1
|
Ramos C, Walterskirchen N, Knöbl V, Zotter C, Müller C, Gerakopoulos V, Rauch A, Falk L, Sachet M, D'Angelo E, Agostini M, Pils D, Aust S, Grusch M, Herzog R, Kratochwill K, Le Blanc S, Lenos KJ, Vermeulen L, Riss S, Bachleitner-Hofmann T, Strobel O, Dolznig H, Bergmann M, Brostjan C, Unger LW, Oehler R. Colorectal cancer peritoneal metastasis is promoted by tissue-specific fibroblasts that can arise in response to various local disorders. Cancer Lett 2025:217686. [PMID: 40228602 DOI: 10.1016/j.canlet.2025.217686] [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: 12/02/2024] [Revised: 03/05/2025] [Accepted: 03/28/2025] [Indexed: 04/16/2025]
Abstract
Peritoneal membrane injury induces the activation of local fibroblasts and tissue remodelling, which ultimately can progress to fibrosis. Metastasis of colorectal cancer (CRC) to the abdominal cavity results in such peritoneal damage. Patients with colorectal cancer peritoneal metastasis (CPM) have a particularly poor prognosis, and CPM tumours are characterised by a high infiltration of fibroblasts. Here, we characterised the molecular and functional features of these fibroblasts, and investigated their interaction with other cells in the peritoneal microenvironment. Primary fibroblasts were isolated from 89 patients with different malignant and benign disorders of the peritoneum. We performed comprehensive analyses of single-cell and transcriptome profiling, secretome characterization, and functional enzymatic activity. We were able to identify a peritoneum-specific fibroblast population that increases in response to different types of damage-inducing peritoneal pathologies, including metastasis. These fibroblasts are characterised by the IGFBP2-dependent expression of CD38, which mediates extracellular non-canonical adenosinergic activity and contributes to the suppression of macrophages and T cells. Importantly, peritoneal fibroblasts promoted the growth and invasiveness of tumour cells in a xenograft mouse model of peritoneal metastasis, highlighting their pro-tumorigenic role. Their specific gene signature was associated with poor prognosis in a dataset of 51 patients suffering from colorectal peritoneal metastasis. This study revealed that the CPM is infiltrated by a peritoneal fibroblast subtype, which is absent in healthy tissue, but also observed in benign peritoneal diseases. Given the limited therapeutic options for these patients, these pro-tumorigenic peritoneal fibroblasts could represent an attractive target for inhibiting the peritoneal spread of tumour cells.
Collapse
Affiliation(s)
- Cristiano Ramos
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Natalie Walterskirchen
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Viktoria Knöbl
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Chiara Zotter
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Catharina Müller
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Vasileios Gerakopoulos
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Anna Rauch
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Lena Falk
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Monika Sachet
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Edoardo D'Angelo
- General Surgery 3, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Marco Agostini
- General Surgery 3, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Dietmar Pils
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Stefanie Aust
- Department of Obstetrics and Gynaecology, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Grusch
- Center for Cancer Research, Medical University of Vienna, 1090 Vienna, Austria
| | - Rebecca Herzog
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Paediatrics, Medical University of Vienna, 1090 Vienna, Austria
| | - Klaus Kratochwill
- Division of Paediatric Nephrology and Gastroenterology, Department of Paediatrics and Adolescent Medicine, Comprehensive Center for Paediatrics, Medical University of Vienna, 1090 Vienna, Austria
| | - Solange Le Blanc
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Kristiaan J Lenos
- Laboratory of Experimental Oncology and Radiobiology, Cancer Center Amsterdam, Amsterdam UMC and University of Amsterdam, 1081 BT, Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory of Experimental Oncology and Radiobiology, Cancer Center Amsterdam, Amsterdam UMC and University of Amsterdam, 1081 BT, Amsterdam, The Netherlands
| | - Stefan Riss
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Bachleitner-Hofmann
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Oliver Strobel
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Helmut Dolznig
- Institute of Medical Genetics, Medical University of Vienna, 1090 Vienna, Austria
| | - Michael Bergmann
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Brostjan
- Division of Vascular Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Lukas W Unger
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria; Department of Colorectal Surgery, Oxford University Hospitals, Old Rd, Headington, Oxford OX3 7LE, United Kingdom
| | - Rudolf Oehler
- Division of Visceral Surgery, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria.
| |
Collapse
|
2
|
Garrett C, Sun L, Hayler R, Wijayawardana R, Ahmadi N, Sarofim M, Morris DL. What is the accuracy, sensitivity and specificity of the radiological peritoneal cancer index in repeat cytoreductive surgery: a retrospective study. World J Surg Oncol 2025; 23:138. [PMID: 40217249 PMCID: PMC11987220 DOI: 10.1186/s12957-025-03775-5] [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] [Received: 12/02/2024] [Accepted: 03/23/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND Repeat cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) (rCRS-HIPEC) has improved the long-term survival of select patients with acceptable perioperative morbidity and mortality. The pattern of peritoneal disease recurrence is critical in determining eligibility for rCRS-HIPEC. This study evaluated the accuracy, sensitivity and specificity of the radiological peritoneal cancer index (PCI) across different imaging modalities in rCRS-HIPEC patients. METHODS This was a retrospective study on patients with peritoneal disease recurrence who underwent rCRS-HIPEC between January 2022 to December 2023. The accuracy, sensitivity, and specificity of the radiological PCI in predicting the surgical PCI was calculated overall and for each imaging modality at each abdominal region. RESULTS 32 patients were included in this study. The accuracy, sensitivity and specificity of the overall radiological PCI was 63.0%, 30.8% and 79.9%, respectively. Accuracy (67.5 vs. 62.6%) and specificity (84.8% vs. 75.8%) were higher in FDG-PET versus CT. The sensitivities of all imaging modalities were low (CT 34.9%, FDG-PET 33.3%). FDG-PET and CT had high sensitivities in detecting pelvic disease (80% and 87.5%) but low sensitivities in identifying small bowel (25-33.3% for both modalities) and epigastric disease (25% and 0%). For each abdominal region, the difference between radiological and surgical PCI did not differ significantly based on imaging modality. CONCLUSIONS Overall, the radiological PCI has a good specificity in rCRS-HIPEC patients and should be used to guide perioperative decision-making. FDG-PET had superior accuracy and specificity in comparison to CT in detecting peritoneal disease recurrence.
Collapse
Affiliation(s)
- Celine Garrett
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia.
- Faculty of Medicine & Health, St George and Sutherland Clinical School (University of New South Wales), St George Hospital, Clinical Sciences (WRPitney) Building, Short Street, Kogarah, NSW, 2217, Australia.
| | - Louise Sun
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
| | - Raymond Hayler
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
- Faculty of Medicine & Health, St George and Sutherland Clinical School (University of New South Wales), St George Hospital, Clinical Sciences (WRPitney) Building, Short Street, Kogarah, NSW, 2217, Australia
| | - Ruwanthi Wijayawardana
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
| | - Nima Ahmadi
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
| | - Mina Sarofim
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
| | - David L Morris
- Liver and Peritonectomy Unit, St George Hospital, Gray Street, Kogarah, NSW, 2217, Australia
- Faculty of Medicine & Health, St George and Sutherland Clinical School (University of New South Wales), St George Hospital, Clinical Sciences (WRPitney) Building, Short Street, Kogarah, NSW, 2217, Australia
| |
Collapse
|
3
|
Rivera‐Piza A, Lee S, Lee HH, Lee S, Shin S, Kim J, Park J, Yu JE, Lee SW, Park G, Wilson BC, Kim H. Real-Time, AI-Guided Photodynamic Laparoscopy Enhances Detection in a Rabbit Model of Peritoneal Cancer Metastasis. Cancer Sci 2025; 116:966-975. [PMID: 39930743 PMCID: PMC11967242 DOI: 10.1111/cas.70009] [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: 10/25/2024] [Revised: 01/16/2025] [Accepted: 01/27/2025] [Indexed: 04/04/2025] Open
Abstract
Accurate diagnosis is essential for effective cancer treatment, particularly in peritoneal surface malignancies, where failure to detect metastatic lesions can mislead the treatment plan. This study assessed the diagnostic accuracy of staging laparoscopy using the integration of artificial intelligence (AI)-guided photodynamic diagnosis (PDD) with the photosensitizer Phonozen, activated at 405 nm in a rabbit model. To create peritoneal carcinomatosis, VX2 cells were inoculated laparoscopically into the peritoneum of female white New Zealand rabbits. Conventional and PDD-guided laparoscopy utilized a customized light source that emitted broad-spectrum white light or 405-nm blue light, respectively. The surgical procedure comprised a tripartite approach: exploration and labeling of suspected nodules under white-light visualization, identification of additional metastatic tumors under blue-excitation fluorescent light, and confirmatory open laparotomy to locate overlooked nodules by palpation. Our results showed that the initial experimental data from 371 nodules in 14 rabbits, comparing conventional diagnostic laparoscopy and PDD, showed increased detection sensitivity from 67% ± 1.9% (conventional) to 98% ± 0.7% (PDD) in the small-size nodule. In the second experimental data set from 265 nodules in 10 rabbits, the addition of a real-time AI algorithm further increased the sensitivity to 100% ± 0.0%. Combining PDD with AI enhances the detection of peritoneal cancer metastasis in staging laparoscopy.
Collapse
Affiliation(s)
- Adriana Rivera‐Piza
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
| | - Sung‐Ho Lee
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
| | - Hannah HeeJung Lee
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
- Department of SurgeryYonsei University College of MedicineSeoulSouth Korea
| | - Seungho Lee
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
- Department of SurgeryYonsei University College of MedicineSeoulSouth Korea
| | - Su‐Jin Shin
- Department of PathologyGangnam Severance HospitalSeoulSouth Korea
| | - Jaehyuk Kim
- CAE Group, Health and Medical Equipment BusinessSamsung Electronics Co. Ltd.SeoulSouth Korea
| | - Jong‐Hyun Park
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
- Department of Nano‐Science and TechnologyGraduate School of Convergence Science and Technology of Seoul National UniversitySeoulSouth Korea
| | - Jae Eun Yu
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
| | - Sang Won Lee
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
| | - Gyuri Park
- Yonsei Biomedical Research Institute, Yonsei University College of MedicineSeoulSouth Korea
| | - Brian C. Wilson
- Princess Margaret Cancer CentreUniversity Health NetworkTorontoOntarioCanada
- Department of Medical Biophysics, Faculty of MedicineUniversity of TorontoTorontoOntarioCanada
| | - Hyoung‐Il Kim
- Yonsei‐Dongsung Photodynamic Therapy Research Center, Avison Biomedical Research CenterYonsei University College of MedicineSeoulSouth Korea
- Department of SurgeryYonsei University College of MedicineSeoulSouth Korea
- Princess Margaret Cancer CentreUniversity Health NetworkTorontoOntarioCanada
| |
Collapse
|
4
|
Gandawidjaja MH, Eyob B, Chmiel A, Eng OS. The Role of Prophylactic or Adjuvant Hyperthermic Intraperitoneal Therapy in Appendiceal and Colorectal Cancer Peritoneal Metastasis. Surg Oncol Clin N Am 2025; 34:227-240. [PMID: 40015801 DOI: 10.1016/j.soc.2024.12.001] [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] [Indexed: 03/01/2025]
Abstract
Appendiceal neoplasms and colorectal cancer have a propensity to develop peritoneal metastases. Despite advancements in systemic therapy and surgical management, the development and management of peritoneal metastases remains a challenging problem. Utilization of adjuvant or prophylactic hyperthermic intraperitoneal chemotherapy has been described, with varying quality of data and reported outcomes. The utilization of prophylactic or adjuvant hyperthermic intraperitoneal chemotherapy in patients with appendiceal neoplasms and colorectal cancer remains an active area of exploration.
Collapse
Affiliation(s)
- Monique H Gandawidjaja
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, 3800 Chapman Avenue, Suite 6200, Orange, CA 92868, USA
| | - Belain Eyob
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, 3800 Chapman Avenue, Suite 6200, Orange, CA 92868, USA
| | - Abigail Chmiel
- Department of Surgery, Washington University School of Medicine, MSC 8109-29-2300, 4590 Nash Way, Suite 2300, St. Louis, MO 63110, USA
| | - Oliver S Eng
- Division of Surgical Oncology, Department of Surgery, University of California Irvine, 3800 Chapman Avenue, Suite 6200, Orange, CA 92868, USA.
| |
Collapse
|
5
|
Baratti D, Riva CG, Guaglio M, Cavalleri T, Colletti G, Kusamura S, Sabella G, Milione M, Kuhn E, Nava FL, Deraco M. Clinical and Pathological Risk Factors for Peritoneal Metastases in a Surgical Series of T4 Colorectal Cancers. Cancers (Basel) 2025; 17:1103. [PMID: 40227594 PMCID: PMC11988146 DOI: 10.3390/cancers17071103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 03/08/2025] [Accepted: 03/17/2025] [Indexed: 04/15/2025] Open
Abstract
Background: T4 colorectal cancer (CRC) is associated with an increased risk of peritoneal metastases (PM), but it is currently not possible to accurately predict which patients with T4 CRC develop PM. We investigated the occurrence and risk factors for PM in these patients. Methods: A mono-institutional prospective database of 352 patients undergoing T4 primary CRC resection from 2012 to 2021 was reviewed. Clinico-pathological variables potentially associated with synchronous or metachronous PM were tested by univariate and multivariate analyses. Results: The prevalence of synchronous PM was 73/352 (20.7%) and was significantly associated with age (p = 0.037), primary site (p = 0.002), positive nodes (p = 0.005), elevated CA19.9 (p = 0.001), and non-intestinal histology (p = 0.001). After a median follow-up of 35.9 months (95% confidence interval [CI] = 29.5-44.9), metachronous CRC-PM occurred in 36/164 patients (22.0%) with available data, accounting for a three-year cumulative incidence of 21.5% (95% CI = 14.3-28.1). Metachronous CRC-PM occurred in 3/48 patients (6.2%) with negative nodes and normal CEA, as compared with 33/116 patients (28.4%) with positive nodes and/or elevated CEA (p < 0.001). Combined nodal and CEA status (hazard ratio [HR] = 1.27; 95% CI = 1.02-1.59; p = 0.033), postoperative chemotherapy (HR= 0.51; 95% CI = 0.33-0.77; p = 0.001), and positive resection margins (HR = 2.01; 95% CI = 1.20-3.39; p = 0.008) were significantly associated with PM. Conclusions: The peritoneum is a major site for treatment failure in T4 CRC. Patients with normal CEA and negative lymph nodes are associated with a significantly lower risk for metachronous CRC-PM. These findings may help in refining patient selection for integrated approaches aiming at the prevention or early treatment of CRC-PM, which are pending validation in prospective studies.
