Torino, Italy
| | - Arnaud Roth
- Dept. of Oncology, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
| | - Elisa Sperti
- Dept. of Oncology, Ospedale Mauriziano Umberto I, Torino, Italy
| | - Pietro Majno
- Dept. of Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
| | - Laura Rubbia-Brandt
- Dept. of Clinical Pathology, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, University Hospitals, Geneva, Switzerland
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Lock JF, Westphal T, Rubin T, Malinowski M, Schulz A, Jara M, Bednarsch J, Stockmann M. LiMAx Test Improves Diagnosis of Chemotherapy-Associated Liver Injury Before Resection of Colorectal Liver Metastases. Ann Surg Oncol 2017; 24:2447-2455. [PMID: 28516292 DOI: 10.1245/s10434-017-5887-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Chemotherapy of colorectal liver metastases (CLMs) prior to liver resection implies the risk of chemotherapy-associated liver injury, leading to increased postoperative morbidity and mortality OBJECTIVE: The aim of this study was to evaluate the LiMAx (liver maximum capacity) test for diagnosis of chemotherapy-associated liver injury. METHODS This was a retrospective analysis of patients with CLMs, prior to liver resection. We performed preoperative assessment of liver function using biochemical parameters and the LiMAx test. The individual history of chemotherapy within 12 months, including regimen, number of cycles, and therapy-free interval were collected, and histopathological evaluation of tumor-free liver tissue was performed in resected patients. RESULTS A total of 204 patients were included, of whom 127 (62%) had received previous chemotherapy. The LiMAx test was worse after chemotherapy (340 ± 95 vs. 391 ± 82 µg/kg/h; p < 0.001). Impaired LiMAx results (<315 µg/kg/h) were determined in 49% of patients after chemotherapy, and no effects of chemotherapy, liver steatosis or fibrosis on biochemical parameters were observed. LiMAx impairment was dependent on the number of oxaliplatin cycles, the therapy-free interval, and obesity in multivariate analysis. In addition, the LiMAx test was worse in patients with relevant steatosis, fibrosis and steatohepatitis. Patients with an impaired LiMAx showed sufficient regeneration during chemotherapy cessation when surgery was postponed (272 ± 57 - 348 ± 72 µg/kg/h; p = 0.003). CONCLUSION The LiMAx test enables non-invasive preoperative diagnosis of chemotherapy-associated liver injury. Preoperative performance of the LiMAx test can augment surgical strategy and timing of surgery after previous chemotherapy, thus avoiding increased postoperative morbidity.
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Affiliation(s)
- Johan F Lock
- Department of General, Visceral, Vascular and Paediatric Surgery, University Hospital of Würzburg, Würzburg, Germany.
| | - Tilman Westphal
- Department of General, Visceral and Transplantation Surgery, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - Tom Rubin
- Department of General, Visceral and Transplantation Surgery, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - Maciej Malinowski
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University Hospital, Homburg (Saar), Germany
| | - Antje Schulz
- Department of General, Visceral, Vascular and Pediatric Surgery, Saarland University Hospital, Homburg (Saar), Germany
| | - Maximilian Jara
- Department of General, Visceral and Transplantation Surgery, Charité -Universitätsmedizin Berlin, Berlin, Germany
| | - Jan Bednarsch
- Department of General, Visceral and Transplantation Surgery, University Hospital Aachen, Rhine Westphalia Institute of Technology, Aachen, Germany
| | - Martin Stockmann
- Department of General, Visceral and Transplantation Surgery, Charité -Universitätsmedizin Berlin, Berlin, Germany.,Evangelisches Krankenhaus Paul Gerhardt Stift, Lutherstadt Wittenberg, Germany
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Khoo E, O'Neill S, Brown E, Wigmore SJ, Harrison EM. Systematic review of systemic adjuvant, neoadjuvant and perioperative chemotherapy for resectable colorectal-liver metastases. HPB (Oxford) 2016; 18:485-93. [PMID: 27317952 PMCID: PMC4913134 DOI: 10.1016/j.hpb.2016.03.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 03/02/2016] [Indexed: 12/12/2022]
Abstract
INTRODUCTION The role of systemic chemotherapy in patients with resectable colorectal liver metastases (CRLM) is ambiguous. The aim of this review was to compare the outcomes of regimens using systemic neoadjuvant, adjuvant or perioperative (combination of pre and postoperative) chemotherapy, for the treatment of resectable CRLM. METHODS MEDLINE was searched for articles investigating the use of chemotherapy for adults with resectable CRLM. Randomized controlled trials reporting overall survival (OS), disease-free survival (DFS) and grade 3-4 adverse events (AEs) were screened for inclusion. PROSPERO record: CRD42015020609. RESULTS Four trials met the inclusion criteria (1098 patients). No significant improvement in median OS was achieved with chemotherapy/surgery compared with surgery-alone. Two trials demonstrated a significant improvement in DFS with chemotherapy/surgery compared to surgery-alone (Hazard ratio 0.78 (0.61-0.99) p = 0.04 and HR 0.66 (0.46-0.96) p = 0.03). Fluorouracil/folinic acid alone had a lower incidence of AEs than combination therapies, and the addition of cetuximab shortened DFS in one trial (HR 1.48 (1.04-2.12) p = 0.03). CONCLUSION There is a lack of adequately powered trials of chemotherapy in combination with liver resection for CRLM, partly due to difficulties in recruitment. In an unselected patient group, FOLFOX in combination with liver resection appears to improve DFS compared to surgery-alone, but trials are underpowered for OS. Future trials will require prospective stratification of patients based on biomarkers predictive of response.
