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1
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Kunte AR, Parray AM, Bhandare MS, Solanki SL. Role of prophylactic HIPEC in non-metastatic, serosa-invasive gastric cancer: a literature review. Pleura Peritoneum 2022; 7:103-115. [PMID: 36159214 PMCID: PMC9467900 DOI: 10.1515/pp-2022-0104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/15/2022] [Indexed: 11/15/2022] Open
Abstract
The role of prophylactic hyperthermic intraperitoneal chemotherapy (p-HIPEC) in serosa invasive gastric cancers without gross or microscopic peritoneal disease, to reduce the rate of peritoneal relapse is an area of ongoing research. Although p-HIPEC is effective in reducing the rate of peritoneal relapse and improving disease free and overall survival with or without adjuvant chemotherapy, when added to curative surgery in locally advanced, non-metastatic gastric cancers, the available literature is at best, heterogeneous, centre-specific and skewed. Apart from that, variations in the systemic therapy used, and the presence of the associated nodal disease further complicate this picture. To evaluate the role of p-HIPEC the PubMed, Cochrane central register of clinical trials, and the American Society of Clinical Oncology (ASCO) meeting library were searched with the search terms, "gastric", "cancer", "hyperthermic", "intraperitoneal", "chemotherapy", prophylactic", "HIPEC" in various combinations, and a critical review of the available evidence was done. Although p-HIPEC is a promising therapy in the management of locally advanced gastric cancers, the current evidence is insufficient to recommend its inclusion into routine clinical practice. Future research should be directed towards identification of the appropriate patient subset and towards redefining its role with current peri-operative systemic therapies.
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Affiliation(s)
- Aditya R. Kunte
- Department of Surgical Oncology, GI & HPB Surgery, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Aamir M. Parray
- Department of Surgical Oncology, GI & HPB Surgery, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Manish S. Bhandare
- Department of Surgical Oncology, GI & HPB Surgery, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
| | - Sohan Lal Solanki
- Department of Anaesthesiology, Critical Care & Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India
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2
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Lin Q, Bai Q, Huang Q, Huang Y, Gao J, Zhang Y. Partial omentectomy maybe practicable for T3 or shallower gastric cancer patients. Cancer Med 2022; 12:1204-1216. [PMID: 35856487 PMCID: PMC9883580 DOI: 10.1002/cam4.4980] [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: 12/13/2021] [Revised: 04/18/2022] [Accepted: 06/15/2022] [Indexed: 02/02/2023] Open
Abstract
BACKGROUND Total omentectomy is often performed with gastrectomy as radical surgery for gastric cancer (GC) patients. However, it remains controversial whether GC patients can benefit from omentectomy. The aim of this study was to analyze the incidence and clinical significance of tumor deposits (TDs) in different anatomical subregions of perigastric omentum in GC patients undergoing gastrectomy with total omentectomy. METHODS From October 2011 to December 2013, 1253 patients who underwent gastrectomy with total omentectomy for GC were retrospective reviewed. The TDs in different anatomical subregions of perigastric omentum were examined. RESULTS Of 1253 patients, TDs positivity was 11.2%. Tumor deposits in the omentum of greater curvature and in the omentum of lesser curvature were associated with lymphovascular invasion, perineural invasion, advanced tumor node metastasis stages, and unfavorable survival. Besides, TDs in the proximal omentum of greater curvature and in the omentum of lesser curvature correlated with older patients and larger tumors. Kaplan-Meier curves showed that patients with TDs had worser overall survival (OS) than those without, regardless of TD positions. Patients with TDs in the omentum of greater curvature had the worst prognosis, followed by patients with TDs in the omentum of lesser curvature and patients with no TDs. Tumor deposits in the proximal omentum of greater curvature was an independent prognostic factor for OS. Moreover, only patients classified as pT4 had TDs in the distal omentum of greater curvature. CONCLUSIONS Patients with TDs in the omentum of greater curvature had the worst prognosis, followed by patients with TDs in the omentum of lesser curvature and patients with no TDs. In addition, partial omentectomy might be practicable for gastric cancer patients classified as T3 or shallower tumors.
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Affiliation(s)
- Qiaowei Lin
- Department of Gastric Surgery, Shanghai Cancer CenterFudan UniversityShanghaiChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Qianming Bai
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina,Department of Pathology, Shanghai Cancer CenterFudan UniversityShanghaiChina
| | - Qiuyi Huang
- Department of Gastric Surgery, Shanghai Cancer CenterFudan UniversityShanghaiChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yakai Huang
- Department of Gastric Surgery, Shanghai Cancer CenterFudan UniversityShanghaiChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Jianpeng Gao
- Department of Gastric Surgery, Shanghai Cancer CenterFudan UniversityShanghaiChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yu Zhang
- Department of Gastric Surgery, Shanghai Cancer CenterFudan UniversityShanghaiChina,Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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3
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Mir TA, Malik AA, Wani MA, Rasool Z, Bari SU. Gastric Carcinoma—a New Biomarker Peritoneal Fluid Lavage Cytology. Indian J Surg 2022. [DOI: 10.1007/s12262-022-03386-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/30/2022] [Indexed: 02/07/2023] Open
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4
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Kimura Y, Ohzawa H, Miyato H, Kaneko Y, Saito A, Takahashi K, Tojo M, Yamaguchi H, Kurashina K, Saito S, Hosoya Y, Lefor AK, Sata N, Kitayama J. MiR-29b may suppresses peritoneal metastases through inhibition of the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells. Sci Rep 2022; 12:205. [PMID: 34997082 PMCID: PMC8742040 DOI: 10.1038/s41598-021-04065-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 11/30/2021] [Indexed: 11/09/2022] Open
Abstract
Peritoneal dissemination is a major metastatic pathway for gastrointestinal and ovarian malignancies. The miR-29b family is downregulated in peritoneal fluids in patients with peritoneal metastases (PM). We examined the effect of miR-29b on mesothelial cells (MC) which play critical a role in the development of PM through mesothelial-mesenchymal transition (MMT). Human peritoneal mesothelial cells (HPMCs) were isolated from surgically resected omental tissue and MMT induced by stimulation with 10 ng/ml TGF-β1. MiR-29b mimics and negative control miR were transfected by lipofection using RNAiMAX and the effects on the MMT evaluated in vitro. HPMC produced substantial amounts of miR-29b which was markedly inhibited by TGF-β1. TGF-β1 stimulation of HPMC induced morphological changes with decreased expression of E-cadherin and calretinin, and increased expression of vimentin and fibronectin. TGF-β1 also enhanced proliferation and migration of HPMC as well as adhesion of tumor cells in a fibronectin dependent manner. However, all events were strongly abrogated by simultaneous transfection of miR-29b. MiR-29b inhibits TGF-β1 induced MMT and replacement of miR-29b in the peritoneal cavity might be effective to prevent development of PM partly through the effects on MC.
