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Etzold C, Lyros O, Mehdorn M, Nowotny R, Niebisch S, Jansen-Winkeln B, Schierle K, Gockel I, Thieme R. Patient-specific 3D-tissue slices from peritoneal metastases - An in vitro model for individual susceptibility analysis. Pleura Peritoneum 2025; 10:1-9. [PMID: 40275876 PMCID: PMC12016018 DOI: 10.1515/pp-2024-0012] [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: 08/22/2024] [Accepted: 02/03/2025] [Indexed: 04/26/2025] Open
Abstract
Objectives The prognosis of patients with peritoneal metastases (PM) is poor, and these patients have a brief overall survival. Most patients with advanced PM receive palliative therapy to maintain their quality of life. In our current study, we investigated whether patient-specific 3D-tissue slices from patients with PM subjected to pressurized intraperitoneal aerosol chemotherapy could be cultured in vitro. Methods Biopsies from gastric cancer patients with PM were characterized for cytokeratin-positive tumor cells and the proliferation marker Ki-67. Biopsies from seven patients were cut to 350 µM thick slices in a standardized manner, cultured with 10 µM 5-fluorouracil, doxorubicin, cisplatin, oxaliplatin, or irinotecan for 96 h, and then examined histopathologically and via immunohistochemistry for persistent cytokeratin and Ki-67 expression. Results In vitro cultured slices revealed a similar morphology to un-cultured specimens, and Ki-67-positive tumor cell areas were present after 96 h. The total amount of tumor cells per slice was determined by pan-cytokeratin staining. In the doxorubicin-treated slices, the cytokeratin-positive tumor cell fraction and proliferative (Ki-67pos) cells were decreased. Patient-specific 3D-tissue-slice cultures from peritoneal biopsies were cultured in vitro for up to 4 days. Conclusions Potentially, these cultures are a reliable model to evaluate the chemosensitivity of patients with PM. Further investigation is needed to match the chemosensitivity with the clinical course of these patients.
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Affiliation(s)
- Christian Etzold
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Robert Nowotny
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
- Department of General, Visceral and Oncological Surgery, St. Georg Hospital Leipzig, Leipzig, Germany
| | - Katrin Schierle
- Institute of Pathology, University Hospital of Leipzig, Leipzig, Germany
- Institute of Pathology, SLK-Kliniken Heilbronn, Heilbronn, Germany
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
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Mano Y, Igarashi Y, Komori K, Hashimoto I, Watanabe H, Takahashi K, Kano K, Fujikawa H, Yamada T, Himuro H, Kouro T, Wei F, Tsuji K, Horaguchi S, Komahashi M, Oshima T, Sasada T. Characteristics and clinical significance of immune cells in omental milky spots of patients with gastric cancer. Front Immunol 2025; 16:1521278. [PMID: 39949777 PMCID: PMC11821591 DOI: 10.3389/fimmu.2025.1521278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Accepted: 01/02/2025] [Indexed: 02/16/2025] Open
Abstract
The omentum is a common site of peritoneal metastasis in various cancers, including gastric cancer. It contains immune cell aggregates known as milky spots, which provide a microenvironment for peritoneal immunity by regulating innate and adaptive immune responses. In this study, we investigated gene expression profiles in cells from omental milky spots of patients with gastric cancer (n = 37) by RNA sequencing analysis and classified the patients into four groups (G1-4). Notably, significant differences were observed between the groups in terms of macroscopic type, lymphatic invasion, venous invasion, and pathological stage (pStage). G3, which was enriched in genes related to acquired immunity, showed earlier tumor stages (macroscopic type 0, Ly0, V0, and pStage I) and a better prognosis. In contrast, G4 showed enrichment of genes related to neutrophils and innate immunity; G1 and G2 showed no enrichment of innate or adaptive immune-related genes, suggesting an immune desert microenvironment. Cytometric analysis revealed significantly more T and B cells and fewer neutrophils in G3. Accordingly, the immune microenvironment in omental milky spots may vary depending on the stage of gastric cancer progression. When univariate Cox proportional hazards regression models were used to search for prognostically relevant genes specific to G3, 23 potential prognostic genes were identified as common genes associated with relapse-free survival and overall survival. In addition, the multivariate Cox proportional hazards model using these prognostic genes and clinicopathological information showed that combining the B cell marker CD19 and Ly had a high predictive accuracy for prognosis. Based on this study's results, it is possible that tumor progression, such as lymphatic and/or venous infiltration of tumor cells, may affect the immune cell composition and proportions in omental milky spots of patients with gastric cancer and analysis of gene expression in omental milky spots may help to predict gastric cancer prognosis.
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Affiliation(s)
- Yasunobu Mano
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Yuka Igarashi
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Keisuke Komori
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Itaru Hashimoto
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Hayato Watanabe
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Kosuke Takahashi
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Kazuki Kano
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Hirohito Fujikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Takanobu Yamada
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Hidetomo Himuro
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Taku Kouro
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Feifei Wei
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Kayoko Tsuji
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Shun Horaguchi
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuru Komahashi
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Department of Pediatric Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Takashi Oshima
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Tetsuro Sasada
- Division of Cancer Immunotherapy, Kanagawa Cancer Center Research Institute, Yokohama, Japan
- Cancer Vaccine and Immunotherapy Center, Kanagawa Cancer Center Research Institute, Yokohama, Japan
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Torun BC, Sobutay E, Akbulut OE, Saglam S, Yilmaz S, Yonemura Y, Canbay E. Important Predictive Factors for the Prognosis of Patients With Peritoneal Metastasis of Gastric Cancer. Ann Surg Oncol 2024; 31:5975-5983. [PMID: 38806761 DOI: 10.1245/s10434-024-15499-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: 02/19/2024] [Accepted: 05/07/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUND This study investigated predictive factors for patients with peritoneal metastases of gastric cancer (PMGC) who underwent conversion cytoreductive surgery (C-CRS) and hyperthermic intraperitoneal intraoperative chemotherapy (HIPEC) after responding to induction chemotherapy (laparoscopic HIPEC [LHIPEC]) followed by concomitant systemic and intraperitoneal chemotherapy (bidirectional intraperitoneal and systemic chemotherapy [BIC]). METHODS Diagnostic laparoscopy was performed for 62 patients with PMGC between January 2017 and December 2022. The patients underwent LHIPEC and BIC induction chemotherapy using intraperitoneal docetaxel (30 mg/m2) and cisplatin (30 mg/m2), and intravenous chemotherapy for three cycles. The predictive parameters for progression-free and overall survival were analyzed using Kaplan-Meier and Cox regression analyses. The optimal cutoff values for Ki-67 parameters were assessed using receiver operating characteristic curve analysis. RESULTS The study retrospectively examined 36 (58 %) of 62 patients who responded to induction therapy and underwent C-CRS or HIPEC. A Ki-67 index lower than 10 (p = 0.000), lymph node involvement (LNI) less than 2 (p = 0.039), and an omental lesion size score lower than 0.5 cm (p = 0.002) were predictive of recurrence-free and overall survival in addition to completeness of cytoreduction and the peritoneal cancer index. Cox regression analysis showed that the independent factors associated with recurrence-free survival were decreased Ki-67 expression (≥10 % vs <10 %) (hazard ratio [HR] 4.7; 95 % confidence interval [CI] 1.6-5.210; p = 0.020) and LNI higher than 2 (HR 1.92; 95% CIS 0.923-4.0; p = 0.023). CONCLUSIONS Lymph node involvement and decreased Ki-67 expression are independent predictive factors of recurrence-free survival for patients with PMGC after induction chemotherapy.
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Affiliation(s)
- Bahar Canbay Torun
- Department of General Surgery, University of Ministry of Health, Haseki Training and Research Hospital, Istanbul, Turkey
| | - Erman Sobutay
- Department of General Surgery, Koç Foundation American Hospital, Istanbul, Turkey
| | - Ozge Eren Akbulut
- Department of Anesthesiology, Koç Foundation American Hospital, ICU, Istanbul, Turkey
| | - Sezer Saglam
- Department of Medical Oncology, Demiroglu Bilim University, Istanbul, Turkey
| | - Serpil Yilmaz
- Department of Pathology, Koç Foundation American Hospital, Istanbul, Turkey
| | - Yutaka Yonemura
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada, Tokushukai Hospital, Kishiwada-Osaka, Japan
| | - Emel Canbay
- NPO for Peritoneal Surface Malignancies Program of Turkey, Husrev Gerede Caddesi, Istanbul, Turkey.
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Zhou Y, Zhang M, Dai L, Yan Z, Wang H, Yang H, Jin X, Wang Q. Long-term survival in a patient with multiple metastatic gastric cancer treated with PTX plus emvolimab and disitamab vedotin: case report and treatment experience: A case report. Medicine (Baltimore) 2024; 103:e36927. [PMID: 38241572 PMCID: PMC10798726 DOI: 10.1097/md.0000000000036927] [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] [Received: 09/26/2023] [Accepted: 12/20/2023] [Indexed: 01/21/2024] Open
Abstract
RATIONALE Most Chinese patients with locally advanced gastric cancer at diagnosis have an overall 5-year survival rate of <50%. Surgical resection alone is not suitable for patients with locally advanced gastric cancer. Currently, comprehensive treatment is the focus of locally advanced gastric cancer. PATIENTS CONCERNS The patient, a 56-year-old female, was admitted to the hospital because of "4 + months of double hydronephrosis found during a physical examination." Who was admitted for computer tomography and gastroscopy examinations, and take pathological tissue specimens during endoscopic examination. DIAGNOSES Computed tomography assessment indicated ulcerative gastric cancer with an abdominal implant, bladder, and bone metastases. An endoscopic examination revealed that the ulcer of the gastric angle was huge, and through relevant auxiliary examinations, the diagnosis of this disease is gastric cancer complicated with multiple metastases to bladder, rectum, lumbar spine, and peritoneum. Clinically diagnosed as cT4bN3M1. INTERVENTIONS The patient is currently undergoing first, second, and third line neoadjuvant therapy, combined with immunotherapy, targeted therapy, neoadjuvant intraperitoneal systemic chemotherapy, nutritional support, and other treatment plans. OUTCOMES After 15 cycles of treatment, the progression-free survival had reached 15 months. The patient had an NRS2002 score of 1, an ECOG score of I, a quality of life score of 55, albumin of 35.27 g/L, and a decrease in abdominal and pelvic fluid accumulation and exudation compared to before. LESSONS We demonstrated high survival of almost 3 years in a patient with gastric cancer that was complicated by bone, peritoneal, rectal, and bladder metastases. The combination of immunotherapy, targeted therapy, and neoadjuvant intraperitoneal systemic chemotherapy, along with the maintenance of nutritional status and CTCs could be a valuable modality for the subsequent treatment and observation of similar patients.
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Affiliation(s)
- Yongjin Zhou
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Meifeng Zhang
- Department of Outpatient Clinic, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Li Dai
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Zhiqiang Yan
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Haibin Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Hongxin Yang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Xiangren Jin
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
| | - Qian Wang
- Department of Gastrointestinal Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
- Guizhou Medical University, Guiyang, Guizhou Province, China
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Guo J, Deng Z, Jin L, Yin S, Xiong Z, Wang C, Chen H, Luo D, Huang D, Peng J, Chen S, Lian L. Prognostic value of hyperthermic intraperitoneal chemotherapy in gastric cancer with synchronous peritoneal metastases: a real-world retrospective study. J Cancer Res Clin Oncol 2023; 149:17881-17896. [PMID: 37947869 DOI: 10.1007/s00432-023-05481-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
PURPOSE Peritoneal metastasis in gastric cancer (GC) is a late-stage condition with a poor prognosis. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a popular treatment for peritoneal metastases. Here, we aim to investigate the real-world application and efficacy of HIPEC alone for GC patients with synchronous peritoneal metastases. METHODS We conducted a retrospective analysis on GC patients with synchronous peritoneal metastasis at the Sixth Affiliated Hospital of Sun Yat-sen University between January 2011 and December 2022. Survival analyses and Cox regression models were performed based on overall survival (OS) and cancer-specific survival (CSS), and subgroup analysis was used to determine the prognostic value of HIPEC across different treatment. RESULTS We enrolled 250 patients, of whom 120 (48%) received HIPEC while 130 (52%) did not. HIPEC showed no survival benefit for GC patients (P = 0.220 for OS and P = 0.370 for CSS). However, subgroup analysis found that HIPEC can only improve OS and CSS when combined with primary tumor resection (P = 0.034 for OS and P = 0.036 for CSS). Moreover, survival analyses also demonstrated that HIPEC independently improved OS (HR for OS = 0.58, 95% CI 0.37-0.92, P = 0.020) and CSS (HR for CSS = 0.58, 95% CI 0.37-0.93, P = 0.024) for patients who underwent primary site resection, but not for those who did not. CONCLUSION HIPEC can improve survival in GC patients with synchronous peritoneal metastases who have primary tumor resection, but not in those without primary tumor resection.
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Affiliation(s)
- Jianping Guo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zijian Deng
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Longyang Jin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shi Yin
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhizhong Xiong
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Caiqin Wang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huaxian Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dandong Luo
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dayin Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Junsheng Peng
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Shi Chen
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Lei Lian
- Department of Gastrointestinal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, 26 Yuancun Er Heng Rd., Guangzhou, Guangdong, China.
- Department of Gastrointestinal Surgery, Department of General Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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Dai W, Chen Y, Xue Y, Wan M, Mao C, Zhang K. Progress in the Treatment of Peritoneal Metastatic Cancer and the Application of Therapeutic Nanoagents. ACS APPLIED BIO MATERIALS 2023; 6:4518-4548. [PMID: 37916787 DOI: 10.1021/acsabm.3c00662] [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: 11/03/2023]
Abstract
Peritoneal metastatic cancer is a cancer caused by the direct growth of cancer cells from the primary site through the bloodstream, lymph, or peritoneum, which is a difficult part of current clinical treatment. In the abdominal cavity of patients with metastatic peritoneal cancer, there are usually nodules of various sizes and malignant ascites. Among them, nodules of different sizes can obstruct intestinal movement and form intestinal obstruction, while malignant ascites can cause abdominal distension and discomfort, and even cause patients to have difficulty in breathing. The pathology and physiology of peritoneal metastatic cancer are complex and not fully understood. The main hypothesis is "seed" and "soil"; i.e., cells from the primary tumor are shed and implanted in the peritoneal cavity (peritoneal metastasis). In the last two decades, the main treatment modalities used clinically are cytoreductive surgery (CRS), systemic chemotherapy, intraperitoneal chemotherapy, and combined treatment, all of which help to improve patient survival and quality of life (QOL). However, the small-molecule chemotherapeutic drugs used clinically still have problems such as rapid drug metabolism and systemic toxicity. With the rapid development of nanotechnology in recent years, therapeutic nanoagents for the treatment of peritoneal metastatic cancer have been gradually developed, which has improved the therapeutic effect and reduced the systemic toxicity of small-molecule chemotherapeutic drugs to a certain extent. In addition, nanomaterials have been developed not only as therapeutic agents but also as imaging agents to guide peritoneal tumor CRS. In this review, we describe the etiology and pathological features of peritoneal metastatic cancer, discuss in detail the clinical treatments that have been used for peritoneal metastatic cancer, and analyze the advantages and disadvantages of the different clinical treatments and the QOL of the treated patients, followed by a discussion focusing on the progress, obstacles, and challenges in the use of therapeutic nanoagents in peritoneal metastatic cancer. Finally, therapeutic nanoagents and therapeutic tools that may be used in the future for the treatment of peritoneal metastatic cancer are prospected.