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Affiliation(s)
- Emily Khoo
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Stephen O'Neill
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Ewan Brown
- Edinburgh Cancer Centre, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XR, UK
| | - Stephen J. Wigmore
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - Ewen M. Harrison
- Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK,Correspondence: Ewen M. Harrison, Department of Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK. Tel.: +44 7974420495.Department of Clinical SurgeryUniversity of EdinburghRoyal Infirmary of Edinburgh51 Little France CrescentEdinburghEH16 4SAUK
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Koo SX, Chan SH, Ngeow J. Genetic predisposition resulting in sinusoidal obstruction syndrome in a patient with resected sigmoid cancer on adjuvant oxaliplatin. BMJ Case Rep 2016; 2016:bcr-2015-212978. [PMID: 26729828 DOI: 10.1136/bcr-2015-212978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A Chinese man who had undergone a curative high anterior resection for sigmoid cancer was administrated XELOX (capecitabine and oxaliplatin) as postoperative adjuvant chemotherapy. He subsequently developed sinusoidal obstruction syndrome (SOS) that resolved on discontinuation of XELOX treatment. Genetic evaluation determined that he had the GSTT1-null and GSTM1-null genotype, known to be an independent risk factor for developing oxaliplatin-induced SOS.
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Affiliation(s)
- Si Xuan Koo
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Joanne Ngeow
- National Cancer Centre Singapore, Singapore, Singapore
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García-Alfonso P, Ferrer A, Gil S, Dueñas R, Pérez MT, Molina R, Capdevila J, Safont MJ, Castañón C, Cano JM, Lara R. Neoadjuvant and conversion treatment of patients with colorectal liver metastasis: the potential role of bevacizumab and other antiangiogenic agents. Target Oncol 2015; 10:453-65. [PMID: 25752908 PMCID: PMC4668275 DOI: 10.1007/s11523-015-0362-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2014] [Accepted: 01/28/2015] [Indexed: 12/25/2022]
Abstract
More than 50 % of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metastases (CRLM). New antiangiogenic targeted therapies, such as bevacizumab, aflibercept, and regorafenib, in combination with neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The present review discusses the available data for antiangiogenic targeted agents in this setting. One of these therapies, bevacizumab, which targets the vascular endothelial growth factor (VEGF) has demonstrated good results in this setting. In patients with initially unresectable CRLM, the combination of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) plus bevacizumab has led to high response and resection rates. This combination is also effective for patients with unresectable CRLM. Moreover, the addition of bevacizumab to chemotherapy in the neoadjuvant setting of liver metastasis has a higher impact on pathological response rate. This drug also has a manageable safety profile, and according to recent data, bevacizumab may protect against the sinusoidal dilation provoked in the liver by certain cytotoxic agents. In phase II trials, antiangiogenic therapy has demonstrated benefits in the presurgical treatment of CRLM and may represent a new treatment pathway for these patients.