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Affiliation(s)
- Yuki Kimura
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hideyuki Ohzawa
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hideyo Miyato
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yuki Kaneko
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Akira Saito
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kazuya Takahashi
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Mineyuki Tojo
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Hironori Yamaguchi
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kentaro Kurashina
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Shin Saito
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Yoshinori Hosoya
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Alan Kawarai Lefor
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan.
- Center for Clinical Research, Jichi Medical University Hospital, Shimotsuke, Tochigi, Japan.
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5
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Zhang Y, Zhao J, Yu H, Li P, Liang W, Liu Z, Lee GB, Liu L, Li WJ, Wang Z. Detection and isolation of free cancer cells from ascites and peritoneal lavages using optically induced electrokinetics (OEK). SCIENCE ADVANCES 2020; 6:eaba9628. [PMID: 32821829 PMCID: PMC7406364 DOI: 10.1126/sciadv.aba9628] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 06/22/2020] [Indexed: 06/11/2023]
Abstract
Detection of free gastric cancer cells in peritoneal lavages and ascites plays a vital role in gastric cancer. However, due to the low content of cancer cells in patients' peritoneal lavages, traditional detection methods lack sensitivity and cannot satisfy clinical demand. In this study, we used an optically induced electrokinetics (OEK) microfluidic method for label-free separation and characterization of patient gastric cancer cells. This method showed high effectiveness and sensitivity. We successfully separated cancer cells from a simulated peritoneal lavage mixture of gastric cancer cell lines and peritoneal lavage cells in a ratio of 1:1000. We further separated gastric cancer cells from six patients' ascites with purity up to 71%. In addition, we measured the cell membrane capacitances, which may be used as a biomarker for gastric cancer cells. Thus, our method can be used to effectively and rapidly detect peritoneal metastasis and to acquire cellular electrical information.
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Affiliation(s)
- Yuzhao Zhang
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junhua Zhao
- Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China
| | - Haibo Yu
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
| | - Pan Li
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Wenfeng Liang
- School of Mechanical Engineering, Shenyang Jianzhu University, Shenyang 110168, China
| | - Zhu Liu
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
| | - Gwo-Bin Lee
- Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Lianqing Liu
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
| | - Wen Jung Li
- State Key Laboratory of Robotics, Shenyang Institute of Automation, Chinese Academy of Sciences, Shenyang 110016, China
- Institutes for Robotics and Intelligent Manufacturing, Chinese Academy of Sciences, Shenyang 110169, China
- Department of Mechanical Engineering, City University of Hong Kong, Hong Kong, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, the First Hospital of China Medical University, Shenyang, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, China
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6
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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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7
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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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8
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Deraco M, Santoro N, Carraro O, Inglese MG, Rebuffoni G, Guadagni S, Somers DC, Vaglini M. Peritoneal Carcinomatosis: Feature of Dissemination a Review. TUMORI JOURNAL 2018; 85:1-5. [PMID: 10228488 DOI: 10.1177/030089169908500101] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Peritoneal carcinomatosis is a common event that develops in the natural history of many neoplastic diseases, representing a major problem encountered in cancer management. Peritoneal seedings are often associated with neoplastic ascites resulting in a source of significant discomfort to the patient. Considered in the past as a terminal condition, peritoneal carcinomatosis was approached during the last two decades as a curable disease. The introduction of cytoreductive surgery or peritonectomy in the treatment of peritoneal neoplastic diseases drastically changed the natural history of peritoneal carcinomatosis. Another technique that showed an important impact on disease control is intraperitoneal hyperthermic perfusion, one of the most fascinating treatments of peritoneal carcinomatosis that results in an impressive increase in overall survival and quality of life in treated patients with low morbidity. This review illustrates the modality of dissemination of peritoneal carcinomatosis in relation to the primary tumor site and grade of malignancy. Peritoneal carcinomatosis is a term used to define an advanced stage of many abdominal neoplastic diseases that differ in biologic aggressiveness and prognosis. The different presentation of peritoneal carcinomatosis in relation to a different primary tumor and different grade of malignancy strongly influences the potentially therapeutic radical approaches using new and advanced modalities like cytoreductive surgery and intraperitoneal hyperthermic perfusion.