Collapse
Affiliation(s)
- Dario Baratti
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Carlo Galdino Riva
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Marcello Guaglio
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Tommaso Cavalleri
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Gaia Colletti
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Shigeki Kusamura
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Giovanna Sabella
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (G.S.); (M.M.)
| | - Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (G.S.); (M.M.)
| | - Elisabetta Kuhn
- Department of Biomedical, Surgical and Dental Sciences, University of Milan, 20122 Milan, Italy;
- Pathology Unit, Foundation IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Francesca Laura Nava
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| | - Marcello Deraco
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milan, Italy; (C.G.R.); (M.G.); (T.C.); (G.C.); (S.K.); (F.L.N.); (M.D.)
| |
Collapse
|
6
|
Liu D, Chen Z, Deng W, Lan J, Zhu Y, Wang H, Xu X, Zhang Y, Wu X, Yang K, Cai J. An Organoid Model for the Therapeutic Effect of Hyperthermic Intraperitoneal Chemotherapy for Colorectal Cancer. Ann Surg Oncol 2025; 32:1925-1940. [PMID: 39589577 PMCID: PMC11811434 DOI: 10.1245/s10434-024-16469-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024]
Abstract
BACKGROUND Consensus regarding the hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC) regimen remains elusive. In this study, patient-derived tumor organoids from CRC were utilized as a preclinical model for in vitro drug testing of HIPEC regimens commonly used in clinical practice. This approach was used to facilitate the clinical formulation of HIPEC. METHOD Tumor tissues and corresponding clinical data were obtained from patients diagnosed with CRC at the Sixth Affiliated Hospital of Sun Yat-Sen University. Qualified samples were cultured and passaged. We aimed to assess the sensitivity of in vitro hyperthermic perfusion using five different regimens, i.e. mitomycin C, mitomycin C combined with cisplatin, mitomycin C combined with 5-fluorouracil, oxaliplatin, and oxaliplatin combined with 5-fluorouracil. RESULTS Tumor organoids obtained from 46 patients with CRC were cultured, and in vitro hyperthermic perfusion experiments were conducted on 42 organoids using five different regimens. The average inhibition rate of mitomycin C was 85.2% (95% confidence interval [CI] 80.4-89.9%), mitomycin C combined with cisplatin was 85.5% (95% CI 80.2-90.7%), mitomycin C combined with 5-fluorouracil was 65.6% (95% CI 59.6-71.6%), oxaliplatin was 37.9% (95% CI 31.5-44.3%), and oxaliplatin combined with 5-fluorouracil was 40.7% (95% CI 33.9-47.5%). CONCLUSION In vitro hyperthermic perfusion demonstrates that the inhibition rate of mitomycin C, both alone and in combination with cisplatin, surpasses that of the combination of mitomycin C with 5-fluorouracil and oxaliplatin. In clinical practice, the combination of mitomycin C and cisplatin can be regarded as the optimal choice for HIPEC in CRC.
Collapse
Affiliation(s)
- Duo Liu
- Department of Colorectal Surgery, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China
| | - Zexin Chen
- Guangdong Research Center of Organoid Engineering and Technology, Accurate International Biotechnology Co. Ltd., Guangzhou, China
| | - Weihao Deng
- Department of Pathology, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jianqiang Lan
- Guangdong Research Center of Organoid Engineering and Technology, Accurate International Biotechnology Co. Ltd., Guangzhou, China
| | - Yu Zhu
- Guangdong Research Center of Organoid Engineering and Technology, Accurate International Biotechnology Co. Ltd., Guangzhou, China
| | - Huaiming Wang
- Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xing Xu
- Department of Breast and Thyroid Surgery, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China
| | - Yuanxin Zhang
- Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiangwei Wu
- Qiantang Biotechnology Co. Ltd., Suzhou, China
| | - Keli Yang
- Department of Colorectal Surgery, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Jian Cai
- Department of Colorectal Surgery, Shenzhen Second People's Hospital, First Affiliated Hospital of Shenzhen University, Medical Innovation Technology Transformation Center of Shenzhen Second People's Hospital, Shenzhen University, Shenzhen, China.
| |
Collapse
|
7
|
Li Q, Xiao Y, Han L, Luo W, Dai W, Fang H, Wang R, Xu Y, Cai S, Goel A, Bai F, Cai G. Microbiome dysbiosis, neutrophil recruitment and mesenchymal transition of mesothelial cells promotes peritoneal metastasis of colorectal cancer. NATURE CANCER 2025; 6:493-510. [PMID: 39966610 DOI: 10.1038/s43018-025-00910-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 01/13/2025] [Indexed: 02/20/2025]
Abstract
Peritoneal metastasis (PM) is common in colorectal cancer (CRC), yet its underlying mechanisms are poorly understood. Here, we explored the transcriptional profile of CRC, PM and adjacent tissues revealing key players that facilitate PM. Single-cell analysis of 48 matched samples from 12 patients revealed that remodeling of malignant cells and the tumor microenvironment promotes CRC progression and metastasis. Multiplexed imaging confirmed depletion in PM by enrichment in CRC tissues of neutrophils associated with mucosal immunity disruption, intestinal microbiota dysbiosis and mesenchymal transition of both cancerous and mesothelial cells. Functional analyses in cell lines, organoids and in vivo models demonstrated that dysbiosis promoted inflammation and protumor neutrophil recruitment, while coupled mesenchymal transition of malignant and mesothelial cells disrupted the stromal structure and increased cancer cell invasiveness. Our findings suggest that targeting mesothelial cells and tumor microenvironment remodeling may offer therapeutic strategies for CRC-PM.
Collapse
Affiliation(s)
- Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yiwei Xiao
- Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University, Beijing, China
| | - Lingyu Han
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wenqin Luo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weixing Dai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hongsheng Fang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Renjie Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ye Xu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
| | - Fan Bai
- Biomedical Pioneering Innovation Center (BIOPIC), Peking-Tsinghua Center for Life Sciences (CLS), School of Life Sciences, Peking University, Beijing, China.
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| |
Collapse
|
8
|
Madonia D, Cashin P, Graf W, Ghanipour L. Appendiceal adenocarcinoma-patterns of tumor spread and prognosis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:108755. [PMID: 39443251 DOI: 10.1016/j.ejso.2024.108755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 09/20/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024]
Abstract
INTRODUCTION Appendiceal adenocarcinoma represents a diagnostic and therapeutic challenge since it is prone to early lymphatic and peritoneal spread. We aimed to analyze the proportion of lymph node metastases in completion right hemicolectomy specimens, risk factors for peritoneal metastases (PM), and prognosis after definitive treatment. METHODS Ninety-three patients with appendiceal adenocarcinoma scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) in Uppsala 2004-2020 were identified from a prospectively maintained registry. Risk factors for PM were assessed based on the presence (CT + group, n = 55) or absence (CT - group, n = 37) of visible PM at baseline CT scan. Prognostic factors were analyzed based on the actual presence (PM group, n = 66) or absence (no PM group, n = 27) of PM. RESULTS The median age was 60 (26-78). Forty-eight patients were women. Resection of PM at initial surgery indicated an 80 % risk of finding PM at a follow-up exploration. R1 appendectomy and perforated appendix had a similar risk for PM (24 %,26 %) which increased to 38 % if both were present. Regional lymph node metastases occurred in 31 % in the CT + group vs. 14 % in the CT - group (p = 0.005) and was associated with poor survival HR 5.16 (1.49-17.81). The 5-year OS and DFS rates were 54 % and 29 % in the PM group. CONCLUSIONS Patients with certain risk factors have a high likelihood of PM despite a normal CT scan, which justifies selective exploration at a HIPEC center. Regional lymph node spread supports the current practice of completion right hemicolectomy and is a significant prognostic factor.
Collapse
Affiliation(s)
- D Madonia
- Department of Surgical Sciences, Uppsala University, Sweden.
| | - P Cashin
- Department of Surgical Sciences, Uppsala University, Sweden
| | - W Graf
- Department of Surgical Sciences, Uppsala University, Sweden
| | - L Ghanipour
- Department of Surgical Sciences, Uppsala University, Sweden
| |
Collapse
|
9
|
Srinivas Rao S, Ghosh S, Vardar BU, Pandey A, Uma Baskaran N, Panwar SS, Catalano OA, Shenoy-Bhangle AS, Harisinghani MG, Brink JA, Kambadakone AR. Imaging in malignant peritoneal neoplasms. Abdom Radiol (NY) 2025; 50:1285-1306. [PMID: 39368001 DOI: 10.1007/s00261-024-04595-z] [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] [Received: 08/21/2024] [Revised: 09/13/2024] [Accepted: 09/14/2024] [Indexed: 10/07/2024]
Abstract
Peritoneal malignancies encompass a diverse range of tumors originating within the peritoneum, including primary tumors such as mesothelioma and primary serous peritoneal carcinoma or secondary tumors resulting from the spread of cancers from gastrointestinal, gynecological, and extra-abdominal sources. The traditional approach of palliative care for these malignancies is being replaced by a multimodal strategies that integrates surgery with systemic or intraperitoneal chemotherapy. Notably, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy has shown significant improvements in survival rates. Imaging is crucial in the multidisciplinary management of these tumors, aiding in diagnosis, staging, restaging, and monitoring therapy response. It is also vital for appropriate patient selection, using the acronym "PAUSE", which involves assessing tumor burden via the peritoneal carcinomatosis index, evaluating patients pre- and post-therapy, detecting complications following therapy, and predicting treatment outcomes. This review explores the imaging manifestations of peritoneal malignancies, distinguishing them from various mimics, and underscores the importance of imaging modalities such as CT, MRI, PET/CT, and PET/MRI in effective decision-making and management.
Collapse
|
10
|
Tang J, Liao L, Xiao B, Sui Q, Zheng M, Jiang W, Han K, Kong L, Pan Z, Ding P. Efficacy and safety of subtotal pelvic peritonectomy for colorectal cancer patients with peritoneal metastasis confined to the pelvic cavity. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109703. [PMID: 40022888 DOI: 10.1016/j.ejso.2025.109703] [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: 08/08/2024] [Revised: 12/21/2024] [Accepted: 02/12/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND Cytoreductive surgery has shown survival benefits for colorectal cancer (CRC) patients with peritoneal metastasis. However, the optimal extent of peritonectomy remains controversial in cases of limited peritoneal metastases. This study modified selective pelvic peritonectomy (SPP) into subtotal pelvic peritonectomy (STPP) for metastasis confined to pelvic cavity, and aimed to evaluate its feasibility, safety, and impact on survival outcomes. MATERIALS AND METHODS CRC patients with limited peritoneal metastasis confined to the pelvic cavity who underwent CC0 (no macroscopic residual cancer remained) resection were included from a prospectively collected database. Surgical complications, disease-free survival (DFS), and overall survival (OS) were analyzed. RESULTS A total of 67 patients were included (26 in the STPP group and 41 in the SPP group). Clinically, STPP was found to be feasible and without increased surgical complications or mortality rates. At a median follow-up of 33.9 months, the 3-year DFS was 65.9 % and 30.7 % in STPP and SPP groups, respectively (P= 0.002). The 3-year OS was 84.1 % and 68.5 % in STPP and SPP groups, respectively (P= 0.006). Moreover, STTP was independently associated with improved DFS (HR = 0.351, 95 % CI 0.165-0.745, P= 0.006) and OS (HR = 0.324, 95 % CI 0.116-0.902, P=0.032). Female gender was also independently associated with poor DFS (HR = 2.146, 95 % CI 1.078-4.271, P= 0.031). Among 24 female patients with remaining ovaries, 9 (37.5 %) cases developed metachronous ovarian metastasis, and of these 6 underwent a second operation. CONCLUSIONS Subtotal pelvic peritonectomy is associated with promising long-term outcomes in CRC patients with peritoneal metastasis confined to the pelvic cavity. Prophylactic bilateral oophorectomy should be strongly considered during cytoreductive surgery.
Collapse
Affiliation(s)
- Jinghua Tang
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Leen Liao
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Binyi Xiao
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Qiaoqi Sui
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Muxu Zheng
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Wu Jiang
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Kai Han
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Lingheng Kong
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China
| | - Zhizhong Pan
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China.
| | - Peirong Ding
- Departments of Colorectal Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, 510060, PR China.
| |
Collapse
|
11
|
Aguirre-Allende I, Pereira-Pérez F, Manzanedo-Romero I, Fernandez-Briones P, Muñoz-Martín M, Serrano-Moral Á, Perez-Viejo E. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A pragmatic comparison of oncological outcomes in synchronous versus metachronous disease. Surg Oncol 2025; 58:102183. [PMID: 39778343 DOI: 10.1016/j.suronc.2024.102183] [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] [Received: 04/27/2024] [Revised: 11/24/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND disease burden (PCI), completeness of cytoreduction or histological features, are known to influence survival after CRS-HIPEC for colorectal peritoneal metastases (CPM). However, there is still debate about influence of CPM onset. The aim of this study is to determine the impact of CPM onset on oncological outcomes after CRS-HIPEC. METHODS all patients with CPM scheduled for CRS-HIPEC at one reference center between December 2007 and September 2022 were included. s-PM were defined as those diagnosed at primary disease treatment; m-PM were considered those diagnosed during follow-up. Survival outcomes and recurrence rates were compared using a pragmatic analysis. RESULTS 125 patients with s-CPM and 170 patients with m-CPM were analyzed. Median follow-up was 58.6 and 50.6 months in s-CPM and m-CPM groups(p = 0.11). Complete cytoreduction (CCS-0/-1) rates were comparable: 84 % s-CPM vs. 88.2 % m-CPM(p = 0.190). Overall survival (OS) was significantly shorter in s-CPM: 24.7 vs. 46.6 months (p = 0.024). Conversely, median disease-free survival was similar in both groups, 10 months vs. 11 months(p = 0.155). Patients in the s-CPM group presented more pN+(p = 0.001), higher histologic grade(p = 0.007) and PCI(p = 0.04), and higher rate of concurrent liver metastases(p = 0.004). RAS/BRAF gene mutations and microsatellite instability did not differ significantly. Perioperative chemotherapy regimens and tolerance were also similar. CONCLUSIONS despite s-CPM being associated with impaired OS after CRS-HIPEC, the onset of PM was not found to be an independent determinant for survival. High-risk molecular and histological features strongly influence oncological outcomes after CRS-HIPEC. This is valuable data that could aid in preoperative patient selection process for CRS-HIPEC.
Collapse
Affiliation(s)
- Ignacio Aguirre-Allende
- Hepatobiliary and Peritoneal Surface Malignancies Unit. General and Digestive Surgery Department, Donostia University Hospital-IHO Donostialdea, IIS Biodonostia, Spain.
| | - Fernando Pereira-Pérez
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Israel Manzanedo-Romero
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Paula Fernandez-Briones
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - María Muñoz-Martín
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Ángel Serrano-Moral
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Estibalitz Perez-Viejo
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| |
Collapse
|
12
|
Cazelles A, Tarhini A, Sabbagh C, Mege D, Bridoux V, Lakkis Z, Voron T, Abdalla S, Lecot F, Karoui M, Manceau G. Risk of metachronous peritoneal metastases after surgery for obstructive colon cancer: Multivariate analysis from a series of 1,085 patients. Surgery 2025; 178:108923. [PMID: 39592328 DOI: 10.1016/j.surg.2024.10.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/01/2024] [Accepted: 10/08/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND Data in the literature suggest that obstruction is an independent predictor of poor prognosis in colon cancer. Of all possible sites of recurrence, peritoneal metastases are associated with worse survival. Our aim was to report the incidence of metachronous peritoneal metastases from a cohort of patients undergoing resection of obstructive colon cancer with curative intent and to identify predictive factors for metachronous peritoneal metastases. METHODS From 2000 to 2015, a total of 2,325 patients were treated for obstructive colon cancer in French surgical centers, members of the French National Surgical Association (AFC). Patients with palliative management, synchronous metastatic disease, and with postoperative mortality were excluded. A multivariate analysis was performed to determine independent predictive factors of metachronous peritoneal metastases. RESULTS The cohort included 1,085 patients. The median follow-up was 21.5 months. Metachronous peritoneal metastases occurred in 12% of patients and were diagnosed after a median interval of 13.5 months. The cumulative 3-year metachronous peritoneal metastasis rate was 10.9%. Three-year overall survival was 85% for patients who did not develop recurrence, 71% for those who develop recurrence without peritoneal metastases, and 56% for those with metachronous peritoneal metastases (P < .0001). In multivariate analysis, 3 variables were identified as independent risk factors for metachronous peritoneal metastases: pT4 stage (odds ratio: 1.98; 95% confidence interval: 1.17-3.36; P = .011), pN2 stage (odds ratio: 2.57; 95% confidence interval: 1.89-4.45; P = .0007), and fewer than 12 lymph nodes examined (odds ratio: 2.01; 95% confidence interval: 1.08-3.74; P = .028). CONCLUSION This study showed a significant risk of metachronous peritoneal metastases after curative-intent resection of obstructive colon cancer. The awareness of factors predisposing to metachronous peritoneal metastases could improve the treatment strategy of these patients.