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Affiliation(s)
- Pilar García-Alfonso
- Medical Oncology Service, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Ana Ferrer
- Medical Oncology Service, Hospital General Universitario de Albacete, Albacete, Spain
| | - Silvia Gil
- Medical Oncology Service, Hospital Universitario Carlos Haya, Málaga, Spain
| | - Rosario Dueñas
- Medical Oncology Service, Complejo Hospitalario de Jaén, Jaén, Spain
| | | | - Raquel Molina
- Medical Oncology Service, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
| | - Jaume Capdevila
- Medical Oncology Service, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | - María José Safont
- Medical Oncology Service, Hospital General Universitario de Valencia, Valencia, Spain
| | - Carmen Castañón
- Medical Oncology Service, Complejo Asistencial de León, León, Spain
| | - Juana María Cano
- Medical Oncology Service, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Ricardo Lara
- Medical Oncology Service, Hospital Obispo Polanco, Teruel, Spain
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Bagia JS, Chai A, Chou R, Chu C, Rouse J, Sinclair E, Vonthethoff L, Teixeira-Pinto A. Prospective diagnostic test accuracy comparison of computed tomography during arterial portography and Primovist magnetic resonance imaging in the pre-operative assessment of colorectal cancer liver metastases. HPB (Oxford) 2015; 17:927-35. [PMID: 26258662 PMCID: PMC4571761 DOI: 10.1111/hpb.12437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 05/01/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To assess and compare the accuracy and inter-observer agreement for the detection of liver lesions using Primovist magnetic resonance imaging (pMRI) and computed tomography during arterial portography (CTAP). METHODS Patients evaluated at St George Hospital Liver Unit for colorectal liver metastases (CRCLM) underwent CTAP as part of standard staging. pMRI was added to the pre-operative assessment. Two radiologists reported CTAP and two reported pMRI. The sensitivity and specificity of CTAP and pMRI were calculated using histopathology as the gold standard. RESULTS Complete data were available for 62 patients corresponding to 219 lesions confirmed on histopathology. Agreement on the detection of lesions between the two radiologists that reported pMRI was higher than for CTAP (Kappa = 0.80 versus 0.74). Specificity of lesion detection for pMRI was 0.88 and 0.83 for CTAP (P = 0.112). Sensitivity for pMRI was 0.83 and 0.81 for CTAP. For patients who had chemotherapy before evaluation, pMRI had a significantly higher specificity than CTAP (0.79 versus 0.63, P = 0.011). CONCLUSIONS pMRI is less invasive, has a good inter-observer agreement, has comparable sensitivity and specificity to CTAP in the pre-chemotherapy population and demonstrates better specificity in patients assessed post-chemotherapy. pMRI is a valid alternative to CTAP in the assessment of CRCLM.
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Affiliation(s)
- Jai S Bagia
- Department of Surgery, St George HospitalSydney, NSW, Australia
| | - Alan Chai
- Department of Radiology, St George HospitalSydney, NSW, Australia
| | - Roger Chou
- Department of Radiology, St George HospitalSydney, NSW, Australia
| | - Christopher Chu
- Department of Radiology, St George HospitalSydney, NSW, Australia
| | - John Rouse
- Department of Radiology, St George HospitalSydney, NSW, Australia
| | - Elizabeth Sinclair
- Department of Histopathology, Douglas Hanly Moir PathologySydney, NSW, Australia
| | - Leon Vonthethoff
- Department of Anatomical Pathology, South Eastern Area Laboratory Services (SEALS)Sydney, NSW, Australia
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Parkin E, O'Reilly D, Plumb A, Manoharan P, Rao M, Coe P, Frystyk J, Ammori B, de Liguori Carino N, Deshpande R, Sherlock D, Renehan A. Digital histology quantification of intra-hepatic fat in patients undergoing liver resection. Eur J Surg Oncol 2015; 41:1020-7. [DOI: 10.1016/j.ejso.2015.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
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Unexpected hepatotoxicity in a phase I study of TAS266, a novel tetravalent agonistic Nanobody® targeting the DR5 receptor. Cancer Chemother Pharmacol 2015; 75:887-95. [DOI: 10.1007/s00280-015-2712-0] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 02/19/2015] [Indexed: 11/26/2022]
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Donati M, Stavrou GA, Stang A, Basile F, Oldhafer KJ. 'Liver-first' approach for metastatic colorectal cancer. Future Oncol 2015; 11:1233-1243. [PMID: 25832880 DOI: 10.2217/fon.14.316] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The liver-first approach was proposed for the first time in 2006 to obtain resectability of stage IV colorectal cancer patients and complete the therapeutic plan. From then some groups have used this new revolutionary approach reporting promising results. Other alternative strategies have been proposed for metastatic patients. The authors reviewed the literature weighing the pros and cons of each strategy proposed to manage these advanced tumor stages. The therapeutic options are analyzed in the light of oncologic problems and evidence. Also problems, questions and perspectives are given. Even if the 'liver-first' approach seems to be a promising strategy, the ideal diagnostic-therapeutic flowchart for metastatic colorectal cancer is still difficult to standardize. The great heterogeneity of this population of patients is one of the main problems. A 'tailored approach' philosophy is necessary to calibrate, in a multidisciplinary setting, a case-by-case choice of therapeutic options.