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Affiliation(s)
- M Deraco
- Division of General Surgery B, Istituto Nazionale Tumori, Milan, Italy
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9
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Youn GJ, Chung WC. [Micrometastasis in Gastric Cancer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 69:270-277. [PMID: 28539031 DOI: 10.4166/kjg.2017.69.5.270] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Although the incidence and mortality rate of gastric cancer have been steadily declining, gastric cancer is still the fourth most common cancer in the world and more than 50% of cases occur in Eastern Asia. In Korea, gastric cancer is the second most common cancer and third cause of cancer related death. The standard surgical procedure for resectable advanced gastric cancer is D2 lymphadenectomy with radical gastrectomy. Even though R0 resection was completed, recurrence is relatively common, and contributes to the limited survival of the patients in gastric cancer. As a clinically relevant factor for detection of the recurrence, the presence of isolating tumor cells has been introduced and it is so called as 'micrometastasis'. Numerous immunohistochemistry and molecular studies have shown that micrometastasis can be demonstrated not only in lymph nodes but also in such body compartments as the bone marrow, peritoneal cavity and blood. Herein, we review the current knowledge and evidence of the prognostic significance of micrometastasis in peritoneal, lymph node, bone marrow. Also, we discuss the current state of research on the circulating tumor cell in peripheral blood.
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Affiliation(s)
- Gun Jung Youn
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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10
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Murata S, Yamamoto H, Shimizu T, Naitoh H, Yamaguchi T, Kaida S, Takebayashi K, Miyake T, Tani T, Tani M. 5-fluorouracil combined with cisplatin and mitomycin C as an optimized regimen for hyperthermic intraperitoneal chemotherapy in gastric cancer. J Surg Oncol 2017; 117:671-677. [PMID: 29266509 DOI: 10.1002/jso.24906] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 10/15/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES Optimized drug regimens for hyperthermic intraperitoneal chemotherapy (HIPEC) have not been standardized completely in patients with advanced gastric cancer (GC). We evaluated an optimized anti-tumor protocol comprising 5-fluorouracil (5-FU) combined with cisplatin (CDDP) and mitomycin C (MMC) in vitro for clinical use of HIPEC. METHODS The sensitivities of 5-FU, CDDP, or MMC, alone or in combination, using different drug concentrations, exposure times, and hyperthermic conditions (42°C) were determined in vitro by the CD-DST method using 3 different differentiated GC cell lines. RESULTS The tumor cell growth-inhibitory effect of 5-FU was concentration-dependent for all cell lines. In addition, 5-FU showed a hyperthermic sensitization effect at all drug concentrations for all cell lines. The appropriate concentration of each drug was 5-FU, 200 µg/mL; CDDP, 10 µg/mL; MMC, 2 µg/mL. Under hyperthermic conditions, most growth-inhibitory effects for each drug at 30 min was equivalent to 60 min of exposure; use of three drugs combined significantly inhibited growth compared with any of the drugs alone. CONCLUSION An appropriate in vitro intraperitoneal chemotherapy regimen for GC was combined use of 5-FU, CDDP, and MMC at 42°C for 30 min.
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Affiliation(s)
- Satoshi Murata
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
- Cancer Center, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Hiroshi Yamamoto
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
- Department of Surgery, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Tomoharu Shimizu
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hiroyuki Naitoh
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
- Department of Surgery, Hino Memorial Hospital, Hino-cho, Gamou-gun, Shiga, Japan
| | - Tsuyoshi Yamaguchi
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Sachiko Kaida
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | | | - Toru Miyake
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tohru Tani
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
- Biomedical Innovation Center, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
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11
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Yarema R. Gastric cancer with high risk of intraperitoneal progression: clinical course and current treatments. CURRENT ISSUES IN PHARMACY AND MEDICAL SCIENCES 2017; 30:190-194. [DOI: 10.1515/cipms-2017-0036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2023] Open
Abstract
Abstract
Locally advanced gastric cancer with a high risk of intraperitoneal progression is characterized by poor prognosis. After radical surgery, most patients die during the first two years post-operation as a result of disease progression. The prevailing type of progression and the leading cause of death in patients with gastric cancer is implantation metastasis.
The main risk factors for peritoneal carcinomatosis in such patients include: gastric tumor invasion into serosa, the presence of tumor cells in peritoneal washings, the largeness of the tumor as accompanied by extensive serous lesions, infiltrative type of tumor growth, histological variants of gastric cancer prone to implantation metastasis and metastatic lesions in regional lymph nodes. Systemic chemotherapy does not provide effective eradication of subclinical peritoneal carcinomatosis in patients with locally advanced gastric cancer.
The vast majority of patients who suffer from locally advanced gastric cancer and run a high risk of implantation metastasis are characterized by subclinical peritoneal dissemination at primary diagnosis, which means a rapidly fatal prognosis for such patients. In recent years, however, the paradigm of treatment of locally advanced gastric cancer has changed: a combination of surgery and adjuvant hyperthermic intraperitoneal chemotherapy is used increasingly, and presents an alternative to the previously accepted surgery only approach. It is also likely to increase the survival rate.