Collapse
Affiliation(s)
- Antoine Cazelles
- Department of Digestive Surgery, Paris Cité University, Georges Pompidou University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. https://twitter.com/AntoineCazelles
| | - Ahmad Tarhini
- Department of Digestive Surgery, Paris Cité University, Georges Pompidou University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Charles Sabbagh
- Department of Digestive Surgery, Amiens University Hospital, Amiens, France
| | - Diane Mege
- Department of Digestive Surgery, Timone University Hospital, Marseille, France. https://twitter.com/DianeMege
| | - Valérie Bridoux
- Department of Digestive Surgery, Charles Nicolle University Hospital, Rouen, France. https://twitter.com/ValBridoux
| | - Zaher Lakkis
- Department of Digestive Surgery, Besançon University Hospital, Besançon, France. https://twitter.com/ZaherLakkis
| | - Thibault Voron
- Department of Digestive Surgery, Sorbonne University, Saint-Antoine Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. https://twitter.com/ThibaultVORON
| | - Solafah Abdalla
- Department of Digestive Surgery, Université Paris-Sud, Bicêtre University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. https://twitter.com/SolafahAbdalla
| | - Frederik Lecot
- Department of Digestive Surgery, Paris Cité University, Georges Pompidou University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France. https://twitter.com/LecotFrederik
| | - Mehdi Karoui
- Department of Digestive Surgery, Paris Cité University, Georges Pompidou University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Gilles Manceau
- Department of Digestive Surgery, Paris Cité University, Georges Pompidou University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
| |
Collapse
|
13
|
Sato K, Matsui S, Chiba T, Noguchi T, Sakamoto T, Mukai T, Yamaguchi T, Akiyoshi T, Fukunaga Y. Prognostic Impact of Potentially Curative Resection for Synchronous Peritoneal Carcinomatosis with Lavage Cytology Positivity in Colorectal Cancer: A Retrospective Observational Study. J Anus Rectum Colon 2025; 9:52-60. [PMID: 39882235 PMCID: PMC11772798 DOI: 10.23922/jarc.2024-079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/09/2024] [Indexed: 01/31/2025] Open
Abstract
Objectives Although curative resection for synchronous peritoneal carcinomatosis has been reported to improve prognosis, cases with positive intraoperative lavage cytology have not been reported. In this study, we investigated the prognostic value of potentially curative resection based on colorectal cancer and lavage cytology positivity in patients with synchronous peritoneal carcinomatosis. Methods We retrospectively evaluated 72 patients who underwent intraoperative lavage cytology and one-stage potentially curative resection of primary and metastatic lesions (lavage cytology-positive, n = 21; lavage cytology-negative, n = 51) between July 2004 and December 2019. We compared the 5-year overall survival and 3-year recurrence rates between the lavage cytology-positive and lavage cytology-negative groups. Results No significant differences were observed in the 5-year overall survival (48.2% vs. 45.5%, P = 0.924) or 3-year recurrence rates (74.5% vs. 62%, P = 0.143) between the two groups. Univariate analysis for 3-year recurrence revealed that lavage cytology-positive status was not an explanatory variable (hazard ratio: 1.552, 95% confidence interval: 0.83-2.902, P = 0.169). Multivariate analysis identified colon cancer as an independent risk factor of recurrence. Conclusions In resectable cases, the resection of synchronous peritoneal carcinomatosis from colorectal cancer can be considered even if intraoperative lavage cytology is positive.
Collapse
Affiliation(s)
- Kentaro Sato
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shimpei Matsui
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomohiro Chiba
- Department of Cytology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tatsuki Noguchi
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Sakamoto
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshiki Mukai
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomohiro Yamaguchi
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Akiyoshi
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yosuke Fukunaga
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| |
Collapse
|
14
|
Chaudhary AJ, Saleem A, Shahzil M, Hafeez N, Jamali T, Ginnebaugh B. A Rare Case of Colorectal Cancer With Delayed Metastasis to the Duodenum. Case Rep Gastrointest Med 2025; 2025:6679555. [PMID: 39840121 PMCID: PMC11745557 DOI: 10.1155/crgm/6679555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/20/2024] [Indexed: 01/23/2025] Open
Abstract
Colorectal cancer (CRC) continues to be a significant global health issue contributing to a high mortality rate. Despite advancements in treatment, the risk of recurrence remains due to inherent mutations and the rapid turnover of intestinal mucosa. We present an exceptionally rare case of CRC metastasis to the duodenum in a 42-year-old female who has been compliant with postsurgical surveillance. Despite previous negative surveillance results, elevated CEA levels and a 3-cm mesenteric mass were detected, raising concerns for carcinoma, which was later confirmed by biopsy. The tumor board deemed her ineligible for surgery due to vascular involvement, leading to palliative care and an attempt at neoadjuvant therapy. Vigilant monitoring is crucial for early detection and intervention.
Collapse
Affiliation(s)
| | - Abdulmalik Saleem
- Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA
| | - Muhammad Shahzil
- Department of Internal Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, Pennsylvania 17033, USA
| | - Nosheen Hafeez
- Department of Internal Medicine, Baptist Health-UAMS, Little Rock, Arkansas 72205, USA
| | - Taher Jamali
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan 48202, USA
| | - Brian Ginnebaugh
- Department of Gastroenterology and Hepatology, Henry Ford Hospital, Detroit, Michigan 48202, USA
| |
Collapse
|
15
|
Raichurkar P, Brown K, Koh C, Dela Cruz A, Sitharthan D, Moran B, Ansari N, Ahmadi N, Solomon M, Steffens D. Reported outcomes following cytoreductive surgery for colorectal peritoneal metastases: A systematic review to inform evidence-based practice and international consensus. Colorectal Dis 2025; 27:e17280. [PMID: 39734262 DOI: 10.1111/codi.17280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/18/2024] [Accepted: 11/19/2024] [Indexed: 12/31/2024]
Abstract
AIM Cytoreductive surgery provides a chance for long-term survival and cure in selected patients with colorectal peritoneal metastases. As clinical and academic interest in this field increases, heterogeneity in outcome reporting hinders the valid and meaningful synthesis of data into high-quality meta-analyses. The aim of this systemic review was to investigate variability in outcome reporting following cytoreductive surgery with or without intraperitoneal chemotherapy for colorectal peritoneal metastases. METHOD Five electronic databases [MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL)] were interrogated from 2000 to October 2023 to identify all reported outcomes in the current literature. Extracted outcomes were catalogued and reviewed by a multidisciplinary working group into standardized terms and domains. RESULTS A total of 294 studies, from 5112 screened, were included for analysis. We extracted 2903 outcomes verbatim from included studies and catalogued them into 85 standardized outcomes across seven outcome domains. The most frequently reported domains were survival, in 274 (93%) studies, and pathological outcomes, in 232 (79%) studies. Outcomes pertaining to function and life impact were only reported in seven (2%) studies. Reported outcomes were only defined in 35% of cases, and significant variability existed between definitions. CONCLUSION This systematic review highlights the heterogeneity of outcome measurement and reporting following cytoreductive surgery for colorectal peritoneal metastases. Patient-reported outcomes are relatively underrepresented in the current literature. The results of this review will inform an international collaborative effort to create a core outcome set to address these issues.
Collapse
Affiliation(s)
- Pratik Raichurkar
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Kilian Brown
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Cherry Koh
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Annie Dela Cruz
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Darshan Sitharthan
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
| | - Brendan Moran
- Peritoneal Malignancy Institute, Basingstoke & North Hampshire Hospital, Basingstoke, UK
| | - Nabila Ansari
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Nima Ahmadi
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
- Department of Colorectal Surgery, St George Hospital, Kogarah, New South Wales, Australia
| | - Michael Solomon
- Department of Colorectal Surgery, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| | - Daniel Steffens
- Surgical Outcomes Research Centre (SOuRCe), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Institute of Academic Surgery (IAS), Royal Prince Alfred Hospital, Sydney, New South Wales, Australia
- Faculty of Medicine and Health, Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia
| |
Collapse
|
16
|
Zhou H, Wang H, Yi S, Yu S. Effectiveness of hyperthermic intraperitoneal chemotherapy during primary curative resection for colorectal carcinoma. Int J Colorectal Dis 2024; 39:197. [PMID: 39643725 PMCID: PMC11624244 DOI: 10.1007/s00384-024-04774-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/26/2024] [Indexed: 12/09/2024]
Abstract
PURPOSE Peritoneal metastasis (PM) is the life-threatening cause of colorectal cancer patients (CRC). Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery exhibited promising effects in preventing recurrence and increasing the survival of CRC patients. However, the outcomes of HIPEC on treating advanced CRC with risk of PM are still controversial. Here, we retrospectively examined the impact of HIPEC on preventing PM and its overall effects on patients with locally advanced CRC who underwent primary curative resection at our center. METHODS We retrospectively analyzed 45 patients diagnosed with locally advanced colorectal cancer (CRC) who underwent primary curative laparoscopic surgery with proactive hyperthermic intraperitoneal chemotherapy (HIPEC), in conjunction with adjuvant systemic chemotherapy at our center between 2019 and 2022. An additional 55 patients with locally advanced CRC who underwent similar surgery and received adjuvant systemic chemotherapy but did not undergo HIPEC during the same period were selected as the control group. Disease-free survival (DFS), overall survival (OS), and PM incidence were compared between patients with and without HIPEC. RESULTS AND CONCLUSIONS The cumulative PM incidence was 2.2% in the HIPEC group and 14.5% in the control group(P = 0.0347). No significant adverse effects were observed in the HIPEC group. Furthermore, Kaplan-Meier survival analysis showed that the HIPEC correlated to better DFS [hazard ratio (HR) 0.4670, 95% confidence interval (CI) 0.2305-0.9462; P = 0.0345] and extended the overall survival of CRC patients [hazard ratio (HR) 0.3978, 95% confidence interval (CI) 0.1684-0.9395; P = 0.0355]. Therefore, our data supports that adjuvant HIPEC can prevent peritoneal failure in CRC patients and improve both PFS and OS survival following primary curative resection.
Collapse
Affiliation(s)
- Hongwei Zhou
- Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan Province, China
| | - Hui Wang
- Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan Province, China
| | - Shijie Yi
- Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan Province, China
| | - Shiyao Yu
- Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan Province, China.
| |
Collapse
|
17
|
Rijsemus CJV, Kok NFM, Aalbers AGJ, Fijneman RJA, Lopez-Yurda M, Lambregts DMJ, Beets-Tan RGH, Snaebjornsson P, Lahaye MJ. Staging peritoneal metastases in colorectal cancer: The correlation between MRI, surgical and histopathological peritoneal cancer index. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108611. [PMID: 39332128 DOI: 10.1016/j.ejso.2024.108611] [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] [Received: 02/25/2024] [Revised: 04/26/2024] [Accepted: 08/16/2024] [Indexed: 09/29/2024]
Abstract
INTRODUCTION DW-MRI is a non-invasive way to determine the peritoneal cancer index (PCI) in colorectal cancer (CRC) patients with peritoneal metastases (PM). However, like surgeons during surgery, radiologists struggle to differentiate between PM and fibrosis. This study aimed to investigate the agreement between the PCI as determined by MRI (mriPCI), during surgery (sPCI) and histopathology examination (pPCI) in CRC patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). MATERIALS AND METHODS This was a single-centre, retrospective study of CRC patients with PM who were staged with DW-MRI and underwent subsequent CRS-HIPEC. All initial patients' radiological, surgical and histopathology reports were reviewed for the PCI. Histopathology was the reference standard. Primary outcome was the correlation and agreement between mriPCI and pPCI. RESULTS Eighty-seven patients were included. All patients had a complete macroscopic resection. Median (interquartile range) PCI for MRI, surgery, and histopathology were respectively 6.0 (2.5-9.0), 6.0 (4.0-11.0) and 6.0 (2.5-9.5). The intraclass correlation coefficient between the sPCI and pPCI was excellent 0.87 (p <0.001), and good between mriPCI and pPCI 0.77 (p <0.001) and between sPCI and mriPCI 0.70 (p <0.001). CONCLUSION MRI is a promising non-invasive tool to assess the PCI rather accurately.
Collapse
Affiliation(s)
- C J V Rijsemus
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands; GROW School for Oncology and Reproduction - University of Maastricht, Maastricht, the Netherlands.
| | - N F M Kok
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - A G J Aalbers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - R J A Fijneman
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - M Lopez-Yurda
- Department of Biometrics, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - D M J Lambregts
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; GROW School for Oncology and Reproduction - University of Maastricht, Maastricht, the Netherlands
| | - R G H Beets-Tan
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; GROW School for Oncology and Reproduction - University of Maastricht, Maastricht, the Netherlands
| | - P Snaebjornsson
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pathology, Faculty of Medicine - University of Iceland, Reykjavik, Iceland
| | - M J Lahaye
- Department of Radiology, Netherlands Cancer Institute, Amsterdam, the Netherlands; GROW School for Oncology and Reproduction - University of Maastricht, Maastricht, the Netherlands
| |
Collapse
|
18
|
Blaj S, Leebmann H, Babucke M, Acs M, Piso P. Peritoneal Carcinomatosis in Colorectal Cancer: Review and Update of Current Clinical Data. Clin Colorectal Cancer 2024; 23:309-317. [PMID: 38879377 DOI: 10.1016/j.clcc.2024.05.007] [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] [Received: 11/06/2023] [Revised: 05/14/2024] [Accepted: 05/15/2024] [Indexed: 12/01/2024]
Abstract
The peritoneal metastasized colorectal cancer (pmCRC) represents a serious health problem worldwide with a special emphasis in the developed countries. Several guidelines recognize the role of multimodal therapy consisting of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of pmCRC. New data suggests that some other factors, eg, tumor biology, immune profile, neoadjuvant chemotherapy may play a predictive role for the oncological outcome of these patients.