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Affiliation(s)
- Marcello Donati
- Department of Surgery & Medical-Surgical Specialties, General & Oncologic Surgery Unit, Vittorio-Emanuele University Hospital, University of Catania, 95122 Catania, Italy
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Pang T, Kaufman A, Choi J, Gill A, Drummond M, Hugh T, Samra J. Peroxisome proliferator-activated receptor-α staining is associated with worse outcome in colorectal liver metastases. Mol Clin Oncol 2014; 3:308-316. [PMID: 25798259 DOI: 10.3892/mco.2014.482] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/09/2014] [Indexed: 01/01/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors involved in lipid metabolism and liver response to injury. We hypothesised that differences in the expression of PPARs may reflect differences in the cellular microenvironment of the liver and, consequently, in the behaviour of colorectal liver metastases. Of the 145 patients who underwent hepatectomy for colorectal liver metastases between 1998 and 2007, 103 had adequate tissue for PPAR staining and histological re-evaluation. The histological characteristics evaluated included sinusoidal dilatation, perisinusoidal fibrosis, ballooning and steatosis. PPAR- α and-γ staining was performed and the results were correlated with clinical and survival data. Lobular inflammation and sinusoidal dilatation were the most common histopathological abnormalities. A total of 50% of the patients were PPAR- α-negative and 34% were PPAR- γ-negative. More patients exhibited lobular inflammation in the PPAR- α -positive group (P=0.023) compared to patients with negative PPAR- α staining, as seen on the multivariate analysis. PPAR- γpositivity was associated with oxaliplatin use, surgical margins ≥1 mm and a trend towards a lesser degree of fibrosis. The median follow-up in this cohort of patients was 48 months. Patients with PPAR- α staining had a worse overall survival (median, 36 vs. 79 months, P=0.037) compared to those with no PPAR- α staining. There was no correlation between PPAR- α or-γpositivity and disease-free survival. In conclusion, PPAR- α staining is associated with lobular inflammation and worse overall survival in patients with colorectal liver metastases. The exact mechanism underlying this finding remains unclear and further research into the diagnostic and therapeutic implications is required.
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Affiliation(s)
- Tony Pang
- Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital ; Northern Clinical School, University of Sydney
| | - Antony Kaufman
- Department of Anatomical Pathology, Royal North Shore Hospital
| | - Julian Choi
- Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital
| | - Anthony Gill
- Northern Clinical School, University of Sydney ; Cancer Diagnosis and Pathology Group, Kolling Institute of Medicine, Royal North Shore Hospital, St. Leonards, NSW 2065
| | - Martin Drummond
- Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital
| | - Thomas Hugh
- Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital ; Northern Clinical School, University of Sydney
| | - Jaswinder Samra
- Upper Gastrointestinal Surgical Unit, Royal North Shore Hospital and North Shore Private Hospital ; Northern Clinical School, University of Sydney ; Australian School of Advanced Medicine, Macquarie University, Macquarie Park, NSW 2109, Australia
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Allard MA, Sebagh M, Baillie G, Lemoine A, Dartigues P, Faitot F, Faron M, Boige V, Vitadello F, Vibert E, Elias D, Adam R, Goéré D, Sa Cunha A. Comparison of complete pathologic response and hepatic injuries between hepatic arterial infusion and systemic administration of oxaliplatin in patients with colorectal liver metastases. Ann Surg Oncol 2014; 22:1925-32. [PMID: 25448804 DOI: 10.1245/s10434-014-4272-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Whether hepatic arterial infusion (HAI) of oxaliplatin influences the rates of complete pathologic response (CPR) and severe oxaliplatin-related lesions (SOxL) in patients with colorectal liver metastases (CRLM) is unknown. This study aimed to compare the incidence of CPR and SOxL between systemic (intravenous, IV) and HAI administration. METHODS All patients with initially unresectable CRLM who had undergone hepatic resection in two expert centers between 2004 and 2010 after at least 6 cycles of oxaliplatin-based chemotherapy administered either via HAI (n = 18) or IV (n = 50) were included. The presence of CPR and SOxL were evaluated by two pathologists. A 1:2 case match using a propensity score was used. RESULTS A CPR was observed significantly more often after HAI (33 vs. 10 %, P = 0.03). However, SOxL had occurred more frequently in patients in the HAI group versus the IV group, 66 and 20 %, respectively (P < 0.001). On a well-balanced cohort, HAI was associated with higher chance of CPR (odds ratio 9.33, 95 % confidence interval 1.59-54.7) but also higher risk of SOxL (odds ratio 13.7, 95 % confidence interval 3.08-61.3). A CPR markedly enhanced overall survival (OS) and disease-free survival (median OS of 114 vs. 42 months, P = 0.02; median disease-free survival of 51 vs. 12 months, P = 0.002). Patients with SOxL did not experience different outcome (median OS of 42 vs. 50 months, respectively; P = 0.92) CONCLUSIONS: HAI of oxaliplatin increases the likelihood of a CPR at the cost of a higher incidence of SOxL in patients with initially unresectable CRLM.