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Affiliation(s)
- Wenjun Dai
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Yidan Chen
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yunxin Xue
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Ke Zhang
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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Lv J, Wu J, Wu H, Ding P, Guo H, Yang P, Tian Y, Liu Y, Zhao Q. Study protocol of a phase II clinical trial evaluating the efficacy of neoadjuvant intraperitoneal and systemic albumin-bound paclitaxel combined with camrelizumab and S-1 in the treatment of patients with exfoliative cell-positive gastric cancer. Front Oncol 2023; 13:1201928. [PMID: 37841441 PMCID: PMC10571916 DOI: 10.3389/fonc.2023.1201928] [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: 04/07/2023] [Accepted: 08/08/2023] [Indexed: 10/17/2023] Open
Abstract
Background Currently, gastric cancer with positive lavage cytology without gross peritoneal dissemination (GC-CY1) is a special type of metastatic form with poor prognosis. Consensus guidelines on treatment strategies for patients with GC-CY1 have not been established. This study involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of neoadjuvant intraperitoneal and systemic (NIPS) albumin-bound paclitaxel combined with Camrelizumab and S-1 in the treatment of GC-CY1 patients. Methods/design This is a prospective single-center exploratory study, and the primary endpoints of the trial are R0 resection rate and conversion rate of abdominal free cancer cells (FCCs), with secondary endpoints of 3-year progression-free survival (PFS); 3-year overall survival (OS); objective remission rate (ORR); disease control rate (DCR); safety and TRG classification. Discussion This study is the first to apply NIPS albumin-bound paclitaxel combined with Camrelizumab and S-1 to the conversion therapy of GC-CY1 patients. It is speculated that this combination of regimens will increase the negative conversion rate of FCCs by 20%, which will provide innovative insights into conversion treatment ideas for GC-CY1 patients to be managed in a more comprehensive and optimized manner. Clinical trial registration http://clinicaltrials.gov/, identifier NCT05410847.
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Affiliation(s)
- Jingxia Lv
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Jiaxiang Wu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Haotian Wu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Ping’an Ding
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Honghai Guo
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Peigang Yang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Yuan Tian
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Yang Liu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, China
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8
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Yu HH, Yonemura Y, Ng HJ, Lee MC, Su BC, Hsieh MC. Benefit of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Bidirectional Chemotherapy for Patients with Gastric Cancer with Peritoneal Carcinomatosis Considering Cytoreductive Surgery. Cancers (Basel) 2023; 15:3401. [PMID: 37444511 DOI: 10.3390/cancers15133401] [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: 05/23/2023] [Revised: 06/17/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
Comprehensive treatment comprising neoadjuvant laparoscopic HIPEC (L-HIPEC) and bidirectional intraperitoneal and systemic induction chemotherapy (BISIC) followed by cytoreductive surgery (CRS) for gastric cancer with peritoneal carcinomatosis (PC) has been developed. However, its benefits and patient selection criteria have not been thoroughly investigated. We retrospectively reviewed 113 patients, with 25 having received comprehensive treatment (L-HIPEC, BISIC, and then CRS-HIPEC; the BISIC group) and 88 having received direct CRS-HIPEC (the CRS group). The BISIC group showed greater tumor clearance in terms of post-CRS peritoneal cancer index ((PCI) 6 vs. 14, p = 0.002) compared to CRS group. The median survival was 20.0 months in the BISIC group and 8.6 months in the CRS group (p = 0.031). Multivariable analysis revealed that the factors associated with increased survival were the BISIC protocol, age, and post-CRS tumor clearance. BISIC significantly improved survival in cases of moderate severity (PCI 11-20) and severe cases (PCI 21-39) without increasing the morbidity rate. We recommend the use of this neoadjuvant strategy for patients with gastric cancer-associated PC and an initial PCI of >10 to provide superior survival outcomes.
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Affiliation(s)
- Hsin-Hsien Yu
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 116, Taiwan
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Comprehensive Care Center for Peritoneal Metastasis, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Yutaka Yonemura
- Peritoneal Dissemination Center, Kishiwada Tokushukai Hospital, Kishiwada 596-8522, Osaka, Japan
- Department of Surgery, Kusatsu General Hospital, Kusatsu 525-8585, Shiga, Japan
| | - Hui-Ji Ng
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Comprehensive Care Center for Peritoneal Metastasis, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Ming-Che Lee
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 116, Taiwan
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
| | - Bor-Chyuan Su
- Department of Anatomy and Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Mao-Chih Hsieh
- Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 116, Taiwan
- Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
- Comprehensive Care Center for Peritoneal Metastasis, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan
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9
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Yang ZY, Yuan F, Lu S, Xu W, Wu JW, Xi WQ, Shi M, Wang ZQ, Ni ZT, He CY, Yao XX, Zheng YN, Zhu ZL, Liu WT, Zhang J, Zhang H, Li C, Yan C, Yan M, Zhu ZG. Efficacy and Safety of Conversion Therapy by Intraperitoneal and Intravenous Paclitaxel Plus Oral S-1 in Gastric Cancer Patients With Peritoneal Metastasis: A Prospective Phase II Study. Front Oncol 2022; 12:905922. [PMID: 35795055 PMCID: PMC9251062 DOI: 10.3389/fonc.2022.905922] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/20/2022] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND Neoadjuvant intraperitoneal and systemic chemotherapy (NIPS) has shown promising results in gastric cancer (GC) with peritoneal metastasis. However, clinical practice experience of NIPS is still lacking in China. In this study, we investigate the efficacy and safety of NIPS in Chinese patients. METHODS Eligible patients received NIPS every 3 weeks. Gastrectomy was performed for patients who met the criteria of conversion surgery. The primary end point was 1-year overall survival (OS) rate. Secondary end points were the response rate, toxic effects, conversion surgery outcomes and median survival time (MST). RESULTS Sixty-seven patients were enrolled. The primary endpoint was achieved with 1-year OS rate reached 67.2% (95% CI, 56.8%-79.4%). Conversion surgery was performed in 42 patients (62.9%), and R0 resection was achieved in 23 patients (54.8%) with the MST of 31.3 months (95% CI, 24.3-38.3). And the MST was 19.3 months (95% CI, 16.4-22.2) for all patients. Toxicity and surgical complications were well-tolerated. Moreover, sex, R0 resection, pathological nodal stage and tumor regression grade (TRG) were independent prognostic factors for patients who underwent conversion surgery. CONCLUSION The NIPS is effective and safe in treating GC patients with peritoneal metastasis. Male patients, patients who underwent R0 resection, patients with ypN0-1 or TRG 1 after conversion surgery are more likely to benefit from the NIPS. CLINICAL TRIAL REGISTRATION http://www.chictr.org.cn/, identifier https://clinicaltrials.gov/ ().
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Affiliation(s)
- Zhong-Yin Yang
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fei Yuan
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng Lu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Xu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun-Wei Wu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Qi Xi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen-Qiang Wang
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen-Tian Ni
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chang-Yu He
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xue-Xin Yao
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ya-Nan Zheng
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Lun Zhu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen-Tao Liu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huan Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Li
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Yan
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Yan
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Gang Zhu
- Department of General Surgery, Gastrointestinal Surgery, Shanghai Key laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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10
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Zeng L, Liao Q, Zeng X, Ye J, Yang X, Zhu S, Tang H, Liu G, Cui W, Ma S, Cui S. Noncoding RNAs and hyperthermic intraperitoneal chemotherapy in advanced gastric cancer. Bioengineered 2022; 13:2623-2638. [PMID: 35089117 PMCID: PMC8973587 DOI: 10.1080/21655979.2021.2021348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors globally. About 20-30% of patients with gastric cancer show peritoneal implantation metastasis at the first diagnosis. Peritoneal metastasis is responsible for 70% of deaths of patients with advanced gastric cancer. Although there are many ways to treat advanced gastric cancer, the prognosis of patients with recurrence is unsatisfactory. An auxiliary treatment with hyperthermic intraperitoneal chemotherapy (HIPEC), is an internationally recognized recommended treatment for advanced gastric cancer. A series of clinical trials have shown that HIPEC significantly improves the overall survival of patients with cancer. Compared with the cytoreductive surgery (CRS) alone, HIPEC combined with CRS markedly reduced the rate of peritoneal metastasis in patients with ovarian cancer and colorectal cancer. It has been demonstrated that HIPEC alters transcription of many genes by affecting non-coding RNAs, which may contribute to the suppressive effect of HIPEC on the synthesis of nucleic acids and proteins in cancer cells. This paper reviews the recent advances in understanding the role of non-coding RNAs in tumor invasion and metastasis of advanced gastric cancer. We also consider changes in noncoding RNA levels and other molecules in advanced gastric cancer cases treated with HIPEC. We hope that our review will provide a reference for future research on molecular epidemiology and etiology of advanced gastric cancer and promote precise treatment of this malignancy using HIPEC.
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Affiliation(s)
- Lisi Zeng
- Institute of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Quanxing Liao
- Department of the Second Area of Gastrointestinal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Xiaohui Zeng
- Institute of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Jiacai Ye
- Department of Radiotherapy, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Xianzi Yang
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Siyu Zhu
- Department of Medical Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Hongsheng Tang
- Department of the Second Area of Gastrointestinal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Gaojie Liu
- Department of the Second Area of Gastrointestinal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Weiwen Cui
- Department of Bioengineering, University of California, Berkeley, California, USA
| | - Shaohua Ma
- Institute of Biopharmaceutical and Health Engineering, Shenzhen International Graduate School, Tsinghua University, Shenzhen, China.,Tsinghua-Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China
| | - Shuzhong Cui
- Department of the Second Area of Gastrointestinal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.,State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China
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11
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Yonemura Y, Ishibashi H, Mizumoto A, Tukiyama G, Liu Y, Wakama S, Sako S, Takao N, Kitai T, Katayama K, Kamada Y, Taniguchi K, Fujimoto D, Endou Y, Miura M. The Development of Peritoneal Metastasis from Gastric Cancer and Rationale of Treatment According to the Mechanism. J Clin Med 2022; 11:458. [PMID: 35054150 PMCID: PMC8781335 DOI: 10.3390/jcm11020458] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/31/2021] [Accepted: 01/10/2022] [Indexed: 02/01/2023] Open
Abstract
In the present article, we describe the normal structure of the peritoneum and review the mechanisms of peritoneal metastasis (PM) from gastric cancer (GC). The structure of the peritoneum was studied by a double-enzyme staining method using alkaline-phosphatase and 5'-nucreotidase, scanning electron microscopy, and immunohistological methods. The fundamental structure consists of three layers, mesothelial cells and a basement membrane (layer 1), macula cribriformis (MC) (layer 2), and submesothelial connective tissue containing blood vessels and initial lymphatic vessels, attached to holes in the MC (layer 3). Macro molecules and macrophages migrate from mesothelial stomata to the initial lymphatic vessels through holes in the MC. These structures are characteristically found in the diaphragm, omentum, paracolic gutter, pelvic peritoneum, and falciform ligament. The first step of PM is spillage of cancer cells (peritoneal free cancer cells; PFCCs) into the peritoneal cavity from the serosal surface of the primary tumor or cancer cell contamination from lymphatic and blood vessels torn during surgical procedures. After PFCCs adhere to the peritoneal surface, PMs form by three processes, i.e., (1) trans-mesothelial metastasis, (2) trans-lymphatic metastasis, and (3) superficial growing metastasis. Because the intraperitoneal (IP) dose intensity is significantly higher when generated by IP chemotherapy than by systemic chemotherapy, IP chemotherapy has a great role in the treatment of PFCCs, superficial growing metastasis, trans-lymphatic metastasis and in the early stages of trans-mesothelial metastasis. However, an established trans-mesothelial metastasis has its own interstitial tissue and vasculature which generate high interstitial pressure. Accordingly, it is reasonable to treat established trans-mesothelial metastasis by bidirectional chemotherapy from both IP and systemic chemotherapy.
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Affiliation(s)
- Yutaka Yonemura
- NPO to Support Peritoneal Surface Malignancy Treatment, Asian School of Peritoneal Surface Malignancy Treatment, 510, Fukushima-Cho, Kyoto 600-8189, Japan
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu 525-8585, Japan; (A.M.); (N.T.)
| | - Haruaki Ishibashi
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Akiyoshi Mizumoto
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu 525-8585, Japan; (A.M.); (N.T.)
| | - Gorou Tukiyama
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Yang Liu
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Satoshi Wakama
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Shouzou Sako
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Nobuyuki Takao
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu 525-8585, Japan; (A.M.); (N.T.)
| | - Toshiyuki Kitai
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Kanji Katayama
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Yasuyuki Kamada
- Department of Regional Cancer Therapy, Peritoneal Dissemination Center, Kishiwada Tokusyukai Hospital, Kishiwada 596-8522, Japan; (H.I.); (G.T.); (Y.L.); (S.W.); (S.S.); (T.K.); (K.K.); (Y.K.)
| | - Keizou Taniguchi
- Department of Surgery, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki 213-8570, Japan; (K.T.); (D.F.)
| | - Daisuke Fujimoto
- Department of Surgery, Mizonokuchi Hospital, Teikyo University School of Medicine, Kawasaki 213-8570, Japan; (K.T.); (D.F.)
| | - Yoshio Endou
- Central Research Resource Center, Cancer Research Institute, Kanazawa 922-1192, Japan;
| | - Masahiro Miura
- Department of Anatomy, Oita Medical University, Kasama-Machi, Oita 879-5593, Japan;
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12
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Zhang G, Li Z, Dong J, Zhou W, Zhang Z, Que Z, Zhu X, Xu Y, Cao N, Zhao A. Acacetin inhibits invasion, migration and TGF-β1-induced EMT of gastric cancer cells through the PI3K/Akt/Snail pathway. BMC Complement Med Ther 2022; 22:10. [PMID: 35000605 PMCID: PMC8744305 DOI: 10.1186/s12906-021-03494-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Epithelial-to-mesenchymal transition (EMT) is a pivotal cellular phenomenon involved in tumour metastasis and progression. In gastric cancer (GC), EMT is the main reason for recurrence and metastasis in postoperative patients. Acacetin exhibits various biological activities. However, the inhibitory effect of acacetin on EMT in GC is still unknown. Herein, we explored the possible mechanism of acacetin on EMT in GC in vitro and in vivo. METHODS In vitro, MKN45 and MGC803 cells were treated with acacetin, after which cell viability was detected by CCK-8 assays, cell migration and invasion were detected by using Transwell and wound healing assays, and protein expression was analysed by western blots and immunofluorescence staining. In vivo, a peritoneal metastasis model of MKN45 GC cells was used to investigate the effects of acacetin. RESULTS Acacetin inhibited the proliferation, invasion and migration of MKN45 and MGC803 human GC cells by regulating the expression of EMT-related proteins. In TGF-β1-induced EMT models, acacetin reversed the morphological changes from epithelial to mesenchymal cells, and invasion and migration were limited by regulating EMT. In addition, acacetin suppressed the activation of PI3K/Akt signalling and decreased the phosphorylation levels of TGF-β1-treated GC cells. The in vivo experiments demonstrated that acacetin delayed the development of peritoneal metastasis of GC in nude mice. Liver metastasis was restricted by altering the expression of EMT-related proteins. CONCLUSION Our study showed that the invasion, metastasis and TGF-β1-induced EMT of GC are inhibited by acacetin, and the mechanism may involve the suppression of the PI3K/Akt/Snail signalling pathway. Therefore, acacetin is a potential therapeutic reagent for the treatment of GC patients with recurrence and metastasis.