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Affiliation(s)
- Roman Yarema
- Department of Oncology and Medical Radiology , Danylo Halytsky Lviv National Medical University , Pekarska 69, 79010 , Lviv , Ukraine
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12
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Sugimura K, Miyata H, Motoori M, Omori T, Fujiwara Y, Yano M. The Significance of SCC and CEA mRNA in the Pleural Cavity After Lymphadenectomy in Esophageal Cancer Patients who Underwent Preoperative Treatment. World J Surg 2017; 42:749-757. [DOI: 10.1007/s00268-017-4203-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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13
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Murata S, Yamamoto H, Naitoh H, Yamaguchi T, Kaida S, Shimizu T, Shiomi H, Naka S, Tani T, Tani M. Feasibility and safety of hyperthermic intraperitoneal chemotherapy using 5-fluorouracil combined with cisplatin and mitomycin C in patients undergoing gastrectomy for advanced gastric cancer. J Surg Oncol 2017; 116:1159-1165. [PMID: 28743181 DOI: 10.1002/jso.24771] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 06/26/2017] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVES We conducted a dose-finding study for 5-fluorouracil (5-FU) administered with cisplatin (CDDP) and mitomycin C (MMC) to find an improved regimen for hyperthermic intraperitoneal chemotherapy (HIPEC) for advanced gastric cancer (GC). METHODS The appropriate HIPEC regimen previously determined in vitro was 5-FU (200 µg/mL), MMC (2 µg/mL), and CDDP (10 µg/mL) at hyperthermic conditions (42°C) for 30 min. This was a clinical study to determine the recommended dose of 5-FU in combination with MMC and CDDP at 42°C for 30 min and to evaluate HIPEC safety in patients at high risk of developing peritoneal metastases following GC surgery. RESULTS Twelve patients were treated with surgery plus HIPEC using 5-FU at 0, 500, 750, and 1000 mg combined with MMC (10 mg) and CDDP (50 mg) in the perfusate (5 L). Dose-limiting toxicities did not develop until 1000 mg 5-FU was reached. Four patients experienced grade 1 or 2 adverse events. The recommended dose was 1000 mg 5-FU/5 L perfusate. Eight (66.7%) patients demonstrated no recurrence of peritoneal metastases; 5-year overall survival rate was 83.3%. CONCLUSION Gastrectomy and HIPEC with MMC, CDDP, and 5-FU is feasible, safe, and may protect against peritoneal metastasis following surgery for advanced GC.
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Affiliation(s)
- Satoshi Murata
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Cancer Center, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Hiroshi Yamamoto
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Department of Surgery, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Hiroyuki Naitoh
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Department of Surgery, Hino Memorial Hospital, Hino-cho, Gamou-gun, Shiga, Japan
| | - Tsuyoshi Yamaguchi
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Sachiko Kaida
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Tomoharu Shimizu
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Hisanori Shiomi
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Department of Surgery, Nagahama Red Cross Hospital, Nagahama, Shiga, Japan
| | - Shigeyuki Naka
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Department of Surgery, Hino Memorial Hospital, Hino-cho, Gamou-gun, Shiga, Japan
| | - Tohru Tani
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan.,Biomedical Innovation Center, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Otsu, Shiga, Japan
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14
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Tustumi F, Bernardo WM, Roncon Dias A, Kodama Pertille Ramos MF, Cecconello I, Zilberstein B, Ribeiro-Júnior U. Detection value of free cancer cells in peritoneal washing in gastric cancer: a systematic review and meta-analysis. Clinics (Sao Paulo) 2016; 71:733-745. [PMID: 28076519 PMCID: PMC5175297 DOI: 10.6061/clinics/2016(12)10] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 08/29/2016] [Accepted: 09/09/2016] [Indexed: 02/05/2023] Open
Abstract
Intraperitoneal free cancer cells in gastric adenocarcinoma are associated with a poor outcome. However, the true prognostic value of intraperitoneal free cancer cells is still unclear, leading to a lack of consensus in the management of gastric cancer. The aim of the present study is to perform a systematic review and meta-analysis to analyze intraperitoneal free cancer cells-positive patients with regard to tumor oncologic stage, recurrence, grade of cellular differentiation, and survival rates and to analyze the clinical significance of intraperitoneal free cancer cells with regard to prognosis. Databases were searched up to January 2016 for prognostic factors associated with intraperitoneal free cancer cells, including oncologic stage, depth of neoplasm invasion, lymph nodal spread, differentiation grade of the tumor, and recurrence and survival rates. A total of 100 studies were identified. Meta-analysis revealed a clear association between intraperitoneal free cancer cells and a poor prognosis. intraperitoneal free cancer cells -positive patients had higher rates of nodal spread (risk difference: 0.29; p<0.01), serosal invasion (risk difference: 0.43; p<0.01), recurrence (after 60 months of follow-up, risk difference: 0.44; p<0.01), and mortality (after 60 months of follow-up, risk difference: 0.34; p<0.01). Intraperitoneal free cancer cells are associated with a poor outcome in gastric cancer. This surrogate biomarker should be used to guide therapy both prior to and after surgery.