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Affiliation(s)
- An Na Seo
- Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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39
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Equivalent survival in patients with and without steatosis undergoing resection for colorectal liver metastases following pre-operative chemotherapy. Eur J Surg Oncol 2014; 40:1436-44. [DOI: 10.1016/j.ejso.2014.07.040] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2014] [Accepted: 07/24/2014] [Indexed: 12/15/2022] Open
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Nalbantoglu ILK, Tan BR, Linehan DC, Gao F, Brunt EM. Histological features and severity of oxaliplatin-induced liver injury and clinical associations. J Dig Dis 2014; 15:553-60. [PMID: 25060628 DOI: 10.1111/1751-2980.12177] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Oxaliplatin, a component of chemotherapy for colorectal carcinoma liver metastases, can result in hepatic sinusoidal injury; rarely, the injury is fatal. The manifestations of injury are variable. There are no known predictors of susceptibility and outcome. A semi-quantitative system for assessing histological features in non-tumor liver was designed to compare with clinical short-term and long-term outcomes. METHODS A review of 47 patients with metastatic colorectal carcinoma who received liver resection utilizing a system for an aggregate liver injury score (0-4) included hepatocellular and sinusoidal features. Immunohistochemistry (IHC) for aberrant capillarization was included. The proliferation of hepatocytes and sinusoidal lining cells was evaluated with Ki-67 stain. RESULTS In total, 32 (68.1%) cases showed light microscopic lesions of oxaliplatin-induced liver injury, in which 26 were moderate to severe. Elevated preoperative aspartate aminotransferase (AST) and alkaline phosphatase levels were noted with higher injury scores (P = 0.01). Patients with higher injury scores had no significant increase in short-term postoperative complications, with one notable exception, who died of liver failure 10 months postoperatively. Increased CD34 expression was associated with higher injury scores (P = 0.00004), and abnormal AST levels (P = 0.04). Preoperative use of bevacizumab was not associated with lower injury scores. Steatosis was correlated with body mass index (P = 0.052) but not with exposure to oxaliplatin, bevacizumab or irinotecan. CONCLUSIONS The proposed liver injury scoring system encompasses the spectrum of sinusoidal and hepatocellular lesions in oxaliplatin-induced liver injury and is correlated with serum liver enzyme levels in this group. Most patients recovered without complications during the 93-month follow-up, indicating that these lesions are reversible.
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Affiliation(s)
- I L Ke Nalbantoglu
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA
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41
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Kuo JC, Tazbirkova A, Allen R, Kosmider S, Gibbs P, Yip D. Serious hepatic complications of selective internal radiation therapy with yttrium-90 microsphere radioembolization for unresectable liver tumors. Asia Pac J Clin Oncol 2014; 10:266-272. [PMID: 25135200 DOI: 10.1111/ajco.12229] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/11/2014] [Indexed: 01/03/2023]
Abstract
AIM Selective internal radiation therapy with yttrium-90 microsphere radioembolization has been used to treat unresectable liver tumors and its acute toxicity has been well described. Subacute and long-term hepatic complications related to radioembolization however may be underreported in the literature. This retrospective study describes the incidence and sequelae of serious hepatic complications in patients who underwent radioembolization for unresectable liver tumors. METHODS A retrospective review of clinical notes of patients who received radioembolization for unresectable liver tumors from 2001 to 2011 at two Australian institutions was performed to identify those who developed clinically significant hepatic complications. Relevant clinical data were obtained and analyzed to determine their incidence and sequelae. RESULTS A total of 205 patients were identified, of whom 10 (4.9%) developed serious hepatic complications with 7 (3.4%) attributable to radioembolization-induced liver disease. None had preexisting underlying liver disease or progressive hepatic metastases at the time of developing hepatic complication. The median time to the onset of hepatic complications was 3.5 months (range 1-67 months); six patients had a complete resolution eventually, including one patient who subsequently underwent hepatic metastasectomy safely. Three patients died as a result of fulminant hepatic failure. CONCLUSION Selective internal radiation therapy with radioembolization was associated with serious hepatic complications with an incidence of 4.9% and a mortality rate of 1.5% in 205 patients from two Australian institutions. The risk of serious hepatic toxicity therefore needs to be discussed when counseling patients regarding this potential treatment option.