Collapse
Affiliation(s)
- S Blaj
- Clinic for General and Visceral Surgery, Hospital Barmherzige Brüder Regensburg, Germany.
| | - H Leebmann
- Clinic for General and Visceral Surgery, Hospital Barmherzige Brüder Regensburg, Germany
| | - M Babucke
- Clinic for General and Visceral Surgery, Hospital Barmherzige Brüder Regensburg, Germany
| | - M Acs
- Clinic for Surgery, University Hospital Regensburg, Germany
| | - P Piso
- Clinic for General and Visceral Surgery, Hospital Barmherzige Brüder Regensburg, Germany
| |
Collapse
|
19
|
Ramalingam K, Ji L, O'Leary MP, Lum SS, Caba Molina D. Medicaid Expansion and Overall Survival of Lower Gastrointestinal Cancer Patients After Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy. Ann Surg Oncol 2024; 32:10.1245/s10434-024-16446-8. [PMID: 39546107 PMCID: PMC11698770 DOI: 10.1245/s10434-024-16446-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/18/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND In the United States, often only tertiary centers offer cytoreductive surgery and heated intraperitoneal chemotherapy (CRS+HIPEC) for peritoneal metastases in advanced lower gastrointestinal malignancies. Growing evidence shows that Medicaid expansion under the Affordable Care Act (ACA) of 2010 enhanced healthcare access and outcomes. OBJECTIVE We sought to determine whether Medicaid expansion was associated with decreased all-cause mortality of lower gastrointestinal cancer patients following CRS+HIPEC. METHODS We analyzed data from the National Cancer Database (2010-2019) on lower gastrointestinal cancer patients who underwent CRS+HIPEC. Medicaid expansion, introduced under the ACA in 2010, extends health insurance to low-income adults. We categorized states by expansion timing: early (2010-2013), immediate (January 2014), late (after January 2014), or no expansion to assess the impact of Medicaid expansion on mortality using a multivariable Cox regression model. RESULTS Of the 1001 study patients, 671 (67%) were diagnosed in Medicaid expansion states. Grade and Medicaid expansion status were the only factors independently associated with overall survival on multivariable analysis. On average, patients in Medicaid expansion states experienced a 4% increase in annual survival compared with those in non-expansion states who had a 1% decrease in annual survival over the study period. CONCLUSIONS Patients from states that had an early expansion of Medicaid and patients with lower-grade tumors had significantly better overall survival. Our study findings suggest that improved access to healthcare through Medicaid expansion was associated with increased survival rates of lower gastrointestinal cancer patients who undergo CRS+HIPEC for the treatment of peritoneal metastases.
Collapse
Affiliation(s)
- Kirithiga Ramalingam
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Liang Ji
- School of Public Health, Loma Linda University, Loma Linda, CA, USA
| | - Michael P O'Leary
- Department of Surgical Oncology, University of California Irvine, Irvine, CA, USA
| | - Sharon S Lum
- Department of Surgery, Loma Linda University, Loma Linda, CA, USA
| | - David Caba Molina
- Loma Linda University, Loma Linda, CA, USA.
- Riverside University Health System Medical Center, Moreno Valley, CA, USA.
| |
Collapse
|
20
|
Furukawa S, Hiraki M, Kimura N, Okuyama K, Kohya N, Sakai M, Kawaguchi A, Ikubo A, Samejima R. The clinical impact of intraoperative bleeding on peritoneal recurrence after surgery for stage II to III colorectal cancer. Asian J Surg 2024:S1015-9584(24)02314-5. [PMID: 39505635 DOI: 10.1016/j.asjsur.2024.10.005] [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: 02/21/2024] [Revised: 07/17/2024] [Accepted: 10/04/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND This study aimed to investigate the risk factors for peritoneal recurrence (PR) in patients with stage II to III colorectal cancer who underwent colorectal surgery. METHODS A retrospective study was conducted on 232 patients who underwent colorectal surgery for stage II to III colorectal cancer. Univariate and multivariate analyses were performed to determine risk factors for PR. RESULTS The overall incidence of PR was 8.2 % (19/232). A univariate Cox regression analysis showed that a higher level of carcinoembryonic antigen (CEA) (P = 0.039), higher levels of carbohydrate antigen 19-9 (CA19-9) (P < 0.001), preoperative bowel obstruction (P = 0.011), tumor invasion of T4 category (P = 0.019), lymph node metastasis (P = 0.016), poorly differentiated, mucinous or signet-ring histological type (P = 0.010), larger amount of intraoperative bleeding (P = 0.002), R1 resection (P = 0.003), anastomotic leakage Clavien-Dindo classification (CD) ≥2 (P = 0.018), longer postoperative stay (P = 0.002), and recurrence of other organs preceding disseminated recurrence (P = 0.004) were observed significantly more frequently in patients with PR than in patients without PR. A multivariate Cox regression analysis revealed that poorly differentiated, mucinous, or signet-ring histological type (HR: 5.067, 95 % CI: 1.192-21.534, P = 0.028) and intraoperative bleeding (HR: 1.003, 95 % CI: 1.000-1.005, P = 0.017) were independent risk factors for PR. Peritoneal recurrence-free survival curves generated using the Kaplan-Meier method gradually worsened with increasing intraoperative bleeding (P < 0.001). In addition, the sub-analyses between stage II and stage III and between ≤ cT3 and cT4 also demonstrated that peritoneal recurrence-free survival worsened with increasing intraoperative bleeding. CONCLUSIONS Our findings suggest that histological type, and intraoperative bleeding are risk factors for PR in patients who undergo colorectal surgery for stage II to III colorectal cancer. In particular, peritoneal recurrence is associated with increased intraoperative bleeding.
Collapse
Affiliation(s)
- Shunsuke Furukawa
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Masatsugu Hiraki
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan.
| | - Naoya Kimura
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Keiichiro Okuyama
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Naohiko Kohya
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Masashi Sakai
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan
| | - Akashi Ikubo
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| | - Ryuichiro Samejima
- Department of Surgery, Japanese Red Cross Society Karatsu Red Cross Hospital, 2430 Watada, Karatsu, Saga, 847-8588, Japan
| |
Collapse
|
21
|
Provenzano L, Gwee YX, Conca V, Lonardi S, Bozzarelli S, Tamburini E, Passardi A, Zaniboni A, Tosi F, Aprile G, Nasca V, Boccaccino A, Ambrosini M, Vetere G, Carullo M, Guaglio M, Battaglia L, Zhao JJ, Chia DKA, Yong WP, Tan P, So J, Kim G, Shabbir A, Ong CAJ, Casella F, Cremolini C, Bencivenga M, Sundar R, Pietrantonio F. Unveiling the prognostic significance of malignant ascites in advanced gastrointestinal cancers: a marker of peritoneal carcinomatosis burden. Ther Adv Med Oncol 2024; 16:17588359241289517. [PMID: 39502404 PMCID: PMC11536604 DOI: 10.1177/17588359241289517] [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: 05/25/2024] [Accepted: 09/19/2024] [Indexed: 11/08/2024] Open
Abstract
Background Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC). Objectives This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients. Design This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM. Methods We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies. Results Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21-2.35, p = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57-3.01, p < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 - 1.34; HR for OS 1.04, 95% CI: 0.84 - 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16-2.52, p = 0.007). Conclusion Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed.
Collapse
Affiliation(s)
- Leonardo Provenzano
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Yong Xiang Gwee
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Singapore
| | - Veronica Conca
- Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Sara Lonardi
- Medical Oncology 3 Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Silvia Bozzarelli
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | | | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) ‘Dino Amadori’, Meldola, Italy
| | - Alberto Zaniboni
- Unity of Oncology, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Federica Tosi
- Department of Hematology, Oncology and Molecular Oncology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Azienda ULSS8, Vicenza, Italy
| | - Vincenzo Nasca
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessandra Boccaccino
- Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Margherita Ambrosini
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | | | | | - Marcello Guaglio
- Colorectal Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luigi Battaglia
- Colorectal Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Joseph Jonathan Zhao
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Singapore
| | - Daryl Kai Ann Chia
- Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
| | - Wei Peng Yong
- Department of Haematology–Oncology, National University Cancer Institute, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Patrick Tan
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore
- SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore, Singapore
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jimmy So
- Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Surgical Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
| | - Guowei Kim
- Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
- Division of Surgical Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
| | - Asim Shabbir
- Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
- Division of Surgical Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
| | - Chin-Ann Johnny Ong
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine, University of Pisa, Pisa, Italy
- Unity of Oncology, University Hospital of Pisa, Pisa, Italy
| | - Maria Bencivenga
- The N.1 Institute for Health, National University of Singapore, Singapore, Singapore
- Department of Surgery, Dentistry, Pediatrics and Gynaecology, Upper GI Surgery Unit, University of Verona, Verona, Italy
| | - Raghav Sundar
- Department of Haematology–Oncology, National University Cancer Institute, 1E Kent Ridge Road, Singapore 119228, Singapore
- Singapore Gastric Cancer Consortium, Singapore, Singapore
- Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- The N.1 Institute for Health, National University of Singapore, Singapore, Singapore
| | - Filippo Pietrantonio
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G.Venezian, 1, Milan 20133, Italy
| |
Collapse
|
22
|
Wu Y, He F, Liu L, Jiang W, Deng J, Zhang Y, Cao Z, Xu X, Gong J. The Use of CellCollector Assay to Detect Free Cancer Cells in the Peritoneal Cavity of Colorectal Cancer Patients: An Experimental Study. Cancer Med 2024; 13:e70378. [PMID: 39503055 PMCID: PMC11538901 DOI: 10.1002/cam4.70378] [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: 01/18/2024] [Revised: 10/04/2024] [Accepted: 10/16/2024] [Indexed: 11/08/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is associated with high incidence and mortality rates globally. The presence of intraperitoneal free cancer cells (IFCCs) is recognized as an independent prognostic factor for CRC patients. However, a clinical gold standard for IFCCs detection is lacking. The GILUPI CellCollector has demonstrated high sensitivity and specificity in detecting free cancer cells, yet its application for CRC IFCCs detection remains unreported. METHODS We selected CRC and normal cell lines to evaluate the CellCollector's ability to detect tumor cells. A total of 70 CRC patients and 17 patients with benign disease undergoing laparoscopic procedures were investigated. Peritoneal lavage fluid was collected pre- and post-operation, and both real-time PCR (CEA mRNA) and CellCollector detection were performed. We compared the sensitivity and specificity of these two methods. RESULTS CellCollector can distinguish well between CRC and normal cells in cell line experiments. CellCollector detects IFCCs better than real-time PCR (CEA) in CRC patients in different TNM Stages. The sensitivity of CellCollector was higher than that of real-time PCR (84.6% vs. 48.4%), and the specificity of CellCollector was also higher than real-time PCR (79.1% vs. 60.4%). There was no significant difference in the results of IFCCs detected by CellCollector before and after total mesorectal excision (TME) or complete mesocolic excision (CME) radical colorectomy (p > 0.05), but there was a significant difference in real-time PCR detection (p < 0.05). CONCLUSIONS The CellCollector demonstrates superior sensitivity and specificity compared to real-time PCR for detecting IFCCs in CRC patients, suggesting its potential as a clinical tool for IFCCs detection. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01978444.
Collapse
Affiliation(s)
- Yudi Wu
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
- GI Cancer Research InstituteTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Fangxun He
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Liang Liu
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Wei Jiang
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Jiao Deng
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Yujie Zhang
- GI Cancer Research InstituteTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Zhixin Cao
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
- GI Cancer Research InstituteTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Xiangshang Xu
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
- GI Cancer Research InstituteTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| | - Jianping Gong
- Department of Gastrointestinal SurgeryTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
- GI Cancer Research InstituteTongji Hospital, Huazhong University of Science and TechnologyWuhanChina
| |
Collapse
|
23
|
Larsen SG, Graf W, Larsen RH, Revheim M, Mariathasan AM, Sørensen O, Spasojevic M, Rashid G, Lundstrøm N, Gjertsen TJ, Aksnes A, Bruland ØS. Eighteen-Months Safety and Efficacy Following Intraperitoneal Treatment With 224Radium-Labeled Microparticles After CRS-HIPEC in Patients With Peritoneal Metastasis From Colorectal Cancer. J Surg Oncol 2024; 130:1395-1402. [PMID: 39428687 PMCID: PMC11826020 DOI: 10.1002/jso.27897] [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: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 10/22/2024]
Abstract
BACKGROUND AND OBJECTIVES Peritoneal metastasis from colorectal cancer carries a high risk for relapse after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). A novel alpha-emitting radiopharmaceutical (Radspherin) has been designed to deliver short-range radiation to micrometastases and free-floating tumor cells. METHODS A Phase 1/2a study evaluated the safety, tolerability, and signal of efficacy of escalating doses of Radspherin injected intraperitoneally after CRS-HIPEC. RESULTS Eleven patients received 1-4 MBq (Group 1) whereas 12 patients received 7 MBq; nine patients single dose/three patients split-dose (Group 2). Median age was 66.5 and 61.5 years, and median peritoneal cancer index 6 and 7, respectively. One hundred and seventy-eight adverse events were reported, only seven were deemed related to Radspherin. Thirteen serious adverse events (SAEs) were reported in eight patients and no SAEs were related to Radspherin. At 18-months, none of the 12 patients receiving 7 MBq experienced peritoneal recurrences, however four had non-peritoneal recurrences. Across both groups (n = 22), 41% had recurrent disease, only 14% of them in the peritoneum. CONCLUSIONS Radspherin was well tolerated. At 18 months, median disease-free survival has not been reached, and none of the patients receiving the recommended dose (7 MBq) had peritoneal recurrences. The results are encouraging and warrant further clinical evaluation.
Collapse
Affiliation(s)
- S. G. Larsen
- Department of Oncological Surgery, Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - W. Graf
- Department of Surgical SciencesUppsala UniversityUppsalaSweden
- Department of SurgeryUppsala Academic HospitalUppsalaSweden
| | | | - M.‐E. Revheim
- Faculty of Medicine, Institute for Clinical MedicineUniversity of OsloOsloNorway
- The Intervention CentreOslo University HospitalOsloNorway
| | - A. M. Mariathasan
- Department of Oncological Surgery, Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - O. Sørensen
- Department of Oncological Surgery, Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - M. Spasojevic
- Department of Oncological Surgery, Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - G. Rashid
- Department of Radiology, Norwegian Radium HospitalOslo University HospitalOsloNorway
| | - N. Lundstrøm
- Department of Nuclear MedicineUppsala Academic HospitalUppsalaSweden
| | | | | | - Ø. S. Bruland
- Faculty of Medicine, Institute for Clinical MedicineUniversity of OsloOsloNorway
- Department of Oncology, Norwegian Radium HospitalOslo University HospitalOsloNorway
| |
Collapse
|
24
|
Sleiman MJ, Jelip A, Buchs N, Toso C, Liot E, Koessler T, Meyer J, Meurette G, Ris F. Pressurized Intraperitoneal Aerosol Chemotherapy for Peritoneal Carcinomatosis in Colorectal Cancer Patients: A Systematic Review of the Evidence. Cancers (Basel) 2024; 16:3661. [PMID: 39518099 PMCID: PMC11544814 DOI: 10.3390/cancers16213661] [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: 09/30/2024] [Revised: 10/21/2024] [Accepted: 10/28/2024] [Indexed: 11/16/2024] Open
Abstract
INTRODUCTION Pressurized intraperitoneal aerosol chemotherapy (PIPAC) consists of the administration of aerosolized chemotherapy into the abdominal cavity of patients suffering from peritoneal carcinomatosis. Our aim was to review the evidence supporting PIPAC in patients with peritoneal carcinomatosis from colorectal cancer. METHODS A systematic review was performed in accordance with the 2020 PRISMA guideline. MEDLINE and CENTRAL were searched using combinations of terms including "Peritoneal carcinomatosis", "Peritoneal metastasis", "PIPAC", "Pressurized intraperitoneal aerosol chemotherapy" and "Colorectal cancer". Original studies, in English, including patients treated with PIPAC for colorectal peritoneal carcinomatosis, were considered eligible. Case reports, non-English or French language articles and secondary analyses were excluded. RESULTS A total of 385 articles were screened and 374 articles were excluded, leaving 11 publications for inclusion in the qualitative analysis. The included studies totalized 949 patients who received PIPAC for peritoneal carcinomatosis due to colorectal cancer. The median peritoneal carcinomatosis index (PCI) ranged from 10 to 31. In all studies, the complete PIPAC protocol was achieved with an average of two to three 3 PIPAC sessions per patient. Oxaliplatin (OX) was used as a chemotherapeutic agent in all studies and could be associated with intravenous 5-FU and leucovorin. Most post-operative adverse events were recorded as mild to moderate with no intraoperative complications. Only four studies reported a decrease in the average PCI score for 50% of the patients. Median overall survival ranged from 8 to 37.8 months. Quality of life indicators were stable between PIPAC-OX cycles with a small but not statistically significant trend of improvement of most functional scales. CONCLUSIONS PIPAC for peritoneal carcinomatosis from colorectal origin is feasible, safe and tolerable. Its impact on survival outcomes or quality of life remains to be demonstrated by randomized trials.