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Affiliation(s)
- Francisco Tustumi
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil
| | | | - Andre Roncon Dias
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil
| | | | - Ivan Cecconello
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil
| | - Bruno Zilberstein
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil
| | - Ulysses Ribeiro-Júnior
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo/SP, Brazil
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15
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Kodera Y. The current state of stomach cancer surgery in the world. Jpn J Clin Oncol 2016; 46:1062-1071. [DOI: 10.1093/jjco/hyw117] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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16
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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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17
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Chae HD, Kim IH. Prognostic significance of CEA expression by RT-PCR in peritoneal wash from patients with gastric cancer: result of a 5-year follow-up after curative resection. Scand J Gastroenterol 2016; 51:956-60. [PMID: 27162096 DOI: 10.3109/00365521.2016.1172339] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Peritoneal recurrence is the most common cause of death after surgery for gastric cancer. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis has been used to detect free cancer cells in peritoneal wash during surgery. This study was conducted to evaluate the prognostic significance of carcinoembrionic antigen (CEA) mRNA detected by RT-PCR in peritoneal wash from patients with gastric cancer after curative resection through a 5-year follow-up. MATERIALS AND METHODS Peritoneal wash were obtained from 117 patients who underwent curative surgery for gastric cancer. The association between the CEA RT-PCR results, clinicopathological factors, and factors affecting gastric cancer recurrence were evaluated. RESULTS Among the 117 cases, 38 (32.5%) revealed positive CEA expression. Patients with positive CEA expression showed a higher rate of peritoneal recurrence than those with negative CEA expression (p = 0.047). Depth of invasion, lymph node metastasis, TNM stage, and CEA expression were factors affecting recurrence. CEA expression and depth of invasion were significant prognostic factors in a multivariate analysis, and CEA expression was the most important prognostic factor for recurrence in patients who had undergone curative resection for gastric cancer (hazard ratio: 2.747, p = 0.046). CONCLUSIONS CEA expression in the peritoneal wash was significantly associated with peritoneal recurrence and was the most important prognostic factor for gastric cancer recurrence after curative resection.
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Affiliation(s)
- Hyun-Dong Chae
- a Department of Surgery, School of Medicine , Catholic University of Daegu , Daegu , Korea
| | - In-Hwan Kim
- a Department of Surgery, School of Medicine , Catholic University of Daegu , Daegu , Korea
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18
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Kitayama J, Yamaguchi H, Ishigami H, Matsuzaki K, Sata N. Intraperitoneal Mesenchymal Cells Promote the Development of Peritoneal Metastasis Partly by Supporting Long Migration of Disseminated Tumor Cells. PLoS One 2016; 11:e0154542. [PMID: 27136922 PMCID: PMC4854412 DOI: 10.1371/journal.pone.0154542] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 04/14/2016] [Indexed: 11/18/2022] Open
Abstract
The human peritoneal cavity contains a small number of free cells of mesenchymal cell lineage. Intraperitoneal mesenchymal cells (PMC) play supportive roles in metastasis formation on the peritoneum. In this study, we found that PMC, when co-cultuerd with human gastric cancer cells, MKN45, enhanced the proliferation of MKN45 when cultured at low, but not high, cellular density. Also, PMC suppressed apoptotic cell death of MKN45 only under low density culture conditions. Time-lapse videoanalysis clearly demonstrated that PMC randomly migrated more vigorously than did MKN45, and strongly enhanced the migration behavior of co-cultured MKN45. In fact, the majority of MKN45 migrated together in direct physical contact with PMC, and the sum of migration lengths from original position of co-cultured MKN45 for 48 hours was approximately 10 times longer than that of MKN45 cultured alone. Our data suggest that enhanced migration can increase the chance of direct contact or positional proximity among sparcely distributed MKN45, which may bring survival advantages to tumor cells. This may be one of the important mechanisms of peritoneal metastasis, since only a small number of tumor cells are considered to be disseminated in the early step of metastasis formation on the peritoneum.
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Affiliation(s)
- Joji Kitayama
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
- * E-mail:
| | - Hironori Yamaguchi
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
| | | | | | - Naohiro Sata
- Department of Gastrointestinal Surgery, Jichi Medical University, Tochigi, Japan
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Deng K, Zhu H, Chen M, Wu J, Hu R, Tang C. Prognostic Significance of Molecular Analysis of Peritoneal Fluid for Patients with Gastric Cancer: A Meta-Analysis. PLoS One 2016; 11:e0151608. [PMID: 26986965 PMCID: PMC4795629 DOI: 10.1371/journal.pone.0151608] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Accepted: 03/01/2016] [Indexed: 02/05/2023] Open
Abstract
Background Accurately distinguishing serosal invasion in patients with gastric cancer (GC) prior to surgery can be difficult. Molecular analysis of peritoneal fluid (MAPF) for free cancer cells with higher sensitivity than other methods; however, its prognostic value for GC remains controversial, precluding its application in clinical practice. Methods PubMed, EMBASE and other databases were systematically searched. Thirty-one studies were eligible for the meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were pooled for overall survival (OS), disease-free survival (DFS) and peritoneal recurrence-free survival (PRF). Results The current meta-analysis focused on patients with GC and negative cytological diagnoses. The results showed that positive MAPF status (MAPF+) led to poorer prognoses for OS (HR 2.59, 95% CI 1.99–3.37), DFS (HR 4.92, 95% CI 3.28–7.37) and PRF (HR 2.81, 95% CI 2.12–3.72) compared with negative MAPF status (MAPF-). Moreover, among the patients with GC who received curative treatment, the MAPF+ patients had poorer prognoses for OS (HR 3.27, 95% CI 2.49–4.29), DFS (HR 3.90, 95% CI 2.74–5.57) and PRF (HR 5.45, 95% CI 3.70–8.03). A meta-analysis of multivariate-adjusted HRs demonstrated that MAPF+ status was an independent prognostic factor for patients with GC who underwent curative treatment (OS: HR 2.19, 95% CI 1.47–3.28; PRF: HR 3.44, 95% CI 2.01–5.87). Using the identical target genes (CEA, CEA/CK20) as molecular markers, the patients with GC who were MAPF+ had significantly worse prognoses for OS (CEA: HR 3.03, 95% CI 2.29–4.01; CEA/CK20: HR 4.24, 95% CI 2.42–7.40), DFS (CEA: HR 3.99, 95% CI 2.24–7.12; CEA/CK20: HR 4.31, 95% CI 1.49–2.48) and PRF (CEA: HR 4.45, 95% CI 2.72–7.31; CEA/CK20: HR 6.46, 95% CI 3.62–11.55) than the patients who were MAPF-. Conclusion/Significance The above results demonstrate that MAPF could be a prognostic indicator for patients with GC who have a negative cytological diagnosis and/or are receiving curative treatment. MAPF could provide clinicians with additional prognostic information that could aid in developing individualized treatment plans prior to surgery. The widely used target genes CEA, CEA/CK20 were confirmed to be valuable MAPF markers for predicting the prognosis of GC.