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Affiliation(s)
- James C Kuo
- Department of Medical Oncology, The Canberra Hospital, Garran, Australian Capital Territory, Australia
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Connor AA, Burkes R, Gallinger S. Strategies in the Multidisciplinary Management of Synchronous Colorectal Cancer and Resectable Liver Metastases. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0222-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Brunt EM, Gouw ASH, Hubscher SG, Tiniakos DG, Bedossa P, Burt AD, Callea F, Clouston AD, Dienes HP, Goodman ZD, Roberts EA, Roskams T, Terracciano L, Torbenson MS, Wanless IR. Pathology of the liver sinusoids. Histopathology 2014; 64:907-20. [PMID: 24393125 DOI: 10.1111/his.12364] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The hepatic sinusoids comprise a complex of vascular conduits to transport blood from the porta hepatis to the inferior vena cava through the liver. Under normal conditions, portal venous and hepatic artery pressures are equalized within the sinusoids, oxygen and nutrients from the systemic circulation are delivered to the parenchymal cells and differentially distributed throughout the liver acini, and proteins of liver derivation are carried into the cardiac/systemic circulation. Liver sinusoid structures are lined by endothelial cells unique to their location, and Kupffer cells. Multifunctional hepatic stellate cells and various immune active cells are localized within the space of Disse between the sinusoid and the adjacent hepatocytes. Flow within the sinusoids can be compromised by physical or pressure blockage in their lumina as well as obstructive processes within the space of Disse. The intimate relationship of the liver sinusoids to neighbouring hepatocytes is a significant factor affecting the health of hepatocytes, or transmission of the effects of injury within the sinusoidal space. Pathologists should recognize several patterns of injury involving the sinusoids and surrounding hepatocytes. In this review, injury, alterations and accumulations within the liver sinusoids are illustrated and discussed.
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Affiliation(s)
- Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University, School of Medicine, St Louis, MO, USA
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Morine Y, Shimada M, Utsunomiya T. Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis. Hepatol Res 2014; 44:59-69. [PMID: 23551330 DOI: 10.1111/hepr.12107] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 02/19/2013] [Accepted: 02/24/2013] [Indexed: 12/23/2022]
Abstract
Patients with colorectal liver metastasis (CRLM) can be cured with surgical resection. Recent advances in systemic chemotherapy, including molecular target agents, can be used to introduce "conversion surgery" and achieve R0 resection even in patients with initially unresectable CRLM. Furthermore, neoadjuvant chemotherapy also tries to be applied in patients with resectable CRLM to maximize the remnant liver and reduce the residual micrometastasis before surgery. The development of chemotherapy-induced hepatic injuries is increasingly being recognized, including sinusoidal obstructive syndrome (SOS), steatosis, steatohepatitis and biliary sclerosis. Especially, oxaliplatin (L-OHP)-based chemotherapy in clinical settings appears to be primarily associated with SOS. Various reports have tried to demonstrate the rationale of the correlation between L-OHP-based chemotherapy and SOS for the following hepatic surgery. While we can recognize that this pathophysiological disadvantage leads to hepatic dysfunction and the increasing postoperative morbidity, the essential part of this problem including clinical disadvantage, onset mechanism, evaluation systems, and targeted agents for prevention and treatment of SOS continue to be unclear. In this review, we summarize the current experience with hepatic injury induced by L-OHP-based chemotherapy, focusing on SOS-based on clinical and experimental data, in order to assist in the resolution of these identified factors. Finally, the need for reliable methods to identify the risk of SOS, to evaluate SOS status and to predict the safety of surgical treatment in patients with chemotherapy prior to surgery will be emphasized.
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Affiliation(s)
- Yuji Morine
- Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan
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Abstract
Drug-induced hepatotoxicity is underrecognized but increasingly identified as causing acute and chronic liver disease. Several prescription drugs, over-the-counter medications, dietary and/or supplementary agents, and herbal products are hepatotoxic. Drug-induced liver injury mimics other primary acute and chronic liver diseases and it should be considered in patients with hepatobiliary disease. Certain drugs result in specific histopathologic patterns of liver injury, which may help in sorting out the responsible drug. The diagnosis of drug-induced hepatotoxicity is challenging. It involves excluding other possible causes, careful medication history, the latent period between drug exposure and symptom onset and/or abnormal liver tests, and histopathologic findings.