Collapse
Affiliation(s)
- Marwan-Julien Sleiman
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Annamaria Jelip
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Nicolas Buchs
- Division of Digestive Surgery, Hôpital La Tour, 1217 Meyrin, Switzerland;
| | - Christian Toso
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Emilie Liot
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Thibaud Koessler
- Division of Oncology, University Hospitals of Geneva, 1205 Geneva, Switzerland;
| | - Jeremy Meyer
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Guillaume Meurette
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| | - Frederic Ris
- Division of Digestive Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; (A.J.); (C.T.); (E.L.); (J.M.); (G.M.); (F.R.)
| |
Collapse
|
25
|
Gurusamy K, Leung J, Vale C, Roberts D, Linden A, Wei Tan X, Taribagil P, Patel S, Pizzo E, Davidson B, Mould T, Saunders M, Aziz O, O'Dwyer S. Hyperthermic intraoperative peritoneal chemotherapy and cytoreductive surgery for people with peritoneal metastases: a systematic review and cost-effectiveness analysis. Health Technol Assess 2024; 28:1-139. [PMID: 39254852 PMCID: PMC11417642 DOI: 10.3310/kwdg6338] [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] [Indexed: 09/11/2024] Open
Abstract
Background We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost-utility analysis. Methods We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost-utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work More randomised controlled trials are necessary. Study registration This study is registered as PROSPERO CRD42019130504. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information.
Collapse
Affiliation(s)
- Kurinchi Gurusamy
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Jeffrey Leung
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Claire Vale
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Danielle Roberts
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Audrey Linden
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Xiao Wei Tan
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Priyal Taribagil
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Sonam Patel
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Elena Pizzo
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Brian Davidson
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Tim Mould
- Department of Gynaecological Oncology, University College London NHS Foundation Trust, London, UK
| | - Mark Saunders
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK
| | - Omer Aziz
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
| | - Sarah O'Dwyer
- Colorectal and Peritoneal Oncology Centre, The Christie NHS Foundation Trust, Manchester, UK
- Institute of Cancer Sciences, University of Manchester, Manchester, UK
| |
Collapse
|
26
|
Özcan P, Düzgün Ö. The Importance of Preoperative NLR, PLR, and MPV Values in Predicting the Risk of Complications in Colorectal Peritoneal Carcinomatosis. J Pers Med 2024; 14:916. [PMID: 39338170 PMCID: PMC11446413 DOI: 10.3390/jpm14090916] [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: 07/11/2024] [Revised: 08/04/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND Colorectal cancer peritoneal carcinomatosis (CRC PC) necessitates preoperative assessment of inflammatory markers to predict postoperative outcomes and guide treatment. This study aims to evaluate the prognostic value of preoperative Neutrophil-Lymphocyte Ratio (NLR), Platelet-Lymphocyte Ratio (PLR), and Mean Platelet Volume (MPV) in predicting complications for CRC PC patients undergoing surgery. METHODS Calculating NLR, PLR, and MPV from patient data: NLR = absolute neutrophil count/total lymphocyte count, PLR = total lymphocyte count/total platelet count × 100, and MPV = platelet crit (PCT)/total platelet count. RESULT The study included 196 CRC PC patients and found significant relationships between these markers and overall survival (OS). Patients with an NLR of 3.77 had a median OS of 22.1 months, compared to 58.3 months for those with lower NLR (HR 2.7, 95% CI 1.1-5.3, p < 0.001). CONCLUSIONS For CRC PC patients undergoing CRS+HIPEC, preoperative assessment of NLR, PLR, and MPV can serve as independent prognostic markers for OS. Incorporating these markers into preoperative evaluations may improve patient selection and outcome prediction.
Collapse
Affiliation(s)
- Pırıltı Özcan
- Department of General Surgery, Cerrahpaşa Faculty of Medicine, Istanbul University, 34098 Istanbul, Turkey
| | - Özgül Düzgün
- Department of Surgical Oncology, İstanbul Umraniye Training and Research Hospital, University of Health Sciences, 34766 Istanbul, Turkey;
| |
Collapse
|
27
|
Ramos C, Gerakopoulos V, Oehler R. Metastasis-associated fibroblasts in peritoneal surface malignancies. Br J Cancer 2024; 131:407-419. [PMID: 38783165 PMCID: PMC11300623 DOI: 10.1038/s41416-024-02717-4] [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] [Received: 01/31/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 05/25/2024] Open
Abstract
Over decades, peritoneal surface malignancies (PSMs) have been associated with limited treatment options and poor prognosis. However, advancements in perioperative systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) have significantly improved clinical outcomes. PSMs predominantly result from the spread of intra-abdominal neoplasia, which then form secondary peritoneal metastases. Colorectal, ovarian, and gastric cancers are the most common contributors. Despite diverse primary origins, the uniqueness of the peritoneum microenvironment shapes the common features of PSMs. Peritoneal metastization involves complex interactions between tumour cells and the peritoneal microenvironment. Fibroblasts play a crucial role, contributing to tumour development, progression, and therapy resistance. Peritoneal metastasis-associated fibroblasts (MAFs) in PSMs exhibit high heterogeneity. Single-cell RNA sequencing technology has revealed that immune-regulatory cancer-associated fibroblasts (iCAFs) seem to be the most prevalent subtype in PSMs. In addition, other major subtypes as myofibroblastic CAFs (myCAFs) and matrix CAFs (mCAFs) were frequently observed across PSMs studies. Peritoneal MAFs are suggested to originate from mesothelial cells, submesothelial fibroblasts, pericytes, endothelial cells, and omental-resident cells. This plasticity and heterogeneity of CAFs contribute to the complex microenvironment in PSMs, impacting treatment responses. Understanding these interactions is crucial for developing targeted and local therapies to improve PSMs patient outcomes.
Collapse
Affiliation(s)
- Cristiano Ramos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Vasileios Gerakopoulos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Rudolf Oehler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
28
|
Ota E, Fukunaga Y, Mukai T, Hiyoshi Y, Yamaguchi T, Nagasaki T, Akiyoshi T. Cytoreductive surgery without intra-peritoneal chemotherapy for metachronous colorectal peritoneal metastases. World J Surg Oncol 2024; 22:205. [PMID: 39085860 PMCID: PMC11290162 DOI: 10.1186/s12957-024-03471-w] [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] [Received: 01/03/2024] [Accepted: 07/16/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Cytoreductive surgery and chemotherapy reportedly improve the prognosis of patients with metachronous peritoneal metastases. However, the types of peritoneal metastases indicated for cytoreductive surgery remains unclear. Therefore, we aimed to clarify the category of cases for which cytoreductive surgery would be effective and report the prognosis associated with cytoreductive surgery for metachronous peritoneal metastases. METHODS This study included 52 consecutive patients who underwent cytoreductive surgery for metachronous peritoneal metastases caused by colorectal cancer between January 2005 and December 2018 and fulfilled the selection criteria. The median follow-up period was 54.9 months. Relapse-free survival was calculated as the time from cytoreductive surgery of metachronous peritoneal metastases to recurrence. Overall survival was defined as the time from cytoreductive surgery of metachronous peritoneal metastases to death or the end of the follow-up period. RESULTS The 5-year relapse-free survival rate was 30.0% and the 5-year overall survival rate was 72.3%. None of the patients underwent hyperthermic intraperitoneal chemotherapy. The analysis indicated no potential risk factors for 5-year relapse-free survival. However, for 5-year overall survival, the multivariate analysis revealed that time to diagnosis of metachronous peritoneal metastases of < 2 years after primary surgery (hazard ratio = 4.1, 95% confidence interval = 2.0-8.6, p = 0.0002) and number of metachronous peritoneal metastases ≥ 3 (hazard ratio = 9.8, 95% confidence interval = 2.3-42.3, p = 0.002) as independent factors associated with a poor prognosis. CONCLUSIONS Long intervals of more than 2 years after primary surgery and 2 or less metachronous peritoneal metastases were good selection criteria for cytoreductive surgery for metachronous peritoneal metastases from colorectal cancer.
Collapse
Affiliation(s)
- Emi Ota
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yosuke Fukunaga
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
| | - Toshiki Mukai
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yukiharu Hiyoshi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tomohiro Yamaguchi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Toshiya Nagasaki
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Akiyoshi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| |
Collapse
|
29
|
Wu Y, Liu L, He F, Zhang Y, Jiang W, Cao Z, Xu X, Gong J. Long noncoding RNA small nucleolar RNA host gene 1 as a potential novel biomarker for intraperitoneal free cancer cells in colorectal cancer. iScience 2024; 27:110228. [PMID: 38993673 PMCID: PMC11237925 DOI: 10.1016/j.isci.2024.110228] [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: 12/23/2023] [Revised: 05/03/2024] [Accepted: 06/06/2024] [Indexed: 07/13/2024] Open
Abstract
Colorectal cancer (CRC) is a prevalent cancer with intraperitoneal free cancer cells (IFCCs) playing a significant role in prognosis, especially during surgeries. The identification of IFCCs is crucial for determining the stage and treatment of patients with CRC. Existing methods for IFCC detection, such as conventional cytology, immunocytochemistry (ICC), and polymerase chain reaction (PCR), have limitations in sensitivity and specificity. This study investigates the potential of long noncoding RNA (lncRNA) SNHG1 as a biomarker for detecting IFCCs in patients with CRC. Testing on a cohort of 91 patients with CRC and 26 patients with gastrointestinal benign disease showed that SNHG1 outperformed CEA in distinguishing CRC cells and detecting IFCCs across different disease stages. SNHG1 demonstrated higher sensitivity (76.1% vs. 43.1%) and specificity (68.4% vs. 52.3%) than CEA for IFCC detection in patients with CRC, suggesting its promising role as a clinical method for identifying IFCCs in CRC.
Collapse
Affiliation(s)
- Yudi Wu
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Liang Liu
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Fangxun He
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Yujie Zhang
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Wei Jiang
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Zhixin Cao
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Xiangshang Xu
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| | - Jianping Gong
- Department of Gastrointestinal Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
- GI Cancer Research Institute, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, P.R. China
| |
Collapse
|
30
|
Parasido E, Ribeiro P, Chingle RM, Rohwetter T, Gupta N, Avetian G, Bladelli E, Pierobon M, Chen Y, Tang Q, Schnermann M, Rodriguez O, Robbins D, Burke TR, Albanese C, Ihemelandu C. Enhancing precision in colorectal cancer surgery: development of an LGR5-targeting RSPO1 peptide mimetic as a contrast agent for intraoperative fluorescence molecular imaging. Cell Cycle 2024:1-12. [PMID: 38984667 DOI: 10.1080/15384101.2024.2364578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/09/2024] [Indexed: 07/11/2024] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. In the United States alone, CRC was responsible for approximately 52,550 deaths in 2023, with an estimated 153,020 new cases. CRC presents with synchronous peritoneal spread in 5-10% of patients, and up to 20-50% of patients with recurrent disease will develop metachronous colorectal cancer peritoneal metastatic (CRC-PM) disease. Eradication of the tumor, tumor margins and microscopic residual disease is paramount, as microscopic residual disease is associated with local recurrences, with 5-year survival rates of less than 35%. The success of resection and reduction of residual disease depends on the accuracy with which cancer cells and normal tissue can be intra-operatively distinguished. Fluorescence Molecular Imaging (IFMI) and tumor-targeted contrast agents represent a promising approach for intraoperative detection and surgical intervention. Proper target selection, the development of scalable imaging agents and enhanced real-time tumor and tumor microenvironment imaging are critical to enabling enhanced surgical resection. LGR5 (leucine-rich repeat-containing G-protein-coupled receptor 5), a colonic crypt stem cell marker and the receptor for the R-spondins (RSPO) in the Wnt signaling pathway, is also expressed on colorectal cancer stem cells (CSC) and on CRC tumors and metastases, suggesting it could be a useful target for imaging of CRC. However, there are numerous diverging reports on the role of LGR5 in CRC therapy and outcomes. Herein, we report on the synthesis and validation of a 37 amino acid RSPO1-mimetic peptide, termed RC18, that was specifically designed to access the R-spondin binding site of LGR5 to potentially be used for interoperative imaging of CRC-PM. The receptor-binding capabilities of the RC18 indicate that direct interactions with LGR5 neither significantly increased LGR5 signaling nor blocked RSPO1 binding and signal transduction, suggesting that the RSPO1-mimetic is functionally inert, making it an attractive contrast agent for intraoperative CRC-PM imaging.
Collapse
Affiliation(s)
- Erika Parasido
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Patricia Ribeiro
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Ramesh M Chingle
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Thomas Rohwetter
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Nikita Gupta
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - George Avetian
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Elisa Bladelli
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA
| | - Mariaelena Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA, USA
| | - Yu Chen
- College of Photonic and Electronic Engineering, Fujian Normal University, Fuzhou, Fujian, P. R. China
| | - Qinggong Tang
- Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK, USA
| | - Martin Schnermann
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Olga Rodriguez
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
- Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA
| | - David Robbins
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Terrence R Burke
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
| | - Chris Albanese
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
- Center for Translational Research, Georgetown University Medical Center, Washington, DC, USA
- Department of Radiology, Georgetown University Medical Center, Washington, DC, USA
| | - Chukwuemeka Ihemelandu
- Department of Oncology and Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| |
Collapse
|
31
|
Sarcinelli GM, Varinelli L, Ghislanzoni S, Padelli F, Lorenzini D, Vingiani A, Milione M, Guaglio M, Kusamura S, Deraco M, Pruneri G, Gariboldi M, Baratti D, Bongarzone I. Sulfatide imaging identifies tumor cells in colorectal cancer peritoneal metastases. Cancer Metab 2024; 12:18. [PMID: 38943216 PMCID: PMC11212237 DOI: 10.1186/s40170-024-00345-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 06/19/2024] [Indexed: 07/01/2024] Open
Abstract
Even with systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC), peritoneal metastases (PM) remain a common site of disease progression for colorectal cancer (CRC) and are frequently associated with a poor prognosis. The mass spectrometry (MS) method known as Matrix-Assisted Laser Desorption/Ionization - Time of Flight (MALDI-TOF) is frequently used in medicine to identify structural compounds and biomarkers. It has been demonstrated that lipids are crucial in mediating the aggressive growth of tumors. In order to investigate the lipid profiles, particularly with regard to histological distribution, we used MALDI-TOF MS (MALDI-MS) and MALDI-TOF imaging MS (MALDI-IMS) on patient-derived tumor organoids (PDOs) and PM clinical samples. According to the MALDI-IMS research shown here, the predominant lipid signature of PDOs in PM tissues, glycosphingolipid (GSL) sulfates or sulfatides, or STs, is unique to the areas containing tumor cells and absent from the surrounding stromal compartments. Bioactive lipids are derived from arachidonic acid (AA), and AA-containing phosphatidylinositol (PI), or PI (18:0-20:4), is shown to be highly expressed in the stromal components. On the other hand, the tumor components contained a higher abundance of PI species with shorter and more saturated acyl chains (C34 and C36 carbons). The cellular subversion of PI and ST species may alter in ways that promote the growth, aggressiveness, and metastasis of tumor cells. Together, these findings suggest that the GSL/ST metabolic programming of PM may contain novel therapeutic targets to impede or halt PM progression.