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Affiliation(s)
- Kai Deng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hong Zhu
- Department of Abdominal Cancer, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mo Chen
- Department of Critical Care Medicine, Chengdu Second People's Hospital, Chengdu, 610041, China
| | - Junchao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Renwei Hu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chengwei Tang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, 610041, China
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20
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Seshadri RA, Glehen O. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer. World J Gastroenterol 2016; 22:1114-30. [PMID: 26811651 PMCID: PMC4716024 DOI: 10.3748/wjg.v22.i3.1114] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/22/2015] [Accepted: 11/30/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer associated peritoneal carcinomatosis (GCPC) has a poor prognosis with a median survival of less than one year. Systemic chemotherapy including targeted agents has not been found to significantly increase the survival in GCPC. Since recurrent gastric cancer remains confined to the abdominal cavity in many patients, regional therapies like aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have been investigated for GCPC. HIPEC has been used for three indications in GC- as an adjuvant therapy after a curative surgery, HIPEC has been shown to improve survival and reduce peritoneal recurrences in many randomised trials in Asian countries; as a definitive treatment in established PC, HIPEC along with CRS is the only therapeutic modality that has resulted in long-term survival in select groups of patients; as a palliative treatment in advanced PC with intractable ascites, HIPEC has been shown to control ascites and reduce the need for frequent paracentesis. While the results of randomised trials of adjuvant HIPEC from western centres are awaited, the role of HIPEC in the treatment of GCPC is still evolving and needs larger studies before it is accepted as a standard of care.
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Clinical importance of a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids obtained pre- and post-lymphadenectomy from gastric cancer patients. Surg Today 2015; 46:654-60. [PMID: 26272486 DOI: 10.1007/s00595-015-1235-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 06/14/2015] [Indexed: 01/08/2023]
Abstract
PURPOSE Our previous study demonstrated that a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids at laparotomy was a potential prognostic factor for gastric cancer patients; however, the clinical importance of a TRC diagnosis from peritoneal lavage fluids after lymphadenectomy remains unclear. METHODS TRC amplification targeting CEA mRNA was utilized to detect free cancer cells before and after lymphadenectomy during gastric cancer resection. Of 120 patients who underwent curative gastrectomy for cT2-T4 gastric cancer, 38 whose peritoneal lavage samples were collected pre- and post-lymphadenectomy were eligible for analysis. RESULTS Six (16.0 %) patients had CEA positivity before lymphadenectomy (pre-CEA), whereas nine (23.7 %) had CEA positivity after lymphadenectomy (post-CEA). Post-CEA was significantly correlated with higher pathological N-stage. Moreover, the positive post-CEA group had significantly worse relapse-free survival than the negative post-CEA group (p = 0.001). Cox multivariate analysis revealed that post-CEA positivity was a significant predictor of poor relapse-free survival (p = 0.012). It was also a predictor of distant metastasis, but not specific for peritoneal recurrence. CONCLUSIONS These findings demonstrated that post-CEA positivity in a TRC diagnosis was a potential predictor of disease recurrence, but not a specific predictor of peritoneal recurrence.
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22
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Prognostic value of CEA and CK20 mRNA in the peritoneal lavage fluid of patients undergoing curative surgery for gastric cancer. World J Surg 2014; 38:1107-11. [PMID: 24305936 DOI: 10.1007/s00268-013-2385-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Peritoneal recurrence is the most common type of recurrence in gastric cancer. Although cytological examination of peritoneal lavage fluid has been used to predict peritoneal spread, peritoneal recurrences often occur even in patients with negative cytology. Our previous retrospective study suggested that reverse transcriptase-polymerase chain reaction (RT-PCR) using peritoneal lavage fluid may be useful for predicting peritoneal recurrence in patients with negative cytology. This prospective study was conducted to validate the clinical impact of this RT-PCR method. METHODS From July 2009 to June 2012, a total of 118 cT2-4 gastric cancer patients underwent surgery. Since 14 patients were ineligible because they had incurable factors, the remaining 104 eligible patients were evaluated for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) messenger RNA (mRNA) using RT-PCR. If either CEA or CK20 mRNA was detected by RT-PCR, the patient was defined as PCR-positive as in our previous study. The association between recurrence-free survival (RFS) and background factors was analyzed using Cox proportional hazards models. RESULTS Of 104 patients, 16 (15.4 %) were positive for either CEA or CK20. PCR-positive patients had significantly worse RFS than PCR-negative patients (log-rank p = 0.007). Regarding the pattern of recurrence, 4 of 16 (25 %) PCR-positive patients and 2 of 88 (2 %) PCR-negative patients had peritoneal recurrence (p < 0.001), but there were no significant differences in recurrence at other sites. Cox multivariate analysis indicated only PCR-positivity as a significant predictor of poor RFS (p = 0.029). CONCLUSION This prospective study demonstrated that CEA and CK20 PCR results could predict peritoneal recurrence after curative surgery.