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Affiliation(s)
- Xuchen Zhang
- Department of Pathology, VA Connecticut Health System and Yale University School of Medicine, 310 Cedar Street, LH 108, New Haven, CT 06516, USA.
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Uchino K, Fujisawa M, Watanabe T, Endo Y, Nobuhisa T, Matsumoto Y, Kai K, Sato S, Notohara K, Matsukawa A. Oxaliplatin-induced liver injury mimicking metastatic tumor on images: a case report. Jpn J Clin Oncol 2013; 43:1034-8. [PMID: 23958518 DOI: 10.1093/jjco/hyt113] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Oxaliplatin-based chemotherapy is widely used for advanced colorectal cancer treatment, but it occasionally induces liver injury that is characterized histologically by sinusoidal dilatation, hepatic plate atrophy and/or venular obstruction. Most of the patients do not reveal apparent radiological abnormalities, however. Here, we report the case of a 47-year-old man with a radiologically detectable mass-forming oxaliplatin-induced sinusoidal injury that mimicked multiple liver tumors. These mass lesions were found on computed tomography images after the administration of six cycles of folinic acid, fluorouracil and oxaliplatin therapy as adjuvant chemotherapy for Stage III rectal cancer. The patient had to undergo liver resection because imaging studies could not exclude metastases. The histological examination revealed that a resected mass lesion was composed of severe sinusoidal dilatation. Milder dilatation was also seen in the surrounding parenchyma. We diagnosed the patient as having an oxaliplatin-induced sinusoidal injury with severe deviation. As oxaliplatin is a standard agent in colorectal cancer therapy today, all clinicians and pathologists should be aware of such non-neoplastic lesions as one of the rare differential diagnoses of metastatic liver tumor, to prevent overtreatment.
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Affiliation(s)
- Kaori Uchino
- *Department of Pathology, Japanese Red Cross Society Himeji Hospital, 1-12-1 Shimoteno, Himeji 670-8540, Japan.
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Jones R, Malik H, Fenwick S, Poston G. Perioperative chemotherapy for resectable colorectal liver metastases: Where now? Eur J Surg Oncol 2013; 39:807-11. [DOI: 10.1016/j.ejso.2013.04.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Revised: 11/27/2012] [Accepted: 04/25/2013] [Indexed: 12/28/2022] Open
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Urdzik J, Bjerner T, Wanders A, Duraj F, Haglund U, Norén A. Magnetic resonance imaging flowmetry demonstrates portal vein dilatation subsequent to oxaliplatin therapy in patients with colorectal liver metastasis. HPB (Oxford) 2013; 15:265-72. [PMID: 23458313 PMCID: PMC3608980 DOI: 10.1111/j.1477-2574.2012.00540.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVES Sinusoidal injury (SI) after oxaliplatin-based therapies for colorectal liver metastasis (CRLM) can increase postoperative morbidity. Preoperative methods to estimate SI are lacking. The aim of this study was to identify SI by evaluating portal vein haemodynamics. METHODS Magnetic resonance imaging flowmetry (MRIF) was used to estimate portal vein haemodynamics in 29 patients with CRLM before liver surgery. Sinusoidal injury was evaluated from resected non-tumorous liver parenchyma according to the combined vascular injury (CVI) score of ≥3. RESULTS All patients with SI (six of 29) received oxaliplatin; however, a significant association could not be proven (P= 0.148). Oxaliplatin-treated patients showed portal vein dilatation in both the SI and non-SI groups compared with patients who had not received oxaliplatin (Bonferroni corrected P= 0.003 and P= 0.039, respectively). Mean portal velocity tended to be lower in patients with SI compared with oxaliplatin-treated patients without SI (Bonferroni corrected P= 0.087). A mean portal velocity of ≤14.35 cm/s together with a cross-section area of ≥1.55 cm(2) was found to predict SI with sensitivity of 100% and specificity of 78%. CONCLUSIONS Oxaliplatin treatment was associated with portal vein dilatation. Patients with SI showed a tendency towards decreased mean portal flow velocity. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma. Portal vein haemodynamic variables estimated by MRIF can identify patients without SI non-invasively.
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Affiliation(s)
- Jozef Urdzik
- Department of Surgery, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
| | - Tomas Bjerner
- Department of Radiology, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
| | - Alkwin Wanders
- Department of Immunology, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
| | - Frans Duraj
- Department of Surgery, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
| | - Ulf Haglund
- Department of Surgery, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
| | - Agneta Norén
- Department of Surgery, Genetics and Pathology, Uppsala UniversityUppsala, Sweden
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Lu QY, Zhao AL, Deng W, Li ZW, Shen L. Hepatic histopathology and postoperative outcome after preoperative chemotherapy for Chinese patients with colorectal liver metastases. World J Gastrointest Surg 2013; 5:30-6. [PMID: 23556058 PMCID: PMC3615301 DOI: 10.4240/wjgs.v5.i3.30] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2012] [Revised: 10/03/2012] [Accepted: 12/20/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the effects of preoperative treatment on the hepatic histology of non-tumoral liver and the postoperative outcome.