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Affiliation(s)
- Guangtao Zhang
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhaoyan Li
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.,Department of Oncology, Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiahuan Dong
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Weili Zhou
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Zhanxia Zhang
- Institute of Traditional Chinese Medicine Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zujun Que
- Institute of Traditional Chinese Medicine Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,School of Oncology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xiaohong Zhu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Yan Xu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Nida Cao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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13
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Shi M, Yang Z, Lu S, Liu W, Ni Z, Yao X, Hua Z, Feng R, Zheng Y, Wang Z, Sah BK, Chen M, Zhu Z, He C, Li C, Zhang J, Yan C, Yan M, Zhu Z. Oxaliplatin plus S-1 with intraperitoneal paclitaxel for the treatment of Chinese advanced gastric cancer with peritoneal metastases. BMC Cancer 2021; 21:1344. [PMID: 34922478 PMCID: PMC8684127 DOI: 10.1186/s12885-021-09027-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 11/19/2021] [Indexed: 03/20/2023] Open
Abstract
BACKGROUND In this study, we tried to access the efficacy and safety of oxaliplatin plus S-1 with intraperitoneal paclitaxel (PTX) for the treatment of Chinese advanced gastric cancer with peritoneal metastases. PATIENTS AND METHODS Thirty patients diagnosed with advanced gastric cancer underwent laparoscopic exploration and were enrolled when macroscopic disseminated metastases (P1) were confirmed. PTX was diluted in 1 l of normal saline and IP administered through peritoneal port at an initial dose of 40 mg/m2 over 1 h on day1,8, respectively. Oxaliplatin was administered intravenously at an initial dose of 100 mg/m2 on day1, and S-1 was administered orally at an initial dose of 80 mg/m2 for 14 days followed by 7 days rest, repeated by every 3 weeks. RESULTS Of all these 30 patients, the median number of cycles was 6 (range 2-16) due to the limitation of hematotoxicity and peripheral neuropathy by oxaliplatin. There were 11 (36.7%) patients received conversion surgery. The median progression free survival (PFS) was 6.6 months (95% CI = 4.7-8.5 months) and the median overall survival (OS) was 15.1 months (95% CI = 12.4-17.8 months). The grade 3-4 hematological toxicities were leucopenia (23.3%), neutropenia (23.3%), anemia (16.7%), and thrombocytopenia (20%), respectively. The grade 3-4 non-hematological toxicities were tolerated, most of which were peripheral sensory neuropathy (40%) due to oxaliplatin, diarrhea (20%), nausea and vomiting (26.7%). CONCLUSIONS SOX+ip PTX regimen was effective in advanced gastric cancer with peritoneal metastasis. Survival time was significantly prolonged by conversion surgery. Grade 3-4 toxicities were uncommon. Large scale clinical trial is necessary to get more evidence to identify its efficacy. TRAIL REGISTRATION ChiCTR, ChiCTR-IIR-16009802 . Registered 9 November 2016.
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Affiliation(s)
- Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zhongyin Yang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Sheng Lu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Wentao Liu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zhentian Ni
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Xuexin Yao
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zichen Hua
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Runhua Feng
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Yanan Zheng
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zhenqiang Wang
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Birendra Kumar Sah
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Mingmin Chen
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zhenglun Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Changyu He
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Chen Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China.
| | - Min Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China
| | - Zhenggang Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197 Ruijin er Road, Shanghai, 200025, China.
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Marano L, Marrelli D, Sammartino P, Biacchi D, Graziosi L, Marino E, Coccolini F, Fugazzola P, Valle M, Federici O, Baratti D, Deraco M, Di Giorgio A, Macrì A, Pasqual EM, Framarini M, Vaira M, Roviello F. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal Metastases: Multicenter Study of 'Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O.'. Ann Surg Oncol 2021; 28:9060-9070. [PMID: 34057569 PMCID: PMC8590997 DOI: 10.1245/s10434-021-10157-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. METHODS The Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. RESULTS A total of 91 patients with a median age of 58 years (range 26-75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8-28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4-10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1-16.2; treated patients: 35.3 months, 95% CI 2.8-67.8; p = 0.022). CONCLUSIONS In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.
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Affiliation(s)
- Luigi Marano
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
| | - Daniele Marrelli
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Paolo Sammartino
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Daniele Biacchi
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Luigina Graziosi
- General and Emergency Surgery, University of Perugia, Perugia, Italy
| | - Elisabetta Marino
- General and Emergency Surgery, University of Perugia, Perugia, Italy
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Pisa, Italy
| | - Paola Fugazzola
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy
| | - Mario Valle
- Department of Digestive Surgery, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Orietta Federici
- Department of Digestive Surgery, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Dario Baratti
- Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Peritoneal Surface Malignancies Unit, Milan, Italy
| | - Marcello Deraco
- Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Peritoneal Surface Malignancies Unit, Milan, Italy
| | - Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Antonio Macrì
- Peritoneal Surface Malignancy and Soft Tissue Sarcoma Program, Messina University Medical School Hospital, Messina, Italy
| | - Enrico Maria Pasqual
- Department of Medical Area, University of Udine, Santa Maria della Misericordia University Hospital Udine, Udine, Italy
| | | | - Marco Vaira
- Candiolo Cancer Institute, Unit of Surgical Oncology, FPO-IRCCS, Candiolo, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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Shimura T, Toden S, Kandimalla R, Toiyama Y, Okugawa Y, Kanda M, Baba H, Kodera Y, Kusunoki M, Goel A. Genomewide Expression Profiling Identifies a Novel miRNA-based Signature for the Detection of Peritoneal Metastasis in Patients With Gastric Cancer. Ann Surg 2021; 274:e425-e434. [PMID: 31663973 PMCID: PMC7577555 DOI: 10.1097/sla.0000000000003647] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE This study aimed to conduct a genomewide transcriptomic profiling to develop a microRNA (miRNA)-based signature for the identification of peritoneal metastasis (PM) in patients with gastric cancer (GC). SUMMARY BACKGROUND DATA Even though PM in patients with GC has long been recognized to associate with poor prognosis, currently there is lack of availability of molecular biomarkers for its robust diagnosis. METHODS We performed a systematic biomarker discovery by analyzing miRNA expression profiles in primary tumors from GC patients with and without PM, and subsequently validated the expression of candidate miRNA biomarkers in 3 independent clinical cohorts of 354 patients with advanced GC. RESULTS Five miRNAs (miR-30a-5p, -134-5p, -337-3p, -659-3p, and -3917) were identified during the initial discovery phase; three of which (miR-30a-5p, -659-3p, and -3917) were significantly overexpressed in the primary tumors from PM-positive patients in the testing cohort (P = 0.002, 0.04, and 0.007, respectively), and distinguished patients with versus without peritoneal metastasis with the value of area under the curve (AUC) of 0.82. Furthermore, high expression of these miRNAs also associated with poor prognosis (hazard ratio = 2.18, P = 0.04). The efficacy of the combination miRNA signature was subsequently validated in an independent validation cohort (AUC = 0.74). Finally, our miRNA signature when combined together with the macroscopic Borrmann's type score offered a much superior diagnostic in all 3 cohorts (AUC = 0.87, 0.76, and 0.79, respectively). CONCLUSIONS We have established an miRNA-based signature that have a potential to identify peritoneal metastasis in GC patients.
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Affiliation(s)
- Tadanobu Shimura
- Center for Gastrointestinal Research; Center from Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
- Department of Molecular Diagnostics, Therapeutics and Translational Medicine, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Shusuke Toden
- Center for Gastrointestinal Research; Center from Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
- Department of Molecular Diagnostics, Therapeutics and Translational Medicine, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Raju Kandimalla
- Center for Gastrointestinal Research; Center from Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
- Department of Molecular Diagnostics, Therapeutics and Translational Medicine, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Yuji Toiyama
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
| | - Yoshinaga Okugawa
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
| | - Ajay Goel
- Center for Gastrointestinal Research; Center from Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
- Department of Molecular Diagnostics, Therapeutics and Translational Medicine, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Tao W, Liu XY, Cheng YX, Kang B, Zhang H, Yuan C, Zhang B, Peng D. Does Extended Intraoperative Peritoneal Lavage Really Bring Benefit on Patients With Gastric Cancer? A Meta-Analysis of Published Clinical Trials. Front Oncol 2021; 11:715040. [PMID: 34504793 PMCID: PMC8421543 DOI: 10.3389/fonc.2021.715040] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/31/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose The purpose of the current meta-analysis is to analyze whether extended intraoperative peritoneal lavage (EIPL) can bring benefit on short-term outcomes or survival for patients undergoing curative gastrectomy for gastric cancer. Methods The PubMed, Embase, and Cochrane Library databases were searched from inception to May 3, 2021, to find eligible studies. Postoperative complications, overall survival (OS), disease-free survival (DFS), and peritoneal recurrence-free survival (PRFS) were compared between EIPL group and No EIPL group. Results A total of five randomized controlled trials with 1,790 patients were included in the current meta-analysis. No difference was found in baseline information (p > 0.05). After pooling up the data of overall postoperative complications, no significant difference was found between EIPL group and No EIPL group (OR = 0.88, 95% CI = 0.51 to 1.53, P = 0.65). Furthermore, there was no significant difference between EIPL group and No EIPL group in terms of OS (HR = 0.77, 95% CI = 0.36 to 1.64, P = 0.49), DFS (HR = 0.97, 95% CI = 0.71 to 1.33, P = 0.87), and PRFS (HR = 1.03, 95% CI = 0.74 to 1.43, P = 0.86). In terms of subgroup analysis of OS, no significant difference was found as well (HR = 1.05, 95% CI = 0.82 to 1.34, P = 0.69). Conclusions EIPL did not bring benefit in terms of short-term outcomes or survival. Therefore, EIPL is not recommended for patients undergoing curative gastrectomy for gastric cancer.
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Affiliation(s)
- Wei Tao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiao-Yu Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yu-Xi Cheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bing Kang
- Department of Clinical Nutrition, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Hua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chao Yuan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Bin Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Dong Peng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Ding P, Yang P, Tian Y, Guo H, Liu Y, Zhang Z, Zheng T, Tan B, Zhang Z, Wang D, Li Y, Zhao Q. Neoadjuvant intraperitoneal and systemic paclitaxel combined with apatinib and S-1 chemotherapy for conversion therapy in gastric cancer patients with positive exfoliative cytology: a prospective study. J Gastrointest Oncol 2021; 12:1416-1427. [PMID: 34532099 PMCID: PMC8421905 DOI: 10.21037/jgo-21-375] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 07/29/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND To explore the efficacy and safety of neoadjuvant intraperitoneal and systemic (NIPS) paclitaxel chemotherapy combined with apatinib and S-1 in the treatment of gastric cancer patients with positive exfoliative cytology. METHODS Patients with gastric cancer (P0CY1) who were confirmed to have free cancer cells (FCCs) in the abdominal cavity after laparoscopic exploration from April 2018 to August 2019 were enrolled. All patients underwent NIPS chemotherapy using paclitaxel combined with apatinib and S-1 treatment. Laparoscopic exploration was performed after 3 cycles of conversion therapy. The primary study endpoint was the FCC negative rate, and the secondary study endpoints were overall survival time (OS), progression-free survival time (PFS), objective response rate (ORR), disease control rate (DCR), and safety indicators. RESULTS Out of 312 advanced gastric cancer patients who underwent laparoscopic exploration, 36 patients with P0CY1 gastric cancer were identified and enrolled in this study. After 3 cycles of conversion therapy, the ORR was 80.56% and the DCR was 94.44%. All patients underwent secondary laparoscopic exploration, and the FCC conversion rate was 77.78%. All patients with negative FCC underwent R0 surgical resection, with a median follow-up time of 11.4 months. The median survival time was 15.5 months, and the 1-year OS was 80.55%. The median PFS was 14.4 months, and the 1-year PFS was 75.00%. Treatment-related grade 3 adverse reactions were mainly leukopenia and neutropenia. No grade 4 adverse reactions were observed. There were no reported deaths related to chemotherapy or surgery in the study cohort. CONCLUSIONS NIPS with paclitaxel combined with apatinib and S-1 treatment may increase the FCC negative rate of P0CY1 gastric cancer patients.
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Affiliation(s)
- Ping'an Ding
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Peigang Yang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yuan Tian
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Honghai Guo
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yang Liu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ze Zhang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Tao Zheng
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bibo Tan
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhidong Zhang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dong Wang
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yong Li
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Intraperitoneal Chemotherapy for Peritoneal Metastases: Technical Innovations, Preclinical and Clinical Advances and Future Perspectives. BIOLOGY 2021; 10:biology10030225. [PMID: 33804167 PMCID: PMC8001167 DOI: 10.3390/biology10030225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
(1) Background: Tumors of the peritoneal serosa are called peritoneal carcinosis. Their origin may be primary by primitive involvement of the peritoneum (peritoneal pseudomyxoma, peritoneal mesothelioma, etc.). This damage to the peritoneum can also be a consequence of the dissipation of cancers-in particular, digestive (stomach, pancreas, colorectal, appendix) and gynecological (ovaries) ones in the form of metastases. The aim of the treatment is a maximal reduction of the macroscopic disease called "cytoreduction" in combination with hyperthermic intra-abdominal chemotherapy to treat residual microscopic lesions. (2) Methods: In this narrative review, we fundamentally synthetize the evolution of this process over time and its impact on clinical applications. (3) Results: Over the last past decade, different evolutions concerning both delivery modes and conditions concerning hyperthermic intra-abdominal chemotherapy have been realized. (4) Conclusion: The final objective of these evolutions is the improvement of the global and recurrence-free survival of primary and secondary malignant peritoneal pathologies. However, more large randomized controlled trials are needed to demonstrate the efficacy of such treatments with the help of molecular biology and genetics.