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23
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Kitayama J, Emoto S, Yamaguchi H, Ishigami H, Onoyama H, Yamashita H, Seto Y, Matsuzaki K, Watanabe T. Flow Cytometric Quantification of Intraperitoneal Free Tumor Cells is a Useful Biomarker in Gastric Cancer Patients with Peritoneal Metastasis. Ann Surg Oncol 2014; 22:2336-42. [PMID: 25404476 DOI: 10.1245/s10434-014-4238-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The frequency of intraperitoneal free tumor cells (IPTC) is considered to reflect the severity of peritoneal metastasis (PM). We quantified the relative number of IPTC against leukocytes in peritoneal fluid and evaluated its clinical relevance in gastric cancer (GC) patients, particularly those with PM. METHODS Cells recovered from ascites or peritoneal lavage fluid were immunostained with monoclonal antibodies (mAb) to CD45 and CD326 (EpCAM). Using flow cytometry (FACS), CD326(+) and CD45(+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated in a total of 506 samples obtained from 300 patients with GC and 33 patients with liver cirrhosis (LC). RESULTS Median (M) of the TLR of the initial samples obtained from 199 patients with PM(+) GC was 1.32 % (0-1,868.44 %), which was significantly higher than that in patients with PM(-) GC (M = 0 %, 0-0.35 %; n = 101) or LC (M = 0 %, 0-0.031 %; n = 33). In 104 PM(+) patients who received combination chemotherapy including intraperitoneal paclitaxel, the TLR was repeatedly measured in peritoneal fluid obtained from the port. In these patients, the TLR showed a strong correlation with clinical features as well as cytological findings and carcinoembryonic antigen messenger RNA status. Finally, the median survival time of the 11 patients with initial TLR > 10 % was significantly shorter than that of the 52 patients with TLR < 10 % (271 vs. 627 days; p = 0.0002). CONCLUSION The TLR excellently reflected tumor burden in the peritoneal cavity, and could be a reliable biomarker to determine the outcome, as well as the effectiveness, of chemotherapy in patients with PM(+) GC.
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Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan,
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Jeon CH, Kim IH, Chae HD. Prognostic value of genetic detection using CEA and MAGE in peritoneal washes with gastric carcinoma after curative resection: result of a 3-year follow-up. Medicine (Baltimore) 2014; 93:e83. [PMID: 25192488 PMCID: PMC4616273 DOI: 10.1097/md.0000000000000083] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Peritoneal metastasis is the most frequent cause of death in patients with gastric cancer. Reverse transcriptase-polymerase chain reaction (RT-PCR) assay of peritoneal washes has been used to predict peritoneal metastasis of gastric carcinoma. We applied carcinoembryonic antigen (CEA) and melanoma-associated gene (MAGE) RT-PCR for the detection of peritoneal metastasis of gastric carcinoma after curative surgery and evaluated its clinical significance. Peritoneal washes were obtained from 117 patients with gastric carcinoma. MAGE A1-A6 and CEA RT-PCR were performed, and the results were evaluated according to their clinicopathologic characteristics. Three-year follow-up clinical studies were periodically performed, and disease-free survival rates were retrospectively investigated using the medical records. Among 117 peritoneal fluids, 11 cases (9.4%) revealed MAGE expression and 38 cases (32.5%) revealed CEA expression. When focusing on recurrence rates, RT-PCR-positive had much higher recurrence rates than RT-PCR-negative cases (32.5% vs 5.2%, P < 0.01). Univariate analysis revealed that depth of invasion, lymph node metastasis, tumor node metastasis (TNM) stage, Lauren classification, and MAGE and CEA expressions were independent prognostic factors for recurrence. In a multivariate analysis, MAGE expression and TNM stage were significantly and independently related to recurrence in patients who underwent curative resection. MAGE expression was determined to be the most important prognostic factor for recurrence (hazard ratio: 12.487, P < 0.01). It is feasible to identify free cancer cells in peritoneal lavage by using a MAGE A1-A6 and CEA RT-PCR. MAGE RT-PCR results disclosed significant associations with peritoneal recurrence and proved to be the most important factor for the recurrence rate in patients with gastric carcinoma who had undergone radical resection.
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Affiliation(s)
- Chang-Ho Jeon
- Department of Laboratory Medicine (C-HJ); and Department of Surgery (I-HK, H-DC), School of Medicine, Catholic University of Daegu, Daegu, Korea
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Kitayama J, Emoto S, Yamaguchi H, Ishigami H, Watanabe T. CD90+ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment. PLoS One 2014; 9:e86516. [PMID: 24466130 PMCID: PMC3897715 DOI: 10.1371/journal.pone.0086516] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2013] [Accepted: 12/13/2013] [Indexed: 01/09/2023] Open
Abstract
The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(−) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, α-smooth muscle actin and fibroblast activated protein-α by the stimulation with TGF-β, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies.
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Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
- * E-mail:
| | - Shigenobu Emoto
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
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Tamura S, Fujiwara Y, Kimura Y, Fujita J, Imamura H, Kinuta M, Yano M, Hiratsuka M, Kobayashi K, Okada K, Mori M, Doki Y. Prognostic information derived from RT-PCR analysis of peritoneal fluid in gastric cancer patients: results from a prospective multicenter clinical trial. J Surg Oncol 2013; 109:75-80. [PMID: 24155213 DOI: 10.1002/jso.23472] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2013] [Accepted: 10/01/2013] [Indexed: 11/05/2022]
Abstract
OBJECTIVE The purpose of this study is to define the clinical significance of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer in a multicenter prospective trial. METHODS Quantitative RT-PCR with CEA and CK-20 mRNA as target markers was introduced for peritoneal lavage diagnosis in 141 patients with clinically advanced gastric cancer from 9 different institutes. We then evaluated the prognostic factors in patients and also evaluated predictive markers for peritoneal recurrence in 124 patients without peritoneal metastasis at surgery RESULTS Out of the 141 cases, 140 patients were successfully analyzed by RT-PCR of peritoneal lavage fluids. According to multivariate analysis, the combined results of RT-PCR (CEA and CK-20) and CK-20 alone in addition to pathological N (pN)-stage were significantly correlated with overall survival. Multivariate analysis showed that the RT-PCR (CEA and CK-20) and CEA alone in addition to pathological T-stage, pN-stage, and histological grade were significantly correlated with peritoneal recurrence after surgery. CONCLUSION This is the first multicenter prospective study to show that RT-PCR analysis of peritoneal lavage fluid with the combination of CEA and CK-20 markers was useful for predicting overall survival and peritoneal recurrence in patients with clinically advanced gastric cancer.