METHODS: One hundred and six patients underwent hepatic resection for colorectal metastases between 1999 and 2009. The surgical specimens were reviewed with established criteria for diagnosis and grading of pathological hepatic injury. The impact of preoperative therapy on liver injury and postoperative outcome was analyzed.
RESULTS: Fifty-three patients (50%) received surgery alone, whereas 42 patients (39.6%) received neoadjuvant chemotherapy and 11 (10.4%) patients received preoperative hepatic artery infusion (HAI). Chemotherapy included oxaliplatin-based regimens (31.1%) and irinotecan-based regimens (8.5%). On histopathological analysis, 16 patients (15.1%) had steatosis, 31 (29.2%) had sinusoidal dilation and 20 patients (18.9%) had steatohepatitis. Preoperative oxaliplatin was associated with sinusoidal dilation compared with surgery alone (42.4% vs 20.8%, P = 0.03); however, the perioperative complication rate was not significantly different between the oxaliplatin group and surgery group (27.3% vs 13.2%, P = 0.1). HAI was associated with more steatosis, sinusoidal dilation and steatohepatitis than the surgery group, with higher perioperative morbidity (36.4% vs 13.2%, P = 0.06) and mortality (9.1% vs 0% P = 0.02).
CONCLUSION: Preoperative oxaliplatin was associated with sinusoidal dilation compared with surgery alone. However, the preoperative oxaliplatin had no significant impact on perioperative outcomes. HAI can cause pathological changes and tends to increase perioperative morbidity and mortality.
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Affiliation(s)
- Qi-Ying Lu
- Qi-Ying Lu, Wei Deng, Lin Shen, Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education, Peking University Cancer Hospital and Institute, Beijing 100142, China
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Qi J, Fong Y, Saltz L, D'Angelica MI, Kemeny NE, Gonen M, Shia J, Shukla-Dave A, Jarnagin WM, Do RKG, Schwartz LH, Koutcher JA, Zakian KL. Serial measurement of hepatic lipids during chemotherapy in patients with colorectal cancer: a 1 H MRS study. NMR IN BIOMEDICINE 2013; 26:204-12. [PMID: 22961714 PMCID: PMC3519948 DOI: 10.1002/nbm.2837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 06/20/2012] [Accepted: 06/21/2012] [Indexed: 05/12/2023]
Abstract
Hepatic steatosis is a hallmark of chemotherapy-induced liver injury. We made serial (1) H MRS measurements of hepatic lipids in patients over the time course of a 24-week chemotherapeutic regimen to determine whether (1) H MRS could be used to monitor the progression of chemotherapy-induced steatosis. Thirty-four patients with stage III or IV colorectal cancer receiving 5-fluorouracil, folinic acid and oxaliplatin (n=21) or hepatic arterial infusion of floxuridine with systemic irinotecan (n=13) were studied prospectively. (1) H MRS studies were performed at baseline and after 6 and 24 weeks of treatment. A (1) H MR spectrum was acquired from the liver during a breath hold and the ratio of fat to fat+water (FFW) was calculated to give a measure of hepatic triglycerides (HTGCs). The methodology was histologically validated in 18 patients and the reproducibility was assessed in 16 normal volunteers. Twenty-seven patients completed baseline, 6-week and 24-week (1) H MRS examinations and one was censored. Thirteen of 26 patients (50%) showed an increase in FFW after completion of treatment. Six patients (23%) developed hepatic steatosis and two patients converted from steatosis to nonsteatotic liver. Patients whose 6-week hepatic lipid levels had increased significantly relative to baseline also had a high probability of lipid elevation relative to baseline at the completion of treatment. Serial (1) H MRS is effective for the monitoring of HTGC changes during chemotherapy and for the detection of chemotherapy-associated steatosis. Six of 26 patients developed steatosis during chemotherapy. Lipid changes were observable at 6 weeks.
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Affiliation(s)
- Jing Qi
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Yuman Fong
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Leonard Saltz
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | | | - Nancy E. Kemeny
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Mithat Gonen
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Jinru Shia
- Memorial Sloan-Kettering Cancer Center, New York, New York, USA
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