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Saito S, Yamaguchi H, Ohzawa H, Miyato H, Kanamaru R, Kurashina K, Hosoya Y, Lefor AK, Sata N, Kitayama J. Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Oxaliplatin as Induction Therapy for Patients with Advanced Gastric Cancer with Peritoneal Metastases. Ann Surg Oncol 2020; 28:3863-3870. [PMID: 33270170 PMCID: PMC8184712 DOI: 10.1245/s10434-020-09388-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 11/04/2020] [Indexed: 12/27/2022]
Abstract
Background Intraperitoneal (IP) administration of paclitaxel (PTX) has a great pharmacokinetic advantage to control peritoneal lesions and can be combined with various systemic chemotherapies. In this study, we evaluate the efficacy and tolerability of a combination of IP-PTX and systemic S-1/oxaliplatin (SOX) for induction chemotherapy for patients with peritoneal metastases (PM) from gastric cancer (GC). Patients and Methods Patients with GC who were diagnosed as macroscopic PM (P1) or positive peritoneal cytology (CY1) by staging laparoscopy between 2016 and 2019 were enrolled. PTX was IP administered at 40 mg/m2 on days 1 and 8. Oxaliplatin was IV administered at 100 mg/m2 on day 1, and S-1 was administered at 80 mg/m2/day for 14 consecutive days, repeated every 21 days. Survival time and toxicities were retrospectively explored. Results Forty-four patients received SOX + IP-PTX with a median (range) of 16 (1–48) courses, although oxaliplatin was suspended due to the hematotoxicity or intolerable peripheral neuropathy in many patients. The 1-year overall survival (OS) rate was 79.5% (95% CI 64.4–88.8%) with median survival time of 25.8 months. Gastrectomy was performed in 20 (45%) patients who showed macroscopic shrinkage of PM with a 1-year OS rate of 100% (95% CI 69.5–100%). Grade 2 and 3 histological responses was achieved in four (20%) and one (5%) patients. Grade 3/4 toxicities included neutropenia (11%), leukopenia (39%), and anemia (14%). There were no treatment-related deaths. Conclusions Combination chemotherapy using SOX + IP-PTX regimen is highly effective and recommended as induction chemotherapy for patients with PM from GC.
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Affiliation(s)
- Shin Saito
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | | | - Hideyuki Ohzawa
- Department of Chemotherapy, Jichi Medical University, Tochigi, Japan
| | - Hideyo Miyato
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Rihito Kanamaru
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Kentaro Kurashina
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Yoshinori Hosoya
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Alan Kawarai Lefor
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Naohiro Sata
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | - Joji Kitayama
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan.
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Neoadjuvant Intraperitoneal Chemotherapy in Patients with Pseudomyxoma Peritonei-A Novel Treatment Approach. Cancers (Basel) 2020; 12:cancers12082212. [PMID: 32784670 PMCID: PMC7465601 DOI: 10.3390/cancers12082212] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 01/17/2023] Open
Abstract
Neoadjuvant intravenous chemotherapy in patients with pseudomyxoma peritonei (PMP) has not shown convincing results. The effectiveness of neoadjuvant intraperitoneal (IP) chemotherapy has never been reported. This prospective, non-randomized phase II study included patients with PMP treated between May 2017 and December 2018, who were not considered suitable for primary cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The majority of patients were treated with laparoscopic HIPEC (oxaliplatin 200 mg/m2, 60 min, 43 °C). IP chemotherapy was started 2 weeks after docetaxel 40 mg/m2 + cisplatin 40 mg/m2, accompanied by oral S1 (tegafur, gimeracil, and oteracil) (50 mg/m2) for 14 days, followed by one week rest. Clinical parameters and complications were recorded. In total, 22/27 patients qualified for CRS and HIPEC after neoadjuvant treatment. A complete cytoreduction (Completeness of cytoreduction Score 0/1) could be achieved in 54.5%. The postoperative morbidity rate was 13.6% and mortality was rate 4.5%. In total, 20/22 patients had major pathological tumor responses. The mean drop in CEA was 28.2% and in the peritoneal carcinomatosis index (PCI) was 2.6. Positive or suspicious cytology turned negative in 69.2% of patients. Thus, for PMP patients who were not amenable for primary surgery, the majority received complete cytoreduction after treatment with neoadjuvant IP chemotherapy, with satisfying tumor regression and with low complication rates. The oncological benefit in terms of survival with this new treatment regimen needs to be proven.
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Song XH, Chen XZ, Chen XL, Liu K, Zhang WH, Mo XM, Hu JK. Peritoneal Metastatic Cancer Stem Cells of Gastric Cancer with Partial Mesenchymal-Epithelial Transition and Enhanced Invasiveness in an Intraperitoneal Transplantation Model. Gastroenterol Res Pract 2020; 2020:3256538. [PMID: 32831823 PMCID: PMC7426763 DOI: 10.1155/2020/3256538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 05/29/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES This preliminary study is aimed at enriching and isolating peritoneal metastatic cancer stem cells (pMCSCs) of gastric cancer and assessing their epithelial-mesenchymal transition (EMT) phenotype and invasiveness. METHODS Cancer stem cells of human gastric cancer (CSC-hGC) were previously isolated and transfected with green fluorescent protein and luciferase genes to validate the mouse model of peritoneal metastasis established via transplantation. The first and second generations ([G1] and [G2], respectively) of pMCSCs were isolated from intraperitoneally transplanted CSC-hGC (pMCSC-tGC) by spherical culture. CSC and EMT-related markers and regulators in the two generations of intraperitoneally transplanted tumors were examined by immunohistochemistry, immunofluorescence staining, and quantitative PCR. Cell mobility was examined by a transwell assay. RESULTS The nude mouse model of intraperitoneally transplanted CSC-hGC was successful in establishing sequential formation of peritoneal tumors and enrichment of pMCSCs. CD44 and CD54 were consistently expressed in the two generations of transplanted tumors. In vitro cell (migration) assays and immunocytofluorescence assays showed that in pMCSC-tGC[G2], E-cad, Survivin, and Vimentin expression was stable; α-SMA expression was decreased; and OVOL2, GRHL2, and ZEB1 expression was increased. PCR analysis indicated that in pMCSC-tGC[G2], the mRNA expression of E-cad, α-SMA, MMP9, MMP2, and Vimentin was downregulated, while that of ZEB1, OVOL2, and GRHL2 was upregulated. In vivo tumor (homing) assays and immunohistochemical assays demonstrated that in pMCSC-tGC[G2], E-cad and Snail were upregulated, while α-SMA was downregulated. The numbers of migrated and invaded pMCSC-tGC[G1] and pMCSC-tGC[G2] were significantly higher than those of CSC-hGC in migration and invasion assays. CONCLUSIONS pMCSCs might be a specific subpopulation that can be sequentially enriched by intraperitoneal transplantation. pMCSCs exhibited a tendency towards partial mesenchymal-epithelial transition, enhancing their invasiveness during homing and the formation of peritoneal tumors. However, these preliminary findings require validation in further experiments.
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Affiliation(s)
- Xiao-Hai Song
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xin-Zu Chen
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xian-Ming Mo
- Laboratory of Stem Cell Biology, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery & Laboratory of Gastric Cancer, West China Hospital, Sichuan University, Chengdu, China
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Lo Dico R, Gornet JM, Guglielmo N, Zaanan A, Taieb J, Pocard M. Bidirectional chemotherapy combining intraperitoneal docetaxel with intravenous 5-fluorouracil and oxaliplatin for patients with unresectable peritoneal metastasis from gastric cancer: the first study in Western countries. Pleura Peritoneum 2020; 5:20190035. [PMID: 32566725 PMCID: PMC7292234 DOI: 10.1515/pp-2019-0035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 03/03/2020] [Indexed: 12/18/2022] Open
Abstract
Background A new treatment using bidirectional intraperitoneal (IP) and intravenous (IV) chemotherapy developed by Asiatic surgeons improves outcomes in patients with synchronous peritoneal metastasis (PM) from gastric cancer (GC). Methods We enrolled six consecutive patients with unresectable PM from GC who underwent bidirectional chemotherapy using IP docetaxel and IV FOLFOX or LV5FU2. In one course, IP docetaxel 30 mg/m2 was administrated on days 1, 8 and 15, and IV FOLFOX or LV5FU2 was administered on days 1 and 15, followed by 7 days of rest. Before and after a complete bidirectional cycle of three courses, the peritoneal cancer index (PCI) was evaluated by laparoscopy. The primary endpoint was to evaluate the feasibility and safety of bidirectional chemotherapy. Secondary endpoints were overall survival (OS), and the success of the therapeutic strategy was reflected by a decrease of 25% of the initial PCI. Results All patients completed one bidirectional cycle. The regimen was well tolerated. The median OS was 13 months [range 5–18], and the 1-year OS rate was 67%. After the first bidirectional cycle, the PCI decrease ≥25% of the initial value in four patients. A major histological response was observed in four patients. Conclusions This is the first Western study and confirms the feasibility and safety of bidirectional treatment using IP and IV chemotherapy for patients with unresectable PM from GC, resulting in a 13-month median OS with limited morbidity. The decrease in PCI after one bidirectional cycle is promising.
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Affiliation(s)
- Rea Lo Dico
- University of Paris, UMR 1275 CAP Paris-Tech, Department of Digestive Surgery, Lariboisière Hospital, AP-HP, F-75010Paris, France
| | - Jean Marc Gornet
- Department of Hepatology, Gastroenterology and Digestive Oncology, Saint-Louis Hospital, AP-HP, Paris, France
| | - Nicola Guglielmo
- Department of Digestive Surgery, Lariboisiere Hospital, AP-HP, Paris, France
| | - Aziz Zaanan
- Department of Hepatology, Gastroenterology and Digestive Oncology, Georges Pompiodou European Hospital, AP-HP, Paris, University of Paris, France
| | - Julien Taieb
- Department of Hepatology, Gastroenterology and Digestive Oncology, Georges Pompiodou European Hospital, AP-HP, Paris, University of Paris, France
| | - Marc Pocard
- University of Paris, UMR 1275 CAP Paris-Tech, Department of Digestive Surgery, Lariboisière Hospital, AP-HP, F-75010Paris, France
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23
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Long Term Survival after Cytoreductive Surgery Combined with Perioperative Chemotherapy in Gastric Cancer Patients with Peritoneal Metastasis. Cancers (Basel) 2020; 12:cancers12010116. [PMID: 31906405 PMCID: PMC7016959 DOI: 10.3390/cancers12010116] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 12/24/2019] [Accepted: 12/29/2019] [Indexed: 12/18/2022] Open
Abstract
The present study demonstrated prognostic factors for long-term survival in patients after a comprehensive treatment (CHT) for peritoneal metastasis (PM) from gastric cancer (GC). Materials and Methods: Among 419 patients treated with neoadjuvant intraperitoneal/systemic chemotherapy (NIPS), 266 (63.5%) patients received complete resection (CC-0) of the macroscopic tumors. In total, 184 (43.9%) patients were treated with postoperative systemic chemotherapy. Results: All patients treated who received incomplete cytoreduction (CC-1) died of GC within 6 years. In contrast, 10- year survival rates (-YSR) of CC-0 resection were 8.3% with median survival time (MST) of 20.5 months. Post-NIPS peritoneal cancer index (PCI) ≤11, and pre-NIPS PCI ≤13 were the significant favorable prognostic factors. Patients with numbers of involved peritoneal sectors ≤5 survived significant longer than those with ≥6. Both negative pre- and post-NIPS cytology was associated with significant favorable prognosis. Multivariate analyses identified pre-PCI (≤13 vs. ≥14), and cytology after NIPS (negative cytology vs. positive cytology) as independent prognostic factors. Ten year-survivors were found in patients with involvement of the greater omentum (9%), pelvic peritoneum (3%), para-colic gutter (13.9%), upper jejunum (5.6%), lower jejunum (5.5%), spermatic cord (21.9%), rectum (9.5%), ureter (6.3%), ovary (6.7%), and diaphragm (7.0%) at the time of cytoreduction. Twenty-one patients survived longer than 5 years, and 17 patients are still alive without recurrence. Conclusions: GC-PM should be removed aggressively, in patients with PCI after NIPS ≤11, PCI before NIPS ≤13, mall bowel PCI ≤2, and complete cytoreduction should be performed for metastasis in ≤5 peritoneal sectors.
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24
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Lei Z, Wang J, Li Z, Li B, Luo J, Wang X, Wang J, Ba M, Tang H, He Q, Liao Q, Yang X, Guan T, Liang H, Cui S, On Behalf Of The Chinese Peritoneal Oncology Study Group. Hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis: A multicenter propensity score-matched cohort study. Chin J Cancer Res 2020; 32:794-803. [PMID: 33447001 PMCID: PMC7797229 DOI: 10.21147/j.issn.1000-9604.2020.06.12] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective Systemic chemotherapy has limited efficacy in the treatment of peritoneal metastasis (PM) in gastric cancer (GC). Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with complete cytoreductive surgery (CRS) has shown promising outcomes but remains controversial. The present study aimed to evaluate the safety and efficacy of HIPEC without CRS in GC patients with PM. Methods This retrospective propensity score-matched multicenter cohort study included GC patients with PM treated with either chemotherapy alone (Cx group) or with HIPEC combined with chemotherapy (HIPEC-Cx group) in four Chinese high-volume gastric medical centers between 2010 and 2017. The primary outcomes were median survival time (MST) and 3-year overall survival (OS). Propensity score matching was performed to compensate for controlling potential confounding effects and selection bias. Results Of 663 eligible patients, 498 were matched. The MST in the Cx and HIPEC-Cx groups was 10.8 and 15.9 months, respectively [hazard ratio (HR)=0.71, 95% confidence interval (95% CI), 0.58−0.88; P=0.002]. The 3-year OS rate was 10.1% (95% CI, 5.4%−14.8%) and 18.4% (95% CI, 12.3%−24.5%) in the Cx and HIPEC-Cx groups, respectively (P=0.017). The complication rates were comparable. The time to first flatus and length of hospital stay for patients undergoing HIPEC combined with chemotherapy was longer than that of chemotherapy alone (4.6±2.4 dvs. 2.7±1.8 d, P<0.001; 14.2±5.8 dvs. 11.4±7.7 d, P<0.001), respectively. The median follow-up period was 33.2 months.
Conclusions Compared with standard systemic chemotherapy, HIPEC combined with chemotherapy revealed a statistically significant survival benefit for GC patients with PM, without compromising patient safety.