Collapse
Affiliation(s)
- G M Sarcinelli
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy
| | - L Varinelli
- Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy
| | - S Ghislanzoni
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy
| | - F Padelli
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy
| | - D Lorenzini
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - A Vingiani
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - M Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - M Guaglio
- Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - S Kusamura
- Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - M Deraco
- Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - G Pruneri
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - M Gariboldi
- Department of Research, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy
| | - D Baratti
- Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Venezian 1, 20133, Milan, Italy
| | - I Bongarzone
- Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale Dei Tumori, Via G. Amadeo 42, 20133, Milan, Italy.
| |
Collapse
|
32
|
Nyström K, Olsson L. A systematic review of population-based studies on metachronous metastases of colorectal cancer. World J Surg 2024; 48:1521-1533. [PMID: 38747538 DOI: 10.1002/wjs.12204] [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: 02/20/2024] [Accepted: 04/22/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND The occurrence of metachronous metastases (MM) of colorectal (CRC), colon (CC), and rectal (RC) cancer of population-based studies has not been compiled in a systematic review previously. METHODS MEDLINE, Embase, and Cochrane Library were searched for primary studies of any design from inception until January 2021 and updated in August 2023 (CRD42021261648). The PRISMA guidelines were adopted, and the Newcastle-Ottawa Quality Assessment Scale used for risk of bias assessment. Outcomes on overall and organ-specific MM were extracted. A narrative analysis followed. RESULTS Out of 2143 unique hits, 162 publications were read in full-text and 37 population-based cohort studies published in 1981-2022 were included. Ten studies adopted time-dependent analyses; eight were registry-based and seven had a low risk of bias. Three studies reported 5-year recurrence rate of MM overall of stages I-III; for CRC, it was 20.5%, for CC, it was 18% and 25.6%, and for RC, it was 23%. Four studies reported 5-year recurrence rate of organ-specific MM of stages I-III-for CRC, it was 2.2% and 5.5% for peritoneal metastases and 5.8% for lung metastases and for CC 4.5% for peritoneal metastases. Twenty-seven studies reported proportions of patients diagnosed with MM, but data on the length of follow-up was incomplete and varied widely. Proportions of patients with CRC stages I-III that developed MM overall was 14.4%-26.1% in 10 studies. In relation to the enrollment period, a downward trend may be discernible. CONCLUSION Studies adopting a more appropriate analysis were highly heterogeneous, whereas uncertain data of partly inadequate studies may indicate that MM are overall declining.
Collapse
Affiliation(s)
- Karin Nyström
- Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Department of Oncology, Örebro University Hospital, Örebro, Sweden
| | - Louise Olsson
- Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Centre for Assessment of Medical Technology, Örebro University Hospital, Örebro, Sweden
| |
Collapse
|
33
|
Gurusamy K, Leung J, Vale C, Roberts D, Linden A, Tan XW, Taribagil P, Patel S, Pizzo E, Davidson B, Saunders M, Aziz O, O’Dwyer ST. Cytoreductive surgery plus hyperthermic intraoperative peritoneal chemotherapy for people with peritoneal metastases from colorectal, ovarian or gastric origin: A systematic review of randomized controlled trials. World J Surg 2024; 48:1385-1403. [PMID: 38658171 PMCID: PMC7617159 DOI: 10.1002/wjs.12186] [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: 11/20/2023] [Accepted: 03/10/2024] [Indexed: 04/26/2024]
Abstract
BACKGROUND There is uncertainty in the relative benefits and harms of hyperthermic intraoperative peritoneal chemotherapy (HIPEC) when added to cytoreductive surgery (CRS) +/- systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric, or ovarian cancers. METHODS We searched randomized controlled trials (RCTs) in the medical literature until April 14, 2022 and applied methods used for high-quality systematic reviews. FINDINGS We included a total of eight RCTs (seven RCTs included in quantitative analysis as one RCT did not provide data in an analyzable format). All comparisons other than ovarian cancer contained only one trial. For gastric cancer, there is high uncertainty about the effect of CRS + HIPEC + systemic chemotherapy. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, CRS + HIPEC + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy. For colorectal cancer, CRS + HIPEC + systemic chemotherapy probably results in little to no difference in all-cause mortality and may increase the serious adverse events proportions compared to CRS +/- systemic chemotherapy, but probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone. INTERPRETATION The role of CRS + HIPEC in gastric peritoneal metastases is uncertain. CRS + HIPEC should be standard of care in women with stage III or greater epithelial ovarian cancer undergoing interval CRS. CRS + systemic chemotherapy should be standard of care for people with colorectal peritoneal metastases, with HIPEC given only as part of a RCT focusing on subgroups and regimes. PROSPERO REGISTRATION CRD42019130504.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Mark Saunders
- The Colorectal and Peritoneal Oncology Centre, Christie NHS Foundation Trust, London, UK
| | - Omer Aziz
- The Colorectal and Peritoneal Oncology Centre, Christie NHS Foundation Trust, London, UK
- Division of Cancer Studies, University of Manchester, London, UK
| | - Sarah T. O’Dwyer
- The Colorectal and Peritoneal Oncology Centre, Christie NHS Foundation Trust, London, UK
- Division of Cancer Studies, University of Manchester, London, UK
| |
Collapse
|
34
|
Herzberg J, Acs M, Guraya SY, Schlitt HJ, Honarpisheh H, Strate T, Piso P. Anastomotic leakage following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: A clinical cohort study. Surg Oncol 2024; 54:102080. [PMID: 38663060 DOI: 10.1016/j.suronc.2024.102080] [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] [Received: 12/30/2023] [Revised: 03/13/2024] [Accepted: 04/15/2024] [Indexed: 05/26/2024]
Abstract
BACKGROUND Extended oncological resections for colorectal cancer surgery are associated with a high rate of complications, especially anastomotic leakage (AL). This study determines the incidence of risk factors for postoperative complications following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal cancer (CRC). METHODS In this cohort study, the clinical data of all patients with CRC, treated with CRS and HIPEC, from 2011 to 2021 was analyzed. We considered patients' characteristics, tumor-specific features, postoperative complications, and hospital stay using Chi-Square-test or Fisher's exact test. The Mann-Whitney-U-test was used to measure the probability of differences between two sets of data. RESULTS Of 1089 HIPEC procedures performed in the study center, 185 patients with CRC and peritoneal metastasis were treated with CRS and HIPEC after formation of at least one anastomosis and therefore included in this study. This included synchronous and metachronous peritoneal metastasis with a mean peritoneal cancer index of 8.67 ± 5.22. In this cohort, AL occurred in 12 (6.5 %) patients. There was no correlation between the number of anastomoses and the occurrence of an AL (p = 0.401). CONCLUSION This study reports a low risk of AL after CRS with HIPEC for CRC, comparable to other published data. If a complete cytoreduction seems possible, the risk of anastomotic leakage should not negatively influence the decision to resect. Further studies on this subject are essential to validate our findings.
Collapse
Affiliation(s)
- Jonas Herzberg
- Department of Surgery - Hospital Reinbek St. Adolf-Stift, Hamburger Strasse 41, 21465, Reinbek, Germany.
| | - Miklos Acs
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, D-93049, Germany; Department of Surgery, University Hospital, Regensburg, D-93049, Germany
| | - Salman Yousuf Guraya
- Clinical Sciences Department, College of Medicine, University of Sharjah, P. O. Box 27272, Sharjah, United Arab Emirates
| | | | - Human Honarpisheh
- Department of Surgery - Hospital Reinbek St. Adolf-Stift, Hamburger Strasse 41, 21465, Reinbek, Germany
| | - Tim Strate
- Department of Surgery - Hospital Reinbek St. Adolf-Stift, Hamburger Strasse 41, 21465, Reinbek, Germany
| | - Pompiliu Piso
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, D-93049, Germany
| |
Collapse
|
35
|
Bootsma S, Dings MPG, Kesselaar J, Helderman RFCPA, van Megesen K, Constantinides A, Moreno LF, Stelloo E, Scutigliani EM, Bokan B, Torang A, van Hooff SR, Zwijnenburg DA, Wouters VM, van de Vlasakker VCJ, Galanos LJK, Nijman LE, Logiantara A, Veenstra VL, Schlingemann S, van Piggelen S, van der Wel N, Krawczyk PM, Platteeuw JJ, Tuynman JB, de Hingh IH, Klomp JPG, Oubrie A, Snaebjornsson P, Medema JP, Oei AL, Kranenburg O, Elbers CC, Lenos KJ, Vermeulen L, Bijlsma MF. Exploiting a subtype-specific mitochondrial vulnerability for successful treatment of colorectal peritoneal metastases. Cell Rep Med 2024; 5:101523. [PMID: 38670098 PMCID: PMC11148637 DOI: 10.1016/j.xcrm.2024.101523] [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] [Received: 06/23/2023] [Revised: 11/22/2023] [Accepted: 04/02/2024] [Indexed: 04/28/2024]
Abstract
Peritoneal metastases (PMs) from colorectal cancer (CRC) respond poorly to treatment and are associated with unfavorable prognosis. For example, the addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery in resectable patients shows limited benefit, and novel treatments are urgently needed. The majority of CRC-PMs represent the CMS4 molecular subtype of CRC, and here we queried the vulnerabilities of this subtype in pharmacogenomic databases to identify novel therapies. This reveals the copper ionophore elesclomol (ES) as highly effective against CRC-PMs. ES exhibits rapid cytotoxicity against CMS4 cells by targeting mitochondria. We find that a markedly reduced mitochondrial content in CMS4 cells explains their vulnerability to ES. ES demonstrates efficacy in preclinical models of PMs, including CRC-PMs and ovarian cancer organoids, mouse models, and a HIPEC rat model of PMs. The above proposes ES as a promising candidate for the local treatment of CRC-PMs, with broader implications for other PM-prone cancers.
Collapse
Affiliation(s)
- Sanne Bootsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Mark P G Dings
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Job Kesselaar
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Roxan F C P A Helderman
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Radiation Oncology, Amsterdam, the Netherlands
| | - Kyah van Megesen
- Laboratory of Translational Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands
| | | | - Leandro Ferreira Moreno
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Ellen Stelloo
- Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Enzo M Scutigliani
- Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Biology, Amsterdam, the Netherlands
| | - Bella Bokan
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Radiation Oncology, Amsterdam, the Netherlands
| | - Arezo Torang
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Sander R van Hooff
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Danny A Zwijnenburg
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Valérie M Wouters
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | | | | | - Lisanne E Nijman
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Adrian Logiantara
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Veronique L Veenstra
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Sophie Schlingemann
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Sterre van Piggelen
- Laboratory of Translational Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands
| | - Nicole van der Wel
- Amsterdam UMC Location University of Amsterdam, Electron Microscopy Center, Amsterdam, the Netherlands
| | - Przemek M Krawczyk
- Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Medical Biology, Amsterdam, the Netherlands
| | | | - Jurriaan B Tuynman
- Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Surgery, Cancer Center Amsterdam, De Boelelaan 1117, Amsterdam, the Netherlands
| | - Ignace H de Hingh
- Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands; GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | | | | | - Petur Snaebjornsson
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Jan Paul Medema
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Arlene L Oei
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam UMC Location University of Amsterdam, Department of Radiation Oncology, Amsterdam, the Netherlands
| | - Onno Kranenburg
- Laboratory of Translational Oncology, UMC Utrecht Cancer Center, Utrecht, the Netherlands
| | - Clara C Elbers
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Kristiaan J Lenos
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Louis Vermeulen
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands.
| |
Collapse
|
36
|
Smith HG, Nilsson PJ, Shogan BD, Harji D, Gambacorta MA, Romano A, Brandl A, Qvortrup C. Neoadjuvant treatment of colorectal cancer: comprehensive review. BJS Open 2024; 8:zrae038. [PMID: 38747103 PMCID: PMC11094476 DOI: 10.1093/bjsopen/zrae038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 03/12/2024] [Accepted: 03/21/2024] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. METHODS A narrative review of the most recent relevant literature was conducted. RESULTS Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. CONCLUSION Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.
Collapse
Affiliation(s)
- Henry G Smith
- Abdominalcenter K, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Per J Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet and Dept. of Pelvic Cancer, Karolinska University Hospital, Stockholm, Sweden
| | - Benjamin D Shogan
- Department of Surgery, The University of Chicago Medicine, Chicago, Illinois, USA
| | - Deena Harji
- Department of Colorectal Surgery, Manchester University NHS Foundation Trust, Manchester, UK
| | - Maria Antonietta Gambacorta
- Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
- Dipartimento di Scienze Radiologiche ed Ematologiche, Universita Cattolica del Sacro Cuore, Rome, Italy
| | - Angela Romano
- Dipartimento di Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
| | - Andreas Brandl
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Camilla Qvortrup
- Department of Oncology, Rigshospital, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
37
|
Bautista-Saiz C, Rivera-Moncada LF, Lino-Silva LS, Pérez-Correa GA, Frías-Fernández P. Identification of an Objective Cut-Off Point to Define the Clinical Stage T4a in Colon Cancer. GASTROENTEROLOGY INSIGHTS 2024; 15:366-374. [DOI: 10.3390/gastroent15020025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
Introduction: The current state of pathology practice and the variability in diagnosing pT4a colon cancer have been underexplored in existing studies. Our objective was to establish a specific cutoff point to distinguish between the pathological stages of pT3 and pT4a in colon cancer. Methods: We conducted a cross-sectional study involving pT3 and pT4 (pN0-2, cM0) colon cancers, measuring the distance to the serosa. Patients were categorized and analyzed based on this distance and the peritoneal reaction, with the aim being to ascertain their prognostic implications. Results: A total of 384 patients were analyzed. Patients with a distance between the invading front of cancer and the serosa ≥ 1 mm without a peritoneal reaction exhibited a median survival of 118 months, contrasting the amount of 70 months for those with <1 mm plus peritoneal reaction. Only lengths <1 mm with peritoneal reaction showed a significant correlation with mortality (p < 0.001). Conclusion: Our study revealed that patients in whom neoplastic cells were less than 1 mm from the serosal surface, accompanied by a peritoneal reaction (hemorrhage, inflammation, neovascularization, fibrin), had significantly lower survival rates compared to those with more than 1 mm distance and without peritoneal response (70 vs. 118 months, p < 0.001). Hence, such cases should be considered within the pT4a stage.
Collapse
Affiliation(s)
- Carolina Bautista-Saiz
- Instituto Nacional de Cancerología (Mexico’s National Cancer Institute), San Fernando 22, Tlalpan, Mexico City 14080, Mexico
| | - Luisa F. Rivera-Moncada
- Instituto Nacional de Cancerología (Mexico’s National Cancer Institute), San Fernando 22, Tlalpan, Mexico City 14080, Mexico
| | - Leonardo S. Lino-Silva
- Instituto Nacional de Cancerología (Mexico’s National Cancer Institute), San Fernando 22, Tlalpan, Mexico City 14080, Mexico
| | - Guillermo A. Pérez-Correa
- Instituto Nacional de Cancerología (Mexico’s National Cancer Institute), San Fernando 22, Tlalpan, Mexico City 14080, Mexico
| | - Pedro Frías-Fernández
- Hospital General de Tula, Carretera Tula-Tepeji Km 1.5, El Carmen, Tula de Allende 42830, Mexico
| |
Collapse
|
38
|
Wang R, Yan Z. Cancer spreading patterns based on epithelial-mesenchymal plasticity. Front Cell Dev Biol 2024; 12:1259953. [PMID: 38665432 PMCID: PMC11043583 DOI: 10.3389/fcell.2024.1259953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Introduction: Metastasis is a major cause of cancer-related deaths, underscoring the necessity to discern the rules and patterns of cancer cell spreading. Epithelial-mesenchymal plasticity contributes to cancer aggressiveness and metastasis. Despite establishing key determinants of cancer aggressiveness and metastatic ability, a comprehensive understanding of the underlying mechanism is unknown. We aimed to propose a classification system for cancer cells based on epithelial-mesenchymal plasticity, focusing on hysteresis of the epithelial-mesenchymal transition and the hybrid epithelial/mesenchymal phenotype. Methods: We extensively reviewed the concept of epithelial-mesenchymal plasticity, specifically considering the hysteresis of the epithelial-mesenchymal transition and the hybrid epithelial/mesenchymal phenotype. Results: In this review and hypothesis article, based on epithelial-mesenchymal plasticity, especially the hysteresis of epithelial-mesenchymal transition and the hybrid epithelial/mesenchymal phenotype, we proposed a classification of cancer cells, indicating that cancer cells with epithelial-mesenchymal plasticity potential could be classified into four types: irreversible hysteresis, weak hysteresis, strong hysteresis, and hybrid epithelial/mesenchymal phenotype. These four types of cancer cells had varied biology, spreading features, and prognoses. Discussion: Our results highlight that the proposed classification system offers insights into the diverse behaviors of cancer cells, providing implications for cancer aggressiveness and metastasis.
Collapse
Affiliation(s)
- Rui Wang
- Department of Critical Care Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhaopeng Yan
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| |
Collapse
|
39
|
Zohar N, Nevler A, Esquivel J, Yeo CJ, Benvenisti H, Elbaz N, Assaf D, Mor E, Bowne WB. International Expert Consensus on Defining Textbook Oncologic Outcomes in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastasis. J Am Coll Surg 2024; 238:387-401. [PMID: 38149780 DOI: 10.1097/xcs.0000000000000937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023]
Abstract
BACKGROUND Textbook oncologic outcome (TOO) is a composite metric shown to correlate with improved survival after curative intent oncologic procedures. Despite increasing use among disciplines in surgical oncology, no consensus exists for its definition in cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). STUDY DESIGN An international consensus-based study employed a Delphi methodology to achieve agreement. Fifty-four senior surgeons from the peritoneal surface malignancies field received a questionnaire comprising TOO parameters divided into 3 surgical domains: operative, short-term, and long-term postoperative outcomes. Two online meetings with participants defined the new criteria. Consensus was achieved when 75% of agreement rate was reached. Clinical data of patients who underwent CRS and HIPEC for colorectal peritoneal metastasis between 2010 and 2022 from 1 designated center (Sheba Medical Center) were collected, the consensus definition applied and outcomes analyzed. RESULTS Thirty-eight surgeons (70%) participated. Expert consensus TOO parameters for colorectal peritoneal metastasis CRS and HIPEC included the absence of unplanned reoperations during 30 days postoperation, absence of severe postoperative complications (Clavien-Dindo ≥III), absence of unplanned readmissions during 30 days postoperation, 90-day postoperative mortality, and absence of contraindications for chemotherapy within 12 weeks from operation, and included the achievement of complete cytoreduction (CC0). The study cohort consisted of 251 patients, and 151 (60%) met TOO criteria. Patients who achieved TOO had significantly better overall survival (median 67.5 months, 95% CI) vs patients who did not achieve TOO (median 44.6 months, 95% CI, p < 0.001) and significantly improved disease-free survival (median, 12 months, 95% CI, vs 9 months, 95% CI, p = 0.01). CONCLUSIONS Achievement of TOO as defined by consensus statement is associated with improved survival.
Collapse
Affiliation(s)
- Nitzan Zohar
- From the Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Health, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
- Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Tel-Hashomer, Israel (Zohar, Benvenisti, Elbaz, Assaf, Mor)
| | - Avinoam Nevler
- From the Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Health, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
| | | | - Charles J Yeo
- From the Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Health, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
| | - Haggai Benvenisti
- Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Tel-Hashomer, Israel (Zohar, Benvenisti, Elbaz, Assaf, Mor)
| | - Nadav Elbaz
- Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Tel-Hashomer, Israel (Zohar, Benvenisti, Elbaz, Assaf, Mor)
| | - Dan Assaf
- Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Tel-Hashomer, Israel (Zohar, Benvenisti, Elbaz, Assaf, Mor)
| | - Eyal Mor
- Department of General and Oncological Surgery-Surgery C, Sheba Medical Center, Tel-Hashomer, Israel (Zohar, Benvenisti, Elbaz, Assaf, Mor)
| | - Wilbur B Bowne
- From the Jefferson Pancreas, Biliary and Related Cancer Center, Jefferson Health, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA (Zohar, Nevler, Yeo, Bowne)
| |
Collapse
|
40
|
Prat R, Villarreal-Compagny M, López N, Ortiz O. Atypical new-onset ascites due to a rare variant of cecal carcinoma in a patient with a ventriculoperitoneal shunt: A case report. MEDICINA CLÍNICA PRÁCTICA 2024; 7:100416. [DOI: 10.1016/j.mcpsp.2023.100416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
41
|
Acs M, Babucke M, Jusufi M, Kaposztas Z, Slowik P, Hornung M, Schlitt HJ, Panczel I, Hevesi J, Herzberg J, Strate T, Piso P. Current clinical practices of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Innov Surg Sci 2024; 9:3-15. [PMID: 38826635 PMCID: PMC11138857 DOI: 10.1515/iss-2023-0055] [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: 09/01/2023] [Accepted: 12/20/2023] [Indexed: 06/04/2024] Open
Abstract
Treatment of peritoneal surface malignancies makes physicians face demanding and new-fangled problems, as there are many uncertain aspects considering the outcomes of affected patients' prognoses. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are associated with favorable long-term outcomes in carefully selected patients with peritoneal metastases (PM). We aim to summarize the current results about the initial malignancies and their peritoneal spreads. The current literature has been scrutinized, and studies between 2016 and 2022 were included wherein long-term, progression-free (PFS), and overall survival (OS) data were considered relevant information. Medline, Embase, and Google Scholar have been the main sources. Hereby, we cover all the primer malignancies: gastric, ovarian, and colorectal cancers with peritoneal metastases (PM), malignant peritoneal mesothelioma, and pseudomyxoma peritonei. Examining the advances in the current peer-reviewed literature about the indications of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), target groups, risk factors, and other influencing elements, we intend to provide a complex state-of-the-art report, establishing the relevant aspects of that emerging treatment method.
Collapse
Affiliation(s)
- Miklos Acs
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Maximilian Babucke
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany
| | - Maximilian Jusufi
- Department of General and Visceral Surgery, AK Barmbek, Hamburg, Germany
| | - Zsolt Kaposztas
- Department of Surgery, Somogy County Kaposi Mor Teaching Hospital, Kaposvar, Hungary
| | - Przemyslaw Slowik
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Matthias Hornung
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Hans J. Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Ivan Panczel
- Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | | | - Jonas Herzberg
- Department of Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany
| | - Tim Strate
- Department of Surgery, Krankenhaus Reinbek St. Adolf-Stift, Reinbek, Germany
| | - Pompiliu Piso
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany
| |
Collapse
|
42
|
Ilyas MIM. Epidemiology of Stage IV Colorectal Cancer: Trends in the Incidence, Prevalence, Age Distribution, and Impact on Life Span. Clin Colon Rectal Surg 2024; 37:57-61. [PMID: 38322602 PMCID: PMC10843881 DOI: 10.1055/s-0043-1761447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2024]
Abstract
Colorectal cancer is a common malignancy in men and women. Historically, stage IV colorectal cancer has 10 to 15% five-year survival. Developments in the management of colorectal metastatic disease have helped improve the overall survival of stage IV colorectal cancers from 12 to 30 months with some patients achieving disease-free survival.
Collapse
|
43
|
Zheng Y, Zhang J, Chen C, Gong Z, Wang Z, Deng Q, Yu S, Hu Y, Liu Y, Cao H, Xiao Q, Wang J, Ding K, Sun L. Prophylactic hyperthermic intraperitoneal chemotherapy in T4 colorectal cancer: Can it improve the oncologic prognosis? - A propensity score matching study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:107958. [PMID: 38219698 DOI: 10.1016/j.ejso.2024.107958] [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] [Received: 07/27/2023] [Revised: 12/08/2023] [Accepted: 01/08/2024] [Indexed: 01/16/2024]
Abstract
BACKGROUND Some studies show that cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) may improve overall survival and is a possible curative treatment for selected colorectal cancer (CRC) patients with restricted peritoneal metastasis (PM). The value of HIPEC in preventing PM of CRC is still controversial. MATERIALS AND METHODS In this retrospective propensity score matching (PSM) cohort study, all patients with cT4N0-2M0 undergoing treatment at a single institution in China (2014-2018) were reviewed. The 3-year disease-free survival (DFS) was set as the primary outcome, and the 3-year PM rate was also analyzed. RESULTS 220 patients were included in this study for analysis. After 1:3 PSM: HIPEC (n = 45) and No HIPEC (n = 135). Through analysis, it was found that prophylactic HIPEC correlated to better DFS [hazard ratio (HR) 0.43, 95 % confidence interval (CI) 0.19-0.95; p = 0.037], and N2 stage correlated to worse DFS [HR 1.97, 95 % CI 1.09-3.56; p = 0.025]. For laparoscopic surgery subgroup analyses, 3-year PM rate of patients with laparoscopic surgery was 13.8 % in No HIPEC group, and 2.6 % in HIPEC group (p = 0.070). Besides, no post-operative death occurred, the anastomotic leakage rate was 2.2 % in HIPEC group and 0.7 % in the control group (p = 0.439). CONCLUSIONS Prophylactic HIPEC may improve the prognosis in patients with cT4N0-1M0 CRC, but not in cT4N2M0 CRC, and it does not significantly increase surgery-related complications. Laparoscopic surgery followed by HIPEC for T4 stage CRC may not increase risk of PM.
Collapse
Affiliation(s)
- Yuyan Zheng
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Jingjing Zhang
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Chao Chen
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Zhiyuan Gong
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Zhanhuai Wang
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Qun Deng
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Shaojun Yu
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Yeting Hu
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Yue Liu
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Hongfeng Cao
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China
| | - Qian Xiao
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China
| | - Jian Wang
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China
| | - Kefeng Ding
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China.
| | - Lifeng Sun
- Zhejiang University School of Medicine Second Affiliated Hospital, Colorectal Surgery, Hangzhou, Zhejiang, China; Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang, China.
| |
Collapse
|
44
|
Qian S, Chen J, Zhao Y, Zhu X, Dai D, Qin L, Hong J, Xu Y, Yang Z, Li Y, Guijo I, Jiménez-Galanes S, Guadalajara H, García-Arranz M, García-Olmo D, Shen J, Villarejo-Campos P, Qian C. Intraperitoneal administration of carcinoembryonic antigen-directed chimeric antigen receptor T cells is a robust delivery route for effective treatment of peritoneal carcinomatosis from colorectal cancer in pre-clinical study. Cytotherapy 2024; 26:113-125. [PMID: 37999667 DOI: 10.1016/j.jcyt.2023.10.007] [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] [Received: 07/05/2023] [Revised: 10/03/2023] [Accepted: 10/19/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND AIMS Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) is a highly challenging disease to treat. Systemic chimeric antigen receptor (CAR) T cells have shown impressive efficacy in hematologic malignancies but have been less effective in solid tumors. We explored whether intraperitoneal (i.p.) administration of CAR T cells could provide an effective and robust route of treatment for PC from CRC. METHODS We generated second-generation carcinoembryonic antigen (CEA)-specific CAR T cells. Various animal models of PC with i.p. and extraperitoneal metastasis were treated by i.p. or intravenous (i.v.) administration of CEA CAR T cells. RESULTS Intraperitoneally administered CAR T cells exhibited superior anti-tumor activity compared with systemic i.v. cell infusion in an animal model of PC. In addition, i.p. administration conferred a durable effect and protection against tumor recurrence and exerted strong anti-tumor activity in an animal model of PC with metastasis in i.p. or extraperitoneal organs. Moreover, compared with systemic delivery, i.p. transfer of CAR T cells provided increased anti-tumor activity in extraperitoneal tumors without PC. This phenomenon was further confirmed in an animal model of pancreatic carcinoma after i.p. administration of our newly constructed prostate stem cell antigen-directed CAR T cells. CONCLUSIONS Taken together, our data suggest that i.p. administration of CAR T cells may be a robust delivery route for effective treatment of cancer.
Collapse
Affiliation(s)
- Siyuan Qian
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
| | - Jun Chen
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yongchun Zhao
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Xiuxiu Zhu
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Depeng Dai
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Lei Qin
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Juan Hong
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yanming Xu
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Zhi Yang
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Yunyan Li
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China
| | - Ismael Guijo
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | | | - Héctor Guadalajara
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mariano García-Arranz
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Damián García-Olmo
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain
| | - Junjie Shen
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China.
| | - Pedro Villarejo-Campos
- Department of Surgery, Fundación Jiménez Díaz University Hospital, Madrid, Spain; Department of Surgery, Universidad Autónoma de Madrid, Madrid, Spain.
| | - Cheng Qian
- Chongqing Key Laboratory of Gene and Cell Therapy, Chongqing Precision Biotechnology Co Ltd, Chongqing, China.
| |
Collapse
|
45
|
Graf W, Ghanipour L, Birgisson H, Cashin PH. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Metastases from Colorectal Cancer-An Overview of Current Status and Future Perspectives. Cancers (Basel) 2024; 16:284. [PMID: 38254775 PMCID: PMC10813964 DOI: 10.3390/cancers16020284] [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: 12/04/2023] [Revised: 01/03/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.