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Affiliation(s)
- Ziying Lei
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Jiahong Wang
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Zhi Li
- Department of General Surgery, Affiliated Tumor Hospital of Zhengzhou University, Tumor Hospital of Henan Province, Zhengzhou 450008, China
| | - Baozhong Li
- Department of Surgery, Anyang Tumor Hospital, Anyang 455000, China
| | - Jiali Luo
- Department of Oncology, Guangzhou Medical University, Guangzhou 510095, China
| | - Xuejun Wang
- Department of Gastrointestinal Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Jin Wang
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Mingchen Ba
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Hongsheng Tang
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Qingjun He
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Quanxing Liao
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Xiansheng Yang
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Tianpei Guan
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - Han Liang
- Department of Gastrointestinal Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Shuzhong Cui
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China
| | - On Behalf Of The Chinese Peritoneal Oncology Study Group
- Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou 510095, China.,Department of General Surgery, Affiliated Tumor Hospital of Zhengzhou University, Tumor Hospital of Henan Province, Zhengzhou 450008, China.,Department of Surgery, Anyang Tumor Hospital, Anyang 455000, China.,Department of Oncology, Guangzhou Medical University, Guangzhou 510095, China.,Department of Gastrointestinal Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
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25
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Rau B, Brandl A, Thuss-Patience P, Bergner F, Raue W, Arnold A, Horst D, Pratschke J, Biebl M. The efficacy of treatment options for patients with gastric cancer and peritoneal metastasis. Gastric Cancer 2019; 22:1226-1237. [PMID: 31065877 DOI: 10.1007/s10120-019-00969-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2018] [Accepted: 04/29/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with peritoneal metastases of gastric cancer have a poor prognosis and median survival of 7 months. This study compared treatment options and outcomes based on the Peritoneal Cancer Index (PCI). METHODS This retrospective analysis included patients with gastric cancer treated between August 2008 and December 2017 with synchronous peritoneal metastases only diagnosed by laparoscopy. The three treatments were as follows: (1) cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in combination with pre- and postoperative systemic chemotherapy (n = 58), (2) laparotomy/laparoscopy without CRS, but HIPEC in combination with pre- and postoperative systemic chemotherapy (n = 11), and (3) systemic chemotherapy only (n = 19). RESULTS A total of 88 patients aged 54.6 ± 10.9 years with mean PCI of 14.3 ± 11.3 were included. The PCI was significantly lower in group 1 (8.3 ± 5.7) than in group 2 (23.9 ± 11.1, p < 0.001) and group 3 (27.3 ± 9.3, p < 0.001). Mean time from diagnosis to laparoscopy was 5.2 ± 2.9 months. The median overall survival was 9.8 ± 0.7 for group 1, 6.3 ± 3.0 for group 2 and 4.9 ± 1.9 months for group 3 (p < 0.001). Predictors for deteriorated overall patient survival included > 4 cycles of preoperative chemotherapy (HR 4.49, p < 0.001), lymph-node metastasis (HR 3.53, p = 0.005), PCI ≥ 12 (HR 2.11, p = 0.036), and incompleteness of cytoreduction (HR 4.30, p = 0.001) in patients treated with CRS and HIPEC. CONCLUSION CRS and HIPEC showed convincing results in selected patients with PCI < 12 and complete cytoreduction. Prolonged duration (> 4 cycles) of preoperative intravenous chemotherapy reduced patient survival in patients suitable for CRS and HIPEC.
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Affiliation(s)
- Beate Rau
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Andreas Brandl
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Peter Thuss-Patience
- Medical Clinic for Hematology, Oncology and Tumor-Immunology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Fabian Bergner
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Wieland Raue
- Department of General, Visceral and Thoracic Surgery, AKH Celle, Celle, Germany
| | - Alexander Arnold
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Matthias Biebl
- Department of Surgery, Campus Virchow-Klinikum and Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
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26
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Guner A, Yildirim R. Surgical management of metastatic gastric cancer: moving beyond the guidelines. Transl Gastroenterol Hepatol 2019; 4:58. [PMID: 31559339 DOI: 10.21037/tgh.2019.08.03] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 08/05/2019] [Indexed: 01/27/2023] Open
Abstract
Despite decreasing incidence, gastric cancer remains a major health problem worldwide and is associated with poor survival. The poor survival is mainly attributed to delayed presentation which may cause local or systemic metastases. The standard of care for patients with metastatic gastric cancer (MGC) is palliative chemotherapy with best supportive care. Although the survival has improved owing to advances in chemotherapeutic agents, it is still unsatisfactory, and some perspective changes are needed in the management of MGC to improve the outcomes. Therefore, various alternative treatment strategies for MGC have formed the most important research topics. Liver-directed treatment (LDT) options such as liver resection, radiofrequency ablation (RFA), microwave ablation (MWA), and hepatic artery infusion chemotherapy (HAIC) have been studied in the management of liver metastasis from gastric cancer (LMGC). Intraperitoneal chemotherapy (IPC) in addition to cytoreductive surgery (CRS) aiming to remove all macroscopic tumor focus resulting from peritoneal dissemination is the treatment option for peritoneal metastasis, while para-aortic lymph node dissection is the treatment option for para-aortic lymph node metastasis which is considered to be M1 disease. Conversion surgery is a novel concept aiming at R0 resection for originally unresectable or marginally resectable tumors after a remarkably good response to the chemotherapy. Large amounts of data in the literature have demonstrated the benefits of individualized approaches such as the combination of systemic and local treatment options in selected patient groups. In this review, we aimed to explore the current and future treatment options by reviewing the literature on this controversial topic.
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Affiliation(s)
- Ali Guner
- Department of General Surgery, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.,Department of Biostatistics and Medical Informatics, Institute of Medical Science, Karadeniz Technical University, Trabzon, Turkey
| | - Reyyan Yildirim
- Department of General Surgery, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey
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27
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Brandl A, Pachmayr E, Gül-Klein S, Alberto M, Thuss-Patience P, Rau B. [Surgical treatment of peritoneal metastases of gastric cancer]. Chirurg 2019; 89:669-677. [PMID: 29616280 DOI: 10.1007/s00104-018-0625-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Up to 17% of all patients with gastric cancer are diagnosed with the presence of peritoneal metastases, which is associated with a poor prognosis. The most promising results were shown with multimodal treatment regimens including systemic chemotherapy and cytoreductive surgery (CRS). A subsequent hyperthermic intraperitoneal chemotherapy (HIPEC).possibly has a positive effect and is currently being tested. OBJECTIVES This manuscript highlights the key role of CRS and HIPEC in patients with peritoneal metastases of gastric cancer and illustrates which patients benefit from this intensive therapy. METHODS We performed a comprehensive review of the literature to demonstrate relevant aspects in the treatment of peritoneal metastases in gastric cancer. RESULTS The use of CRS and HIPEC improves the overall survival to 11 months compared to best supportive care in selected patients. Patients who present with low volume peritoneal disease (peritoneal cancer index ≤6) have the best prognosis. This intensive treatment is associated with a relatively high morbidity (15-50%) and mortality (1-10%). Complete cytoreduction, i.e. a complete macroscopic absence of tumor tissue after resection is the most important prognostic factor. CONCLUSION The CRS and HIPEC procedures have a proven survival benefit in selected patients. Due to the relatively high morbidity and mortality, the evaluation should be performed by an experienced team including a surgical oncologist, medical oncologist and intensive care physician, to achieve the highest rate of complete cytoreduction in combination with low morbidity; however, the effect of HIPEC has to be proven and the results of the randomized GASTRIPEC trial are awaited.
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Affiliation(s)
- A Brandl
- Chirurgische Klinik, Campus Virchow-Klinikum und Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland
| | - E Pachmayr
- Chirurgische Klinik, Campus Virchow-Klinikum und Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland
| | - S Gül-Klein
- Chirurgische Klinik, Campus Virchow-Klinikum und Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland
| | - M Alberto
- Chirurgische Klinik, Campus Virchow-Klinikum und Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland
| | - P Thuss-Patience
- Medizinische Klinik mit Schwerpunkt Hämatologie, Onkologie und Tumorimmunologie, Charité - Universitätsmedizin Berlin, Berlin, Deutschland
| | - B Rau
- Chirurgische Klinik, Campus Virchow-Klinikum und Charité Campus Mitte, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Deutschland.
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28
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Ham IH, Lee D, Hur H. Role of Cancer-Associated Fibroblast in Gastric Cancer Progression and Resistance to Treatments. JOURNAL OF ONCOLOGY 2019; 2019:6270784. [PMID: 31281359 PMCID: PMC6590541 DOI: 10.1155/2019/6270784] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/23/2019] [Indexed: 12/21/2022]
Abstract
Although the survival of gastric cancer (GC) patients has gradually improved, the outcomes of advanced GC patients remain unsatisfactory despite standard treatment with conventional chemotherapy or targeted agents. Several studies have shown that cancer-associated fibroblasts (CAFs), a major component of tumor stroma in GC, may have significant roles in GC progression and resistance to treatments. CAFs are a major source of various secreted molecules in the tumor microenvironment, which stimulate cancer cells and other noncancerous components of GC. Surprisingly, these factors could be involved in gastric carcinogenesis. Cytokines, including interleukin-6 and interleukin-11, or growth factors, such as fibroblast growth factor produced from CAFs, can directly activate GC cells and consequently lead to the development of an aggressive phenotype. Galectin-1 or hepatocyte growth factor can be involved in CAF-derived neovascularization in GC. In addition, recent studies showed that CAFs can affect tumor immunity through M2 polarization of tumor-associated macrophages. Finally, the current study aimed to introduce several inhibitory agents and evaluate their suppressive effects on CAFs in patients with GC progression. However, further studies are required to evaluate their safety and select appropriate patients for application in clinical settings.
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Affiliation(s)
- In-Hye Ham
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Dagyeong Lee
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
- Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea
| | - Hoon Hur
- Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea
- Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea
- Department of Biomedical Science, Graduated School of Ajou University, Suwon, Republic of Korea
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29
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Koemans WJ, van der Kaaij RT, Boot H, Buffart T, Veenhof AAFA, Hartemink KJ, Grootscholten C, Snaebjornsson P, Retel VP, van Tinteren H, Vanhoutvin S, van der Noort V, Houwink A, Hahn C, Huitema ADR, Lahaye M, Los M, van den Barselaar P, Imhof O, Aalbers A, van Dam GM, van Etten B, Wijnhoven BPL, Luyer MDP, Boerma D, van Sandick JW. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy versus palliative systemic chemotherapy in stomach cancer patients with peritoneal dissemination, the study protocol of a multicentre randomised controlled trial (PERISCOPE II). BMC Cancer 2019; 19:420. [PMID: 31060544 PMCID: PMC6501330 DOI: 10.1186/s12885-019-5640-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 04/25/2019] [Indexed: 02/13/2023] Open
Abstract
BACKGROUND At present, palliative systemic chemotherapy is the standard treatment in the Netherlands for gastric cancer patients with peritoneal dissemination. In contrast to lymphatic and haematogenous dissemination, peritoneal dissemination may be regarded as locoregional spread of disease. Administering cytotoxic drugs directly into the peritoneal cavity has an advantage over systemic chemotherapy since high concentrations can be delivered directly into the peritoneal cavity with limited systemic toxicity. The combination of a radical gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results in patients with gastric cancer in Asia. However, the results obtained in Asian patients cannot be extrapolated to Western patients. The aim of this study is to compare the overall survival between patients with gastric cancer with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with palliative systemic chemotherapy, and those treated with gastrectomy, CRS and HIPEC after neoadjuvant systemic chemotherapy. METHODS In this multicentre randomised controlled two-armed phase III trial, 106 patients will be randomised (1:1) between palliative systemic chemotherapy only (standard treatment) and gastrectomy, CRS and HIPEC (experimental treatment) after 3-4 cycles of systemic chemotherapy.Patients with gastric cancer are eligible for inclusion if (1) the primary cT3-cT4 gastric tumour including regional lymph nodes is considered to be resectable, (2) limited peritoneal dissemination (Peritoneal Cancer Index < 7) and/or tumour positive peritoneal cytology are confirmed by laparoscopy or laparotomy, and (3) systemic chemotherapy was given (prior to inclusion) without disease progression. DISCUSSION The PERISCOPE II study will determine whether gastric cancer patients with limited peritoneal dissemination and/or tumour positive peritoneal cytology treated with systemic chemotherapy, gastrectomy, CRS and HIPEC have a survival benefit over patients treated with palliative systemic chemotherapy only. TRIAL REGISTRATION clinicaltrials.gov NCT03348150 ; registration date November 2017; first enrolment November 2017; expected end date December 2022; trial status: Ongoing.
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Affiliation(s)
- W. J. Koemans
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - R. T. van der Kaaij
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - H. Boot
- Department of Gastro-Intestinal Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - T. Buffart
- Department of Gastro-Intestinal Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - A. A. F. A. Veenhof
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - K. J. Hartemink
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - C. Grootscholten
- Department of Gastro-Intestinal Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - P. Snaebjornsson
- Department of Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - V. P. Retel
- Department of Psychosocial Research and Epidomiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - H. van Tinteren
- Department of Biometrics, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - S. Vanhoutvin
- Department of Biometrics, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - V. van der Noort
- Department of Biometrics, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - A. Houwink
- Department of Anaesthesiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - C. Hahn
- Department of Anaesthesiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - A. D. R. Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - M. Lahaye
- Department of Radiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
| | - M. Los
- Department of Oncology, Sint Antonius Hospital, Koekoekslaan 1, Nieuwegein, 3435 CM The Netherlands
| | | | - O. Imhof
- Clinical perfusion, Heartbeat, Kerkstraat 3A, Eemnes, 3755 CK The Netherlands
| | - A. Aalbers
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
| | - G. M. van Dam
- Department of Surgery, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ The Netherlands
| | - B. van Etten
- Department of Surgery, University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ The Netherlands
| | - B. P. L. Wijnhoven
- Department of Surgery, Erasmus Medical Center, Doctor Molewaterplein 40, Rotterdam, 3015 GD The Netherlands
| | - M. D. P. Luyer
- Department of Surgery, Catharina Hospital, Michelangelolaan 2, Eindhoven, 5623 EJ The Netherlands
| | - D. Boerma
- Department of Surgery, Sint Antonius Hospital, Koekoekslaan 1, Nieuwegein, 3435 CM The Netherlands
| | - J. W. van Sandick
- Department of Surgery, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam, 1066CX The Netherlands
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Zhu BY, Yuan SQ, Nie RC, Li SM, Yang LR, Duan JL, Chen YB, Zhang XS. Prognostic Factors and Recurrence Patterns in T4 Gastric Cancer Patients after Curative Resection. J Cancer 2019; 10:1181-1188. [PMID: 30854127 PMCID: PMC6400673 DOI: 10.7150/jca.28993] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Accepted: 01/04/2019] [Indexed: 12/26/2022] Open
Abstract
Background: To investigate prognostic factors and recurrence patterns in T4 gastric cancer (GC) patients after curative resection. Methods: Between January 2004 and December 2014, 249 patients with T4 gastric cancer undergoing curative resection were recruited. Patient characteristics, survival, prognostic factors and recurrence patterns were analyzed. Results: Our results showed that the median survival time (MST) for T4 gastric cancer after curative resection was 55.47 months, with 59.47 months for T4a (tumor perforating serosa) and 25.90 months for T4b (tumor invasion of the adjacent structure). Multivariate analysis indicated that age (hazard ratio [HR], 1.86; P = 0.006), location of tumor (HR, 1.25, 0.90 - 5.64; P < 0.001) and intraoperative blood loss (HR, 1.85; P = 0.010) were independent prognostic factors for overall survival (OS). After a median follow-up of 25.87 months, a total of 109 (43.8%) patients suffered from recurrence, and 90 patients had been observed specific recurrence sites, among which peritoneal metastasis was the most common recurrence pattern, 59.0% for T4a and 88.3% for T4b, respectively. Conclusions: For T4 gastric cancer patients after curative resection, older age, gastric cancer of the entire stomach and more intraoperative blood loss were associated with poor OS. The recurrence rate after curative resection for T4 was high, and the most common recurrence pattern was peritoneal metastasis.