Collapse
Affiliation(s)
- Wilhelm Graf
- Uppsala Sweden and Department of Surgery, Institution of Surgical Sciences, Uppsala University, Akademiska Sjukhuset, SE-751 85 Uppsala, Sweden; (L.G.); (H.B.); (P.H.C.)
| | | | | | | |
Collapse
|
46
|
Mizumoto A, Takao N, Imagami T, An B, Oe Y, Togawa T, Yonemura Y. Cytoreductive surgery for synchronous and metachronous colorectal peritoneal dissemination: Japanese P classification and peritoneal cancer index. Ann Gastroenterol Surg 2024; 8:88-97. [PMID: 38250692 PMCID: PMC10797820 DOI: 10.1002/ags3.12721] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 06/25/2023] [Accepted: 07/10/2023] [Indexed: 01/23/2024] Open
Abstract
Aim The outcomes of cytoreductive surgery (CRS) for synchronous and metachronous colorectal peritoneal dissemination were investigated using the Japanese P classification and peritoneal cancer index (PCI). Methods CRS was performed in 111 cases of synchronous peritoneal dissemination and 115 cases of metachronous peritoneal dissemination. The P classification and PCI were determined at the time of laparotomy. Results In the synchronous dissemination group, the 5-year overall survival rates after CRS in P1/P2 and P3 cases were 51% and 13%, respectively. Even for P3, 51% of the patients achieved macroscopic cytoreductive complete resection (CC-0), with a 5-year survival rate of 40%. When P3 cases were classified into PCI 0-9, 10-19, 20-29, and 30-39, CC-0 was achieved in 93%, 70%, 6%, and 0% of the cases, respectively, and the 5-year survival rate of PCI 0-9 was 41%. In the metachronous dissemination group, the 5-year survival rates were 62% for PCI 0-9 and 22% for PCI 10-19; 5-year survival was not observed in patients with a PCI ≥ 20. CC-0 was significantly associated with the postoperative prognosis in both synchronous and metachronous peritoneal dissemination. Conclusion In cases of synchronous dissemination, CRS must be performed for P1 and P2 cases or those with a PCI < 10, while detailed examination using PCI is required for P3 cases. In cases of metachronous dissemination, CRS should be considered when the PCI score is <20.
Collapse
Affiliation(s)
- Akiyoshi Mizumoto
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Nobuyuki Takao
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Toru Imagami
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Byonggu An
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Yasumitsu Oe
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Takeshi Togawa
- Department of Gastrointestinal Surgery and Peritoneal Dissemination Center, Omi Medical CenterKusatsuJapan
| | - Yutaka Yonemura
- NPO to support Peritoneal Surface Malignancy TreatmentKyotoJapan
| |
Collapse
|
47
|
Tonello M, Baratti D, Sammartino P, Di Giorgio A, Robella M, Sassaroli C, Framarini M, Valle M, Macrì A, Graziosi L, Coccolini F, Lippolis PV, Gelmini R, Deraco M, Biacchi D, Santullo F, Vaira M, Di Lauro K, D'Acapito F, Carboni F, Milone E, Donini A, Fugazzola P, Faviana P, Sorrentino L, Pizzolato E, Cenzi C, Del Bianco P, Sommariva A. Is Systemic Chemotherapy Useful in Patients Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Colorectal Peritoneal Metastases? A Propensity-Score Analysis. Ann Surg Oncol 2024; 31:594-604. [PMID: 37831280 DOI: 10.1245/s10434-023-14417-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 09/25/2023] [Indexed: 10/14/2023]
Abstract
PURPOSE Multimodal treatment of colorectal (CRC) peritoneal metastases (PM) includes systemic chemotherapy (SC) and surgical cytoreduction (CRS), eventually with hyperthermic intraperitoneal chemotherapy (HIPEC), in select patients. Considering lack of clear guidelines, this study was designed to analyze the role of chemotherapy and its timing in patients treated with CRS-HIPEC. METHODS Data from 13 Italian centers with PM expertise were collected by a collaborative group of the Italian Society of Surgical Oncology (SICO). Clinicopathological variables, SC use, and timing of administration were correlated with overall survival (OS), disease-free survival (DFS), and local (peritoneal) DFS (LDFS) after propensity-score (PS) weighting to reduce confounding factors. RESULTS A total of 367 patients treated with CRS-HIPEC were included in the propensity-score weighting. Of the total patients, 19.9% did not receive chemotherapy within 6 months of surgery, 32.4% received chemotherapy before surgery (pregroup), 28.9% after (post), and 18.8% received both pre- and post-CRS-HIPEC treatment (peri). SC was preferentially administered to younger (p = 0.02) and node-positive (p = 0.010) patients. Preoperative SC is associated with increased rate of major complications (26.9 vs. 11.3%, p = 0.0009). After PS weighting, there were no differences in OS, DFS, or LDFS (p = 0.56, 0.50, and 0.17) between chemotherapy-treated and untreated patients. Considering SC timing, the post CRS-HIPEC group had a longer DFS and LDFS than the pre-group (median DFS 15.4 vs. 9.8 m, p = 0.003; median LDFS 26.3 vs. 15.8 m, p = 0.026). CONCLUSIONS In patients with CRC-PM treated with CRS-HIPEC, systemic chemotherapy was not associated with overall survival benefit. The adjuvant schedule was related to prolonged disease-free intervals. Additional, randomized studies are required to clarify the role and timing of systemic chemotherapy in this patient subset.
Collapse
Affiliation(s)
- Marco Tonello
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Dario Baratti
- Peritoneal Surface Malignancy Unit, Dept. of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo Sammartino
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Manuela Robella
- Surgical Oncology Unit, Candiolo Cancer Institute, Candiolo, Turin, Italy
| | - Cinzia Sassaroli
- Abdominal Oncology Department, Fondazione Giovanni Pascale, IRCCS, Naples, Italy
| | - Massimo Framarini
- General and Oncologic Department of Surgery, Morgagni - Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Mario Valle
- Peritoneal Tumours Unit, IRCCS, Regina Elena Cancer Institute, Rome, Italy
| | - Antonio Macrì
- Department of Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, Messina, Italy
| | - Luigina Graziosi
- General and Emergency Surgery Department, University of Perugia, Santa Maria Della Misericordia Hospital, Perugia, Italy
| | - Federico Coccolini
- General Emergency and Trauma Surgery, Bufalini Hospital, Cesena, Italy
- General Emergency and Trauma Surgery, Pisa University Hospital, Pisa, Italy
| | - Piero Vincenzo Lippolis
- General and Peritoneal Surgery, Department of Surgery, Hospital University Pisa (AOUP), Pisa, Italy
| | - Roberta Gelmini
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy
| | - Marcello Deraco
- Peritoneal Surface Malignancy Unit, Dept. of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Daniele Biacchi
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Francesco Santullo
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Marco Vaira
- Surgical Oncology Unit, Candiolo Cancer Institute, Candiolo, Turin, Italy
| | - Katia Di Lauro
- Department of Advanced Biomedical Sciences, "Federico II" University, Naples, Italy
| | - Fabrizio D'Acapito
- General and Oncologic Department of Surgery, Morgagni - Pierantoni Hospital, AUSL Romagna, Forlì, Italy
| | - Fabio Carboni
- Peritoneal Tumours Unit, IRCCS, Regina Elena Cancer Institute, Rome, Italy
| | - Erica Milone
- University Hospital "G. Martino", Messina, Italy
| | - Annibale Donini
- General and Emergency Surgery Department, University of Perugia, Santa Maria Della Misericordia Hospital, Perugia, Italy
| | - Paola Fugazzola
- General surgery, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Pinuccia Faviana
- Pathological Anatomy III, Laboratory Medicine Department, Hospital University Pisa (AOUP), Pisa, Italy
| | - Lorena Sorrentino
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Modena, Italy
| | - Elisa Pizzolato
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Carola Cenzi
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Paola Del Bianco
- Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Antonio Sommariva
- Unit of Surgical Oncology of Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
| |
Collapse
|
48
|
Marcinak CT, Schwartz PB, Basree MM, Hurst N, Bassetti M, Kratz JD, Uboha NV. Treatment of Oligometastatic GI Cancers. Am Soc Clin Oncol Educ Book 2024; 44:e430152. [PMID: 38190577 DOI: 10.1200/edbk_430152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Oligometastatic state is believed to potentially represent a transitional stage between early, locoregional state disease and widely metastatic disease. Historically, locoregional approaches, particularly in advanced colorectal cancers, have demonstrated efficacy in select patients with limited burden of metastatic disease. Recent strides in systemic therapies, including biomarker-based treatments and immunotherapy, alongside innovations in surgical techniques and novel locoregional approaches such as stereotactic radiotherapy and ablation, have ushered in a new era of therapeutic possibilities across all oligometastatic GI cancers. Despite these advancements, there remains a significant gap in high-quality prospective evidence guiding patient selection and treatment decisions across various disease types. Ongoing clinical trials are anticipated to provide crucial insights into oligometastatic states, fostering the refinement of disease-specific oligometastatic state definitions and treatment algorithms. This article reviews existing data on the management of oligometastatic GI cancer, summarizes current state of knowledge for each disease state, and provides updates on ongoing studies in this space.
Collapse
Affiliation(s)
- Clayton T Marcinak
- Department of Surgery, University of Wisconsin School of Medicine and Public Health University of Wisconsin-Madison, Madison, WI
| | - Patrick B Schwartz
- Department of Surgery, University of Wisconsin School of Medicine and Public Health University of Wisconsin-Madison, Madison, WI
| | - Mustafa M Basree
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Newton Hurst
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Michael Bassetti
- Department of Human Oncology, University of Wisconsin Hospital and Clinics, Madison, WI
| | - Jeremy D Kratz
- University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI
- Center for Human Genomics and Precision Medicine, University of Wisconsin, Madison, WI
- William S. Middleton Memorial Veterans Hospital, Madison, WI
| | - Nataliya V Uboha
- University of Wisconsin-Madison, Madison, WI
- University of Wisconsin Carbone Cancer Center, University of Wisconsin, Madison, WI
| |
Collapse
|
49
|
Grávalos C, Pereira F, Vera R, Arjona-Sánchez A, Losa F, Ramos I, García-Alfonso P, Gonzalez-Bayón L, Cascales-Campos PA, Aranda E. Recommendations for the optimal management of peritoneal metastases in patients with colorectal cancer: a TTD and GECOP-SEOQ expert consensus statement. Clin Transl Oncol 2023; 25:3378-3394. [PMID: 37140736 DOI: 10.1007/s12094-023-03204-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 04/13/2023] [Indexed: 05/05/2023]
Abstract
Peritoneal metastases (PM) occur when cancer cells spread inside the abdominal cavity and entail an advanced stage of colorectal cancer (CRC). Prognosis, which is poor, correlates highly with tumour burden, as measured by the peritoneal cancer index (PCI). Cytoreductive surgery (CRS) in specialized centres should be offered especially to patients with a low to moderate PCI when complete resection is expected. The presence of resectable metastatic disease in other organs is not a contraindication in well-selected patients. Although several retrospective and small prospective studies have suggested a survival benefit of adding hyperthermic intraperitoneal chemotherapy (HIPEC) to CRS, the recently published phase III studies PRODIGE-7 in CRC patients with PM, and COLOPEC and PROPHYLOCHIP in resected CRC with high-risk of PM, failed to show any survival advantage of this strategy using oxaliplatin in a 30-min perfusion. Final results from ongoing randomized phase III trials testing CRS plus HIPEC based on mitomycin C (MMC) are awaited with interest. In this article, a group of experts selected by the Spanish Group for the Treatment of Digestive Tumours (TTD) and the Spanish Group of Peritoneal Oncologic Surgery (GECOP), which is part of the Spanish Society of Surgical Oncology (SEOQ), reviewed the role of HIPEC plus CRS in CRC patients with PM. As a result, a series of recommendations to optimize the management of these patients is proposed.
Collapse
Affiliation(s)
- Cristina Grávalos
- Medical Oncology Department, 12 de Octubre University Hospital, Madrid, Spain
| | - Fernando Pereira
- Departamento de Cirugía, Hospital Universitario de Fuenlabrada, Camino del Molino, 2, 28942, Fuenlabrada, Madrid, Spain.
| | - Ruth Vera
- Medical Oncology Department, Navarra University Hospital, Navarra's Health Research Institute (IdiSNA), Pamplona, Spain
| | - Alvaro Arjona-Sánchez
- Unit of Surgical Oncology and GE09 Research in Peritoneal and Retroperitoneal Oncology Surgery, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain
| | - Ferran Losa
- Medical Oncology Department, Sant Joan Despí - Moisés Broggi Hospital/ICO-Hospitalet, Barcelona, Spain
| | - Isabel Ramos
- Surgery Department, Sant Joan Despí - Moisés Broggi Hospital, Hospitalet de Llobregat, Spain
| | - Pilar García-Alfonso
- Medical Oncology Department, Gregorio Marañón General University Hospital, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - Luis Gonzalez-Bayón
- Surgery Department, Gregorio Marañón General University Hospital, Madrid, Spain
| | | | - Enrique Aranda
- Medical Oncology Department, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba University, Center for Biomedical Research in Cancer Network (CIBERONC), Carlos III Health Institute, Córdoba, Spain
| |
Collapse
|
50
|
Kozman MA, Fisher OM, Liauw W, Morris DL, Cashin PH. External validation of prognostic scores and comparison of predictive accuracy for patients with colorectal cancer with peritoneal metastases considered for cytoreductive surgery and intraperitoneal chemotherapy. J Surg Oncol 2023; 128:1150-1159. [PMID: 37602499 DOI: 10.1002/jso.27416] [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] [Received: 02/02/2023] [Revised: 06/28/2023] [Accepted: 07/26/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND AND OBJECTIVES Prognostic scores are developed to facilitate the selection of patients with colorectal cancer peritoneal metastases (CRPM) for treatment with cytoreductive surgery (CRS) ± intraperitoneal chemotherapy (IPC). Three prominent prognostic scores are the Peritoneal Surface Disease Severity Score (PSDSS), the Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), and the modified COloREctal-Pc (mCOREP). We externally validate these scores and compare their predictive accuracy. METHODS Data from consecutive CRPM patients who underwent CRS/IPC from 1996 to 2018 was used to externally validate COMPASS, PSDSS, and mCOREP. Analysis evaluated the efficacy of each score in predicting (1) open-close laparotomy-those found at laparotomy to not be eligible for curative intent CRS/IPC, (2) surgical futility-those who underwent open-close laparotomy, palliative debulking surgery, or had an overall survival of less than 12 months, and (3) overall and recurrence-free survival (OS, RFS). RESULTS Prognostic scores were calculated for the 174-patient external validation cohort. COMPASS was most accurate in predicting open-close laparotomy, futile surgery, and survival (OS and RFS). Area under the curve (AUC) for open-close prediction was 0.78 (95% confidence interval, CI: 0.68-0.87), representing useful discrimination. However, AUC for futility prediction was 0.62 (95% CI: 0.52-0.71), and C-statistic for OS was 0.65 indicating only possibly helpful discrimination. C-statistic for RFS was 0.59 indicating poor discrimination. CONCLUSION While COMPASS showed the best statistical behavior, accuracy for several clinically relevant outcomes remains low, and thus applicability to clinical practice limited.
Collapse
Affiliation(s)
- Mathew A Kozman
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- Cancer Care Centre, St George Hospital, Kogarah, New South Wales, Australia
| | - Oliver M Fisher
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
- School of Medicine, University of Notre Dame, Sydney, New South Wales, Australia
| | - Winston Liauw
- Cancer Care Centre, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - David L Morris
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Peter H Cashin
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| |
Collapse
|