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Affiliation(s)
- Bao-Yan Zhu
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shu-Qiang Yuan
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Run-Cong Nie
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shu-Man Li
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Li-Rong Yang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jin-Ling Duan
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ying-Bo Chen
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao-Shi Zhang
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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31
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Fugazzola P, Ansaloni L, Sartelli M, Catena F, Cicuttin E, Leandro G, De' Angelis GL, Gaiani F, Di Mario F, Tomasoni M, Coccolini F. Advanced gastric cancer: the value of surgery. ACTA BIO-MEDICA : ATENEI PARMENSIS 2018; 89:110-116. [PMID: 30561428 PMCID: PMC6502221 DOI: 10.23750/abm.v89i8-s.7897] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Indexed: 02/06/2023]
Abstract
Gastric cancer is a common disease with high mortality. The definition of advanced gastric cancer is still debated. Radical surgery associated to appropriate systemic and intra-abdominal chemotherapy is the gold standard treatment. In presence of peritoneal carcinosis, reaching a complete cytoreduction is the key to achieve long-term survival. Adequate lymphadenectomy is also fundamental. Conversion therapy could be applied to selected IV stage patients. No definitive evidences exist regarding the oncological and surgical superiority of mini-invasive approaches over the classical open techniques.
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Affiliation(s)
- Paola Fugazzola
- Emergency, General and Trauma Surgery dept., Bufalini hospital, Cesena, Italy.
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32
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Yepuri N, Bahary N, Jain A, Dhir M. Review and Update on the Role of Peritoneal Cytology in the Treatment of Gastric Cancer. J Surg Res 2018; 235:607-614. [PMID: 30691849 DOI: 10.1016/j.jss.2018.10.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 08/12/2018] [Accepted: 10/26/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Positive peritoneal cytology (Cyt+) even in the absence of macroscopic disease is associated with poor prognosis in patients with gastric cancer and deemed as M1 disease. Recent years have seen advancements in the evaluation strategies for peritoneal washings and management of patients with Cyt+. The aim of this review was to describe the newest paradigms in the management of patients with gastric cancer who have Cyt+ without macroscopic peritoneal metastases. METHODS A comprehensive literature review was performed to identify studies on the management of gastric cancer and thereby to summarize relevant information on the accuracy of various diagnostic tests and controversies involved in the treatment of patients with Cyt+. RESULTS Although conventional cytology remains the standard technique for assessment of peritoneal washings, it is limited by low sensitivity. The role of immunohistochemistry and molecular techniques for the assessment of peritoneal washings is evolving. Although systemic chemotherapy remains the standard of care for patients with Cyt+ disease, the role of gastrectomy, intraperitoneal chemotherapy, extensive intraperitoneal saline lavage, and hyperthermic intraperitoneal chemotherapy is being evaluated. CONCLUSIONS Clinical decision-making in patients with Cyt+ remains controversial given the seemingly technical resectable albeit biologically unresectable or aggressive disease that portends an overall poor prognosis. Current management strategies are evolving, and further studies are needed to develop an optimal treatment strategy for these patients.
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Affiliation(s)
- Natesh Yepuri
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York
| | - Nathan Bahary
- Division of Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ajay Jain
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York
| | - Mashaal Dhir
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York.
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33
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Gockel I, Jansen-Winkeln B, Haase L, Rhode P, Mehdorn M, Niebisch S, Moulla Y, Lyros O, Lordick F, Schierle K, Wittekind C, Thieme R. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) in Gastric Cancer Patients with Peritoneal Metastasis (PM): Results of a Single-Center Experience and Register Study. J Gastric Cancer 2018; 18:379-391. [PMID: 30607301 PMCID: PMC6310762 DOI: 10.5230/jgc.2018.18.e37] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 12/03/2018] [Accepted: 12/03/2018] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Gastric cancer (GC) patients with peritoneal metastasis (PM) have poor prognosis. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in combination with systemic chemotherapy is a novel treatment option for patients in stage IV of the disease. MATERIALS AND METHODS Between November 2015 and June 2018, prospective data collection was performed in 24 patients with GC and PM (median age, 57; range, 44-75 years). These patients underwent 46 PIPAC procedures with a median number of 2 interventions per patient (range, 1-6). A laparoscopic access was used and a combined therapy of cisplatin and doxorubicin aerosol was administered. RESULTS The median peritoneal carcinomatosis index before the 1st PIPAC was 14 (range, 2-36), and the median ascites volume in patients before the 1st PIPAC was 100 mL (range, 0-6 mL, 300 mL). Eleven patients, who received 2 or more PIPAC procedures, had decreased and stable volumes of ascites, while only 3 patients displayed increasing volume of ascites. The median overall survival was 121 days (range, 66-625 days) after the 1st PIPAC procedure, while 8 patients who received more than 3 PIPAC procedures had a median survival of 450 days (range, 206-481 days) (P=0.0376). CONCLUSIONS Our data show that PIPAC is safe and well tolerated, and that the production of ascites can be controlled by PIPAC in GC patients. Patients, who received 2 or more PIPAC procedures, reported a stable overall quality of life. Further studies are required to document the significance of PIPAC as a palliative multimodal therapy. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03100708.
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Affiliation(s)
- Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Linda Haase
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Philipp Rhode
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Matthias Mehdorn
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Yusef Moulla
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Orestis Lyros
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Florian Lordick
- University Cancer Center Leipzig, University Hospital of Leipzig, Leipzig, Germany
| | - Katrin Schierle
- Institute of Pathology, University Hospital of Leipzig, Leipzig, Germany
| | | | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
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Dahdaleh FS, Turaga KK. Evolving Treatment Strategies and Outcomes in Advanced Gastric Cancer with Peritoneal Metastasis. Surg Oncol Clin N Am 2018; 27:519-537. [PMID: 29935687 DOI: 10.1016/j.soc.2018.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric cancer (GC) has a predilection to metastasize to the peritoneum, denoting a poor prognosis. Treatment strategies available for advanced GC have significantly evolved over time and can be categorized into systemic, regional, and surgical. Although systemic therapies have been the mainstay for the treatment of advanced GC, their ability in achieving long-term survival in patients with peritoneal involvement is modest at best. This article describes advances in combined modality treatment of peritoneal metastases, specifically with an emphasis on peritoneal-directed therapies.
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Affiliation(s)
- Fadi S Dahdaleh
- Complex General Surgical Oncology, Section of General Surgery/Surgical Oncology, The University of Chicago Medicine, 5841 South Maryland Avenue, Room S214, MC 5094, Chicago, IL 60637, USA
| | - Kiran K Turaga
- The University of Chicago Medicine, Section of General Surgery/Surgical Oncology, 5841 South Maryland Avenue, Room G207, MC 5094, Chicago, IL 60637, USA.
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35
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Liu J, Huang C, Peng C, Xu F, Li Y, Yutaka Y, Xiong B, Yang X. Stromal fibroblast activation protein alpha promotes gastric cancer progression via epithelial-mesenchymal transition through Wnt/ β-catenin pathway. BMC Cancer 2018; 18:1099. [PMID: 30419872 PMCID: PMC6233532 DOI: 10.1186/s12885-018-5035-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 11/01/2018] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND To investigate the influence of fibroblast activation protein alpha (FAP) derived from cancer-associated fibroblasts (CAFs), as well as potential mechanism of epithelial mesenchymal transition (EMT), on gastric cancer (GC) progression. METHODS Correlation between CAFs-derived FAP and clinical results has been studied by using 60 GC cases. To confirm this relationship, SGC7901 cells were co-cultured with pre-established FAP-overexpressed fibroblasts in vitro and the characteristics including proliferation, migration, invasion and apoptosis abilities were detected subsequently. Meanwhile, SGC and GES1 cells cocultured with FAP-overexpressed fibroblasts were treated with cis-platinum for apoptotic analysis. The underlying EMT was detected by analyzing expression level of E-cadherin, ZO-1, N-cadherin, Vimentin, α-SMA, DKK1 and LEF-1 through western blot and immunofluorescence staining assay. Finally, the tumor-promoting ability of FAP was investigated by utlizing a xenograft gastric cancer nude mouse model. RESULTS It show that FAP has a high-risk correlation with the malignant level of clinical outcomes in GC patients. FAP promotes the ability of proliferation, migration, invasion, apoptosis-inhibition of SGC7901 cells and induces apoptosis of GES1 cells in vitro. The mechanism study shows that epithelial markers have been down-regulated and mesenchymal markers and Wnt/β-catenin signal pathway related proteins have been up-regulated. Animal assay suggests that tumor burden has been enhanced by FAP significantly in vivo. CONCLUSIONS Stromal FAP could be a potential prognostic biomarker in GC by promoting cancer progression via EMT through Wnt/ β-catenin signal pathway.
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Affiliation(s)
- Jiuyang Liu
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, China.,Department of Thyroid and Breast Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Chaoqun Huang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, China
| | - Chunwei Peng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, China
| | - Fei Xu
- Department of General Surgery, Yingshan Renmin Hospital, Yingshan, 438700, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Yonemura Yutaka
- Peritoneal Dissemination Center, Kishiwada Tokushukai Hospital, Kishiwada, 596-0032, Japan.,Department of Surgery, Kusatsu General Hospital, Shiga, 600-8189, Japan
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, China.,Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, China
| | - Xiaojun Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, China. .,Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, China.
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36
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Honoré C, Gelli M, Francoual J, Benhaim L, Elias D, Goéré D. Ninety percent of the adverse outcomes occur in 10% of patients: can we identify the populations at high risk of developing peritoneal metastases after curative surgery for colorectal cancer? Int J Hyperthermia 2018; 33:505-510. [PMID: 28540831 DOI: 10.1080/02656736.2017.1306119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Peritoneal metastases (PM) occur in 3.4-6.3% after curative surgery for non-metastatic colorectal cancer. Systematic "2nd look" surgery helps overcoming the diagnostic problem but can be only proposed to selected patients. The aim of this study was to update the knowledge on risk factors of developing PM after curative surgery for colorectal cancer. METHODS A systematic review of the literature published between 2011 and 2016 was made, searching for all clinical studies reporting the incidence of recurrent PM after curative surgery for colorectal cancer and factors associated with the primary tumour that were likely to influence this recurrence rate. RESULTS Seven new clinical studies were considered informative for risk factors and added to the 16 reviewed in 2013. Even if the level of evidence was low, data suggested rates of recurrent PM at 1 year between 54% and 71% after completely resected synchronous PM, between 62% and 71% after resection of isolated synchronous ovarian metastases, of 27% after surgery for a perforated primary tumour, of 16% after surgery for a pT4 tumour, and between 11% and 36% after surgery for a mucinous histological subtype. No new risk factor was identified. CONCLUSIONS Evidence regarding the incidence of recurrent PM after curative surgery for colorectal cancer is poor. Situations at higher risk of recurrent PM are synchronous PM, synchronous isolated ovarian metastases, perforated primary tumour with serosa invasion and mucinous histological subtype.
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Affiliation(s)
- Charles Honoré
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
| | - Maximiliano Gelli
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
| | - Julie Francoual
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
| | - Léonor Benhaim
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
| | - Dominique Elias
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
| | - Diane Goéré
- a Department of Surgical Oncology , Gustave Roussy , Cancer Campus , Villejuif , France
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Morano WF, Khalili M, Chi DS, Bowne WB, Esquivel J. Clinical studies in CRS and HIPEC: Trials, tribulations, and future directions-A systematic review. J Surg Oncol 2017; 117:245-259. [PMID: 29120491 DOI: 10.1002/jso.24813] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 07/24/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND The field of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has suffered from a lack of clinical trials to validate its expanding use. OBJECTIVE To evaluate published and ongoing clinical trials seeking to better define role of CRS/HIPEC in the treatment of peritoneal surface malignancies. METHODS Systematic review by PubMed search was performed using terms "Clinical trial," "intraperitoneal chemotherapy," and "HIPEC." ClinicalTrials.gov and EudraCT registries were searched for active clinical trials. Eligibility included CRS/HIPEC trials investigating adult patient populations from published clinical reports and/or trials currently accruing or at completion. RESULTS Thirteen published trials and 57 active clinical trials were included for review. CONCLUSIONS Published and ongoing U.S. and international clinical trials for CRS and HIPEC are defining important parameters that include improving patient selection, strategic sequences of treatment, cytoreductive strategies, chemotherapeutics, optimal hyperthermic temperature and timing, and toxicity profiles. Main barriers or limitations to trial development remain patient enrollment, trial design, and oncologic community collaboration. Overall progress is positive with increasing number of clinical trials throughout the world. Collaboration between surgeons and the wider oncologic community will be crucial to validate this important treatment strategy.
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Affiliation(s)
- William F Morano
- Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Marian Khalili
- Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Dennis S Chi
- Section of Ovarian Cancer Surgery, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Wilbur B Bowne
- Department of Surgery, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Jesus Esquivel
- Department of Surgery, Frederick Memorial Hospital, Frederick, Maryland
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38
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Hultman B, Gunnarsson U, Nygren P, Sundbom M, Glimelius B, Mahteme H. Prognostic factors in patients with loco-regionally advanced gastric cancer. World J Surg Oncol 2017; 15:172. [PMID: 28915886 PMCID: PMC5602959 DOI: 10.1186/s12957-017-1243-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 09/03/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate epidemiologic and prognostic factors relevant to the treatment of loco-regionally advanced gastric cancer (GC). METHODS Two hundred and fifty-five patients with GC were identified in Uppsala County between 2000 and 2009. Patient records were analyzed for loco-regionally advanced GC defined as tumor with peritoneal involvement, excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. The presence or not of distant metastasis (DM), including hematogenous metastases (e.g., liver, lung, and bone) and/or distant lymph node metastases, was also analyzed. The Cox proportional hazard model was used for multivariate analysis of factors influencing survival. RESULTS One hundred and twenty patients (47% of all patients with GC; median age 70.5 years) had loco-regionally advanced disease, corresponding to an incidence of 3.8 per 100,000 person-years. Forty-one percent of these also had DM. Median overall survival (mOS) from the time of the diagnosis of loco-regionally advanced disease was 4.8 months for the total patient cohort, 5.1 months for the subgroup of patients without DM, and 4.7 months for the subgroup with DM. There was no significant difference in mOS between the subgroups with synchronous versus metachronous loco-regionally advanced GC: 4.8 months (range 0.0-67.4) versus 4.7 months (range 0.0-28.3). Using multivariate Cox analysis, positive prognostic factors for survival were good performance status at diagnosis and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative prognostic factor. The mOS did not differ when comparing the time period 2000-2004 (5.1 months, range 0-67.4) with the period 2005-2009 (4.0 months, range 0.0-28.3). CONCLUSION Peritoneal involvement occurred in almost half of the patients with GC in this study and was associated with short life expectancy. New treatment strategies are warranted.
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Affiliation(s)
- Bo Hultman
- Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden.
| | - Ulf Gunnarsson
- Department of Surgical and Perioperative Sciences, Umeå University, SE 901 85, Umeå, Sweden
| | - Peter Nygren
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85, Uppsala, Sweden
| | - Haile Mahteme
- Department of Surgical Sciences, Uppsala University, SE-751 85, Uppsala, Sweden
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van der Kaaij RT, Braam HJ, Boot H, Los M, Cats A, Grootscholten C, Schellens JH, Aalbers AG, Huitema AD, Knibbe CA, Boerma D, Wiezer MJ, van Ramshorst B, van Sandick JW. Treatment of Peritoneal Dissemination in Stomach Cancer Patients With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Rationale and Design of the PERISCOPE Study. JMIR Res Protoc 2017; 6:e136. [PMID: 28705789 PMCID: PMC5532515 DOI: 10.2196/resprot.7790] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 05/30/2017] [Indexed: 01/16/2023] Open
Abstract
Background Patients with gastric cancer and peritoneal carcinomatosis have a very poor prognosis; median survival is 3 to 4 months. Palliative systemic chemotherapy is currently the only treatment available in the Netherlands. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has an established role in the treatment of peritoneal carcinomatosis originating from colorectal cancer, appendiceal cancer, and pseudomyxoma peritonei; its role in gastric cancer is uncertain. Currently, there is no consensus on the choice of chemotherapeutic agents used in HIPEC for gastric cancer. Objective The main objectives of this study are (1) to investigate the safety, tolerability, and feasibility of gastrectomy combined with cytoreductive surgery and HIPEC after systemic chemotherapy, as a primary treatment option for patients with advanced gastric cancer with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis; and (2) to determine the maximum tolerated dose (MTD) of intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin. Methods The PERISCOPE study is a multicenter, open label, phase I-II dose-escalation study. The MTD of docetaxel will be studied using a 3+3 design. Patients with locally advanced (cT3-cT4) gastric adenocarcinoma are eligible for inclusion if the primary gastric tumor is considered resectable, tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis is confirmed by diagnostic laparoscopy/ laparotomy, and prior systemic chemotherapy was without disease progression. At laparotomy, cytoreductive surgery (complete removal of all macroscopically visible tumor deposits) and a total or partial gastrectomy with a D2 lymph node dissection is performed. An open HIPEC technique is used with 460mg/m2 hyperthermic oxaliplatin for 30 minutes (41°C to 42°C) followed by normothermic docetaxel for 90 minutes (37°C) in a dose that will be escalated per 3 patients (0, 50, 75, 100, 125, 150 mg/m2). The primary endpoint is treatment related toxicity. Results Patient accrual is ongoing and the first results are expected in 2017. Conclusions The PERISCOPE study will determine the safety, tolerability, and feasibility of gastrectomy combined with cytoreduction and HIPEC using oxaliplatin in combination with docetaxel after systemic chemotherapy as primary treatment option for gastric cancer patients with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis. This study will provide pharmacokinetic data on the intraperitoneal administration of oxaliplatin and docetaxel, including the MTD of intraperitoneal-administered docetaxel. These data are a prerequisite for the safe conduct of future HIPEC studies in patients with gastric cancer. Trial Registration Netherlands Trial Registration (NTR): NTR4250; http://www.trialregister.nl/trialreg/admin/ rctview.asp?TC=4250 (Archived by WebCite at http://www.webcitation.org/6rWJONgkt)
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Affiliation(s)
- Rosa T van der Kaaij
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Surgical Oncology, Amsterdam, Netherlands
| | - Hidde Jw Braam
- St. Antonius Hospital, Department of Surgery, Nieuwegein, Netherlands
| | - Henk Boot
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Gastroenterology, Amsterdam, Netherlands
| | - Maartje Los
- St. Antonius Hospital, Department of Medical Oncology, Nieuwegein, Netherlands
| | - Annemieke Cats
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Gastroenterology, Amsterdam, Netherlands
| | - Cecile Grootscholten
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Medical Oncology, Amsterdam, Netherlands
| | - Jan Hm Schellens
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Clinical Pharmacology, Amsterdam, Netherlands
| | - Arend Gj Aalbers
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Surgical Oncology, Amsterdam, Netherlands
| | - Alwin Dr Huitema
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Pharmacy and Pharmacology, Amsterdam, Netherlands.,University Medical Center Utrecht, Department of Clinical Pharmacy, Utrecht, Netherlands
| | | | - Djamila Boerma
- St. Antonius Hospital, Department of Surgery, Nieuwegein, Netherlands
| | - Marinus J Wiezer
- St. Antonius Hospital, Department of Surgery, Nieuwegein, Netherlands
| | | | - Johanna W van Sandick
- The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Department of Surgical Oncology, Amsterdam, Netherlands
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40
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Ni X, Wu P, Wu J, Ji M, Tian B, Jiang Z, Sun Y, Xing X, Jiang J, Wu C. Hyperthermic intraperitoneal perfusion chemotherapy and response evaluation in patients with gastric cancer and malignant ascites. Oncol Lett 2017; 14:1691-1696. [PMID: 28789396 DOI: 10.3892/ol.2017.6342] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 03/03/2017] [Indexed: 12/11/2022] Open
Abstract
The present study describes the use of bidirectional chemotherapy in the treatment of patients with gastric cancer and peritoneal carcinomatosis (PC), using newly developed response criteria for the treatment of malignant ascites. In addition, the association between effusion response and survival was analyzed. Between June 2010 and May 2014, patients affected by malignant ascites secondary to unresectable PC of gastric origin were treated with a combination of systemic and loco-regional chemotherapy. Cisplatin (75 mg/m2) at an inflow temperature of 43°C was infused intraperitoneally, and docetaxel (75 mg/m2) was infused simultaneously via a peripheral vein, on day 1 every 3 weeks. The primary endpoint was overall survival rate, and the secondary endpoint was efficacy against malignant ascites using new response criteria. In total, 41 patients were enrolled, the majority of whom received 6 cycles of intraperitoneal chemotherapy in combination with hyperthermia. The majority of patients exhibited clinical regression of ascites and relief of associated symptoms. Malignant ascites disappeared [complete response (CR)] or decreased by 50% [partial response (PR)] in 73.2% of patients. No mortalities associated with the procedures occurred. The median survival time was 8.6 months, and the 1-year survival rate was 24.4%. As these new response criteria for the treatment of malignant ascites were found to be feasible, bidirectional chemotherapy may be the preferred strategy for the treatment of gastric cancer with PC. The CR, PR and non-PR groups showed significant differences in overall survival, indicating that decreased effusion was associated with improved patient survival.
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Affiliation(s)
- Xuefeng Ni
- Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Ping Wu
- Department of Pharmacology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Jun Wu
- Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Mei Ji
- Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Bo Tian
- Department of Pathology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Zhenxing Jiang
- Department of Radiology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Yue Sun
- Department of Ultrasonography, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Xiaoxiao Xing
- Department of Ultrasonography, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Jingting Jiang
- Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu 213003, P.R. China
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de Bree E, Michelakis D, Stamatiou D, Romanos J, Zoras O. Pharmacological principles of intraperitoneal and bidirectional chemotherapy. Pleura Peritoneum 2017; 2:47-62. [PMID: 30911633 PMCID: PMC6405033 DOI: 10.1515/pp-2017-0010] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 04/05/2017] [Indexed: 12/19/2022] Open
Abstract
Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Dimosthenis Michelakis
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Dimitris Stamatiou
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - John Romanos
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Odysseas Zoras
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
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Tan HL, Chia CS, Tan GHC, Choo SP, Tai DWM, Chua CWL, Ng MCH, Soo KC, Teo MCC. Gastric peritoneal carcinomatosis - a retrospective review. World J Gastrointest Oncol 2017; 9:121-128. [PMID: 28344747 PMCID: PMC5348627 DOI: 10.4251/wjgo.v9.i3.121] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 12/13/2016] [Accepted: 01/02/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To characterize patients with gastric peritoneal carcinomatosis (PC) and their typical clinical and treatment course with palliative systemic chemotherapy as the current standard of care. METHODS We performed a retrospective electronic chart review of all patients with gastric adenocarcinoma with PC diagnosed at initial metastatic presentation between January 2010 and December 2014 in a single tertiary referral centre. RESULTS We studied a total of 271 patients with a median age of 63.8 years and median follow-up duration of 5.1 mo. The majority (n = 217, 80.1%) had the peritoneum as the only site of metastasis at initial presentation. Palliative systemic chemotherapy was eventually planned for 175 (64.6%) of our patients at initial presentation, of which 171 were initiated on it. Choice of first-line regime was in accordance with the National Comprehensive Cancer Network Guidelines for Gastric Cancer Treatment. These patients underwent a median of one line of chemotherapy, completing a median of six cycles in total. Chemotherapy disruption due to unplanned hospitalizations occurred in 114 (66.7%), while cessation of chemotherapy occurred in 157 (91.8%), with 42 cessations primarily attributable to PC-related complications. Patients who had initiation of systemic chemotherapy had a significantly better median overall survival than those who did not (10.9 mo vs 1.6 mo, P < 0.001). Of patients who had initiation of systemic chemotherapy, those who experienced any disruptions to chemotherapy due to unplanned hospitalizations had a significantly worse median overall survival compared to those who did not (8.7 mo vs 14.6 mo, P < 0.001). CONCLUSION Gastric PC carries a grim prognosis with a clinical course fraught with disease-related complications which may attenuate any survival benefit which palliative systemic chemotherapy may have to offer. As such, investigational use of regional therapies is warranted and required validation in patients with isolated PC to maximize their survival outcomes in the long run.
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Kobayashi D, Kodera Y. Intraperitoneal chemotherapy for gastric cancer with peritoneal metastasis. Gastric Cancer 2017; 20:111-121. [PMID: 27803990 DOI: 10.1007/s10120-016-0662-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 10/15/2016] [Indexed: 02/07/2023]
Abstract
Peritoneal metastasis is the most frequent pattern of gastric cancer recurrence or metastasis and is a definitive determinant of prognosis. However, an effective means of treating peritoneal disease has not yet been established. Systemic chemotherapy has only a limited effect on peritoneal metastasis, although some progress has been shown in terms of median survival time, especially among patients with a minimal or moderate disease burden. Clinical research related to intraperitoneal administration of anticancer drugs is currently underway. An advantage of intraperitoneal chemotherapy is the ability to achieve high concentrations of anticancer drugs in the peritoneal cavity and the direct exposure of peritoneal deposits and free cancer cells to those drugs. In addition, pharmacokinetic studies with taxanes have shown that these high intraperitoneal drug concentrations are sustained for a considerable length of time, allowing prolonged exposure. As taxanes are the most appropriate drugs for intraperitoneal administration, the development of repeated intraperitoneal chemotherapy using taxanes for gastric cancer peritoneal metastasis-either alone or in combination with systemic chemotherapy-has taken place over the past decade, mostly in Japan. Several phase II trials and a phase III trial have recently demonstrated the efficacy of this therapy, including median survival times of 14.4-24.6 months and one-year overall survival rates of 67-91%. These results may lead to the approval of intraperitoneal taxanes, especially paclitaxel, for official insurance coverage in the near future.
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Affiliation(s)
- Daisuke Kobayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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Sgarbura O, Samalin E, Carrere S, Mazard T, de Forges H, Alline M, Pissas MH, Portales F, Ychou M, Quenet F. Preoperative intraperitoneal oxaliplatin for unresectable peritoneal carcinomatosis of colorectal origin: a pilot study. Pleura Peritoneum 2016; 1:209-215. [PMID: 30911625 DOI: 10.1515/pp-2016-0018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 11/02/2016] [Indexed: 02/07/2023] Open
Abstract
Background Peritoneal carcinomatosis in colorectal cancer is an advanced stage of the disease where improved survival can be attained whenever the resection associated with hyperthermic intreperitoneal chemotherapy is possible. In unresectable cases, systemic chemotherapy is administered to obtain conversion to resectability but results have not yet been clearly evaluated. Local chemotherapy in this setting has been proven useful in several similar situations. The aim of the present pilot study was to evaluate the feasibility of pre-operative intraperitoneal chemotherapy with oxaliplatin in these patients. Methods Six patients with unresectable peritoneal disease of colorectal origin were included in the study. An intraperitoneal implantable chamber catheter was inserted during the laparotomy that evaluated the extent of the peritoneal disease (peritoneal carcinomatosis index 25 to 39). Patients then underwent intraperitoneal chemotherapy with oxaliplatin 85 mg/m2 in combination with systemic chemotherapy (FOLFIRI or simplified LV5FU) and a targeted therapy every 2 weeks. Results Two catheter perfusion incidents were reported due to the abdominal wall thickness. Two patients completed the four intraperitoneal (IP) chemotherapy cycles without major toxicity. One patient developed grade 3 or 4 diarrhea requiring a short intensive care unit (ICU) stay, though it is not clear whether the event was induced by intravenous irinotecan, IP oxaliplatin or the combination of both. Grade 3 fatigue and abdominal pain were also recorded. For one patient with aggressive disease, best supportive care was initiated after the first course of chemotherapy. Conclusions Our study is the first to assess intraperitoneal oxaliplatin-based chemotherapy in the preoperative setting for patients with unresectable peritoneal metastases. The tolerance was acceptable for 85 mg/m2 IP oxaliplatin combined with systemic therapy in these patients. Our results justify carrying on with a phase I/II trial to determine the recommended dose of oxaliplatin in this clinical context and its efficacy.
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Affiliation(s)
- Olivia Sgarbura
- Surgical Oncology Department, Institut régional du Cancer de Montpellier (ICM), 208 avenue des Apothicaires, 34298 Montpellier, France
| | - Emmanuelle Samalin
- Medical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Sébastien Carrere
- Surgical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Thibault Mazard
- Medical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Hélène de Forges
- Clinical Research Unit, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Mathias Alline
- Surgical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Marie-Hélène Pissas
- Surgical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Fabienne Portales
- Medical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - Marc Ychou
- Medical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
| | - François Quenet
- Surgical Oncology Department, Institut régional du Cancer de Montpellier (ICM), Montpellier, France
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Beeharry MK, Liu WT, Yao XX, Yan M, Zhu ZG. A critical analysis of the cytoreductive surgery with hyperthermic intraperitoneal chemotherapy combo in the clinical management of advanced gastric cancer: an effective multimodality approach with scope for improvement. Transl Gastroenterol Hepatol 2016; 1:77. [PMID: 28138643 DOI: 10.21037/tgh.2016.08.05] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 08/22/2016] [Indexed: 12/16/2022] Open
Abstract
Peritoneal carcinomatosis (PC) is manifested in up to 40% of gastric cancer (GC) patients, after which their 5-year survival drops to less than 5%. The currently most acceptable treatment option for advanced GC (AGC) is systemic chemo and radio therapies with however generally very unsatisfying results and this led to a resurgence of interest in regional therapies like cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Small trials have indicated an association with prolonged survival when applying this technique to AGC manifesting with PC. High procedure-related morbidity and mortality associated with the CRS-HIPEC approach have however brought by a polemic on the merits of the latter: with the advent of regulatory approval of more effective as well as novel, more personalized treatment options in AGC, along with advances in tailoring investigational agents specifically for peritoneal delivery, there clearly is a need to outline the appropriate role of CRS-HIPEC in this disease. In a clear objective to improve the therapeutic efficiency of HIPEC, there have been immense developments in the technical aspects of this technology including the use of nanotechnology in more precise drug delivery systems (DDS) or choice of more efficient drugs such as gene-target technology, laparoscopy and so on. Henceforth, in this review, we will be highlighting the past and current status of the CRS + HIPEC procedure, shedding light on the pros and cons in order to boost up the efficiency of this multimodality approach.
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Affiliation(s)
- Maneesh K Beeharry
- Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Wen-Tao Liu
- Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Xue-Xin Yao
- Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Min Yan
- Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zheng-Gang Zhu
- Department of Surgery, Rui Jin Hospital, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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46
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Geng X, Liu H, Lin T, Hu Y, Chen H, Zhao L, Mou T, Qi X, Yu J, Li G. Survival benefit of gastrectomy for gastric cancer with peritoneal carcinomatosis: a propensity score-matched analysis. Cancer Med 2016; 5:2781-2791. [PMID: 27650694 PMCID: PMC5083731 DOI: 10.1002/cam4.877] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 07/21/2016] [Accepted: 07/28/2016] [Indexed: 12/23/2022] Open
Abstract
Peritoneal carcinomatosis (PC) is the most frequent pattern of metastasis in stage IV gastric cancer (GC). The study aims to investigate the efficacy of gastrectomy in GC with PC. Clinicopathological data of 518 stage IV GC patients were retrospectively collected in Nanfang Hospital. Among all cases, 312 GC patients with PC (without other site of metastasis) were eligible. Univariate and multivariate analyses were performed to identify the independent prognostic factors. Propensity score matching analysis was performed to balance the characteristics and treatment-related factors. There was a significantly improved overall survival in gastrectomy group (148 patients) compared with nonresection group (164 patients) (P < 0.001). The 1-year and 2-year survival rates were 49.8% and 21.5% in gastrectomy group, whereas 28.8% and 9.7% in nonresection group, respectively. Further analysis showed that gastrectomy had also improved survival in P1 (P = 0.017) and P2 stage patients (P < 0.001), but not P3 stage (P = 0.495). The modality of gastrectomy plus chemotherapy plus hyperthermic intraperitoneal chemotherapy (HIPEC) showed an optimum survival. In addition, P3 disease, nongastrectomy, nonchemotherapy, non-HIPEC, and age ≥ 60 years were independently associated with poor survival. The gastrectomy plus chemotherapy plus HIPEC modality showed a significant survival benefit for gastric adenocarcinoma patients, particularly in those with P1 and P2 diseases.
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Affiliation(s)
- Xiuwen Geng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastrointestinal Surgery, The First People's Hospital of Yueyang, Yueyang, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tian Lin
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Liying Zhao
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tingyu Mou
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaolong Qi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
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47
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Ji ZH, Peng KW, Li Y. Intraperitoneal free cancer cells in gastric cancer: pathology of peritoneal carcinomatosis and rationale for intraperitoneal chemotherapy/hyperthermic intraperitoneal chemotherapy in gastric cancer. Transl Gastroenterol Hepatol 2016; 1:69. [PMID: 28138635 DOI: 10.21037/tgh.2016.08.03] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Accepted: 08/15/2016] [Indexed: 12/19/2022] Open
Abstract
Peritoneal carcinomatosis (PC) is one of the most common causes of death in gastric cancer patients. Intraperitoneal free cancer cells (IFCCs) play a very important role in forming PC, but the administration of intraperitoneal chemotherapy (IPC) and/or hyperthermic intraperitoneal chemotherapy (HIPEC) could be an effective treatment for IFCCs. This review focuses on the origin of IFCCs, the mechanism of PC formatting, the rationale of IPC/HIPEC, and the current clinical trials on IPC/HIPEC to treat advanced gastric cancer patients.
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Affiliation(s)
- Zhong-He Ji
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
| | - Kai-Wen Peng
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
| | - Yan Li
- Department of Peritoneal Cancer Surgery, Cancer Center of Beijing Shijitan Hospital affiliated to the Capital Medical University, Beijing 100038, China
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Yonemura Y, Ishibashi H, Hirano M, Mizumoto A, Takeshita K, Noguchi K, Takao N, Ichinose M, Liu Y, Li Y. Effects of Neoadjuvant Laparoscopic Hyperthermic Intraperitoneal Chemotherapy and Neoadjuvant Intraperitoneal/Systemic Chemotherapy on Peritoneal Metastases from Gastric Cancer. Ann Surg Oncol 2016; 24:478-485. [PMID: 27506661 DOI: 10.1245/s10434-016-5487-6] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The Peritoneal Cancer Index (PCI) is the most important prognostic factor following comprehensive treatment for peritoneal metastasis (PM) from gastric cancer (GCPM); however, 70 % of patients with GCPM showed a PCI score above the cut-off level at the time of diagnosis. Furthermore, neoadjuvant chemotherapy may reduce the PCI score to lower than the cut-off levels. In this study, the effects of neoadjuvant laparoscopic hyperthermic intraperitoneal chemoperfusion (NLHIPEC) and neoadjuvant intraperitoneal/systemic chemotherapy (NIPS) were investigated. MATERIALS AND METHODS In group A, NLHIPEC was performed twice in 53 patients with GCPM, separated by a 1-month rest interval. Changes in the PCI were studied at the time of first and second laparoscopy. In group B, after NLHIPEC, a series of 3-week cycles of NIPS were performed over three courses in 52 patients. A laparotomy for cytoreductive surgery (CRS) was then carried out and the PCI changes were studied. RESULTS In group A, the PCI score at the time of the second session (11.8 ± 11.0) was significantly lower than at the time of the first session (14.2 ± 10.7), while in group B, the PCI at the time of laparotomy (9.9 ± 11.3) was significantly lower than at the time of NLHIPEC (14.8 ± 11.4). After NLHIPEC plus NIPS, complete cytoreduction was achieved in 30 (57.6 %) patients. CONCLUSIONS NLHIPEC and NIPS are effective methods of reducing PCI levels before CRS.
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Affiliation(s)
- Yutaka Yonemura
- NPO Organization to Support Peritoneal Surface Malignancy Treatment, Osaka, Shiga, Japan. .,Department of Regional Cancer Therapies, Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kusatsu General Hospital, Kishiwada, Japan. .,Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan. .,Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan.
| | - Haruaki Ishibashi
- Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan
| | - Masamitu Hirano
- Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Akiyoshi Mizumoto
- Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Kazuyosi Takeshita
- Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan
| | - Kousuke Noguchi
- Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Nobuyuki Takao
- Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Masumi Ichinose
- Peritoneal Dissemination Center, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Yang Liu
- NPO Organization to Support Peritoneal Surface Malignancy Treatment, Osaka, Shiga, Japan.,Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan
| | - Yan Li
- Department of Peritoneal Surface Oncology, Beijing Shijitan Hospital of Capital Medical University, Beijing, China
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Huang O, Lu X, Xu X, Shi Y. Fibrin-sealant-delivered cisplatin chemotherapy versus cisplatin hyperthermic intraperitoneal perfusion chemotherapy for locally advanced gastric cancer without peritoneal metastases: a randomized phase-II clinical trial with a 40-month follow-up. Cell Biochem Biophys 2016; 71:1171-80. [PMID: 25398590 DOI: 10.1007/s12013-014-0326-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
A new intraoperative cisplatin administration method for patients with locally advanced gastric cancer (AGC) and without peritoneal metastasis, fibrin-sealant-delivered cisplatin chemotherapy, was reported, and its safety, pharmacokinetics, and efficacy were compared with cisplatin hyperthermic intraperitoneal perfusion chemotherapy. Forty-two AGC patients were randomly divided into 2 groups: fibrin-sealant-delivered cisplatin chemotherapy (FS) (n = 21) and cisplatin hyperthermic intraperitoneal perfusion chemotherapy (CHIC) (n = 21). Both groups received 120 mg cisplatin after complete cytoreductive surgery. At different time points, cisplatin concentrations in patients' sera and urine samples were measured to determine time-dependent maximal concentration (Cmax) and the area under the curve (AUC). The primary and secondary end-points were overall survival (OS) and safety profiling, respectively. Occurrence of grade-3 to grade-4 liver or kidney dysfunction was less frequent in the FS group than in the CHIC group (28.6 % vs 47.6 %). Cisplatin Cmax and AUC for the serum and urine of the FS patients were significantly lower than that of the CHIC patients. Elimination half-life of cisplatin in the FS group was significantly longer than in the CHIC group (24.1 h vs 14.2 h). After a median follow-up of 40 months, 1-, 2-, and 3-years OS were 90.5 %, 71.4 %, and 61.9 % in the FS group, and 61.9 %, 47.6 %, and 42.8 % in the CHIC group, respectively. The median OS was 35.9 months in the FS group and 29.1 months in the CHIC group. Fibrin-sealant-delivered cisplatin chemotherapy was as effective and had a favorable pharmacokinetic profile with similar survival outcomes as cisplatin hyperthermic intraperitoneal perfusion chemotherapy following complete cytoreductive surgery of locally advanced GC without peritoneal metastases.
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Affiliation(s)
- Ou Huang
- Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200025, China
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50
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Yonemura Y, Canbay E, Li Y, Coccolini F, Glehen O, Sugarbaker PH, Morris D, Moran B, Gonzaletz-Moreno S, Deraco M, Piso P, Elias D, Batlett D, Ishibashi H, Mizumoto A, Verwaal V, Mahtem H. A comprehensive treatment for peritoneal metastases from gastric cancer with curative intent. Eur J Surg Oncol 2016; 42:1123-31. [PMID: 27160355 DOI: 10.1016/j.ejso.2016.03.016] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 03/12/2016] [Accepted: 03/16/2016] [Indexed: 12/29/2022] Open
Abstract
Recently, Peritoneal Surface Oncology Group International (PSOGI) developed a novel comprehensive treatment consisting of cytoreductive surgery (CRS) and perioperative chemotherapy (POC) for the treatment of peritoneal metastases (PM) from gastric cancer with curative intent. This article reviews the results of this treatment and verifies its indication. In this strategy, peritoneal cancer index (PCI) is determined by laparoscopy, and a peritoneal port is placed. Neoadjuvant bidirectional intraperitoneal/systemic chemotherapy (NIPS) is performed for 3 cycles, and then laparotomy is performed. Cytoreductive surgery with peritonectomy procedures and hyperthermic intraperitoneal chemoperfusion (HIPEC) are performed. Multivariate analyses showed that completeness of cytoreduction, pathologic response to NIPS and PCI level and cytologic status after NIPS, as independent prognostic factors. PCI less than cut-off level after NIPS, negative cytology after NIPS, and positive response to NIPS were identified as the indications for comprehensive treatment. Patients who hold these criteria should be considered as the candidates for CRS and HIPEC.
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Affiliation(s)
- Y Yonemura
- Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kusatsu General Hospital, Kishiwada, Shiga, Japan; NPO to Support Peritoneal Surface Malignancy Treatment, Oosaka, 600 8189, Japan.
| | - E Canbay
- NPO to Support Peritoneal Surface Malignancy Treatment, Oosaka, 600 8189, Japan
| | - Y Li
- Department of Peritoneal Surface Oncology, Beijin Shijitan Hospital of Capital Medical University, Beijin, 100038, China
| | - F Coccolini
- General Surgery Papa Giovanni XXIII Hospital, Bergamo, Italy
| | - O Glehen
- Dēpartement de Chirurgie Gēnerale, Centre Hospitalier Lyon-Sud Hospices Civils de Lyon, Universitē Lyon, 69495, France
| | - P H Sugarbaker
- Center of Gastrointestinal Malignancies, Program in Peritoneal Surface Malignancies, MedStar Washington Hospital Center, Washington, DC, 20010, USA
| | - D Morris
- Department of Surgery, St George Hospital, University of New South Wales, Australia
| | - B Moran
- Peritoneal Malignancy Institute Basingstoke, Hampshire Hospitals Foundation Trust, Adelmaston Road, Basingstoke RG24 9NA, UK
| | - S Gonzaletz-Moreno
- Department of Surgical Oncology, Peritoneal Surface Oncology Program, MD Anderson Cancer Center, Madrid, Spain
| | - M Deraco
- National Cancer Institute of Milan, Italy
| | - P Piso
- Krankenhaus Barmherzige Brieder, Teaching Hospital of the University of Regensburg, Regensburg, Germany
| | - D Elias
- Département de Chirurgie Générale, Institut Gustave Roussy, Villejuif, Cedex, France
| | - D Batlett
- Division of Surgical Oncology, Hillman Cancer Center, 5115 Centre Ave, Pittsburgh, PA, 15232, USA
| | - H Ishibashi
- Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kusatsu General Hospital, Kishiwada, Shiga, Japan
| | - A Mizumoto
- Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kusatsu General Hospital, Kishiwada, Shiga, Japan
| | - V Verwaal
- Oncologisch GE Chirurg, Catharina, Ziekenhuis Eindhoven, The Netherlands
| | - H Mahtem
- Department of Surgical Sciences, Uppsala University, Övriga Samarbeten, Akademiska Sjukhuset, Ing 70 1 Tr, 751 85, Uppsala, Sweden
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