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Affiliation(s)
- Shigeyuki Tamura
- Department of Gastroenterological Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
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Fujiwara Y, Okada K, Hanada H, Tamura S, Kimura Y, Fujita J, Imamura H, Kishi K, Yano M, Miki H, Okada K, Takayama O, Aoki T, Mori M, Doki Y. The clinical importance of a transcription reverse-transcription concerted (TRC) diagnosis using peritoneal lavage fluids in gastric cancer with clinical serosal invasion: a prospective, multicenter study. Surgery 2013; 155:417-23. [PMID: 24439740 DOI: 10.1016/j.surg.2013.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 10/07/2013] [Indexed: 01/01/2023]
Abstract
PURPOSE We have developed a novel molecular method of diagnosis using the technique of transcriptase-reverse transcriptase concerted reaction (TRC) for the detection of cancer micrometastasis. This study prospectively examined the clinical importance of the TRC diagnosis with peritoneal lavage fluids collected from gastric cancer operations at multiple institutes. METHODS TRC amplification targeting carcinoembryonic antigen mRNA was applied to detect gastric cancer cells in peritoneal lavage fluids obtained during gastric cancer resections from nine different hospitals. A total of 137 patients with a clinical diagnosis of serosa-invading neoplasms were enrolled to investigate the correlation between the TRC diagnosis and patient prognosis. RESULTS Of the 137 patients, 27 (20%) were positive by cytologic examination. In contrast, TRC targeting carcinoembryonic antigen mRNA was positive in 59 of 137 (54%) patients. TRC positivity was associated with a poorer overall survival in all patients and in the 104 patients who underwent a curative operation. TRC positivity also was associated with the peritoneal recurrence-free survival rate in the 104 curative cases. Multivariate analysis showed that TRC positivity and the pathologic N factor were prognostic factors for the overall survival time. CONCLUSION Our prospective multicenter study showed that the TRC test using peritoneal lavage fluids could be a potential prognostic factor to predict patient survival and peritoneal recurrence with clinically diagnosed, serosa-invading gastric cancer.
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Affiliation(s)
- Yoshiyuki Fujiwara
- Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
| | - Kaoru Okada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hiroyuki Hanada
- Division of Laboratory for Clinical Investigation, Department of Medical Technology, Osaka University Hospital, Suita, Osaka, Japan
| | - Shigeyuki Tamura
- Department of Gastroenterological Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | | | | | | | - Kentaro Kishi
- Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Masahiko Yano
- Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
| | - Hirohumi Miki
- Department of Gastroenterological Surgery, Kansai Rosai Hospital, Amagasaki, Hyogo, Japan
| | | | - O Takayama
- Itami Municipal Hospital, Itami, Hyogo, Japan
| | - Taro Aoki
- Kinki Chuo Hospital, Itami, Hyogo, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Kitayama J, Emoto S, Yamaguchi H, Ishigami H, Kamei T, Yamashita H, Seto Y, Matsuzaki K, Watanabe T. Flow cytometric quantification of intraperitoneal free tumor cells in patients with peritoneal metastasis. CYTOMETRY PART B-CLINICAL CYTOMETRY 2013; 86:56-62. [PMID: 24115348 DOI: 10.1002/cyto.b.21126] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/21/2013] [Accepted: 08/12/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND Peritoneal metastasis (PM) is the most life-threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis. METHODS Cells were recovered from ascites or peritoneal lavages from 106 patients who underwent abdominal surgery and additional 89 samples which were obtained from peritoneal catheter or access port in patients with PM (+) gastric cancer. The cells were immunostained with monoclonal antibodies to CD45 and to CD326 (EpCAM). Using flow cytometry, CD326 (+) and CD45 (+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated. RESULTS In 106 samples obtained by laparotomy, Median (M) of the TLR of PM (+) patients was 1.39% (0-807.87%) which was significantly higher than PM (-) patients (M=0%, 0-2.14%, P < 0.001). In PM (+) patients, 86 CY (+) samples showed higher TLR than 61 CY (-) samples (M=2.81%, 0.02-1868.44% vs. M=0%, 0-3.45%, p<0.0001). In all of the 24 patients who were monitored for TLR before and after intraperitoneal (IP) chemotherapy, the TLR was reduced which was more dramatic than the results of the change in cytology. CONCLUSIONS TLR measured with FACS is an excellent reflection of the tumor spread in the peritoneal cavity and could be a reliable diagnostic biomarker to determine the severity of PM as well as effectiveness of IP chemotherapy.
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Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
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Munasinghe A, Kazi W, Taniere P, Hallissey MT, Alderson D, Tucker O. The incremental benefit of two quadrant lavage for peritoneal cytology at staging laparoscopy for oesophagogastric adenocarcinoma. Surg Endosc 2013; 27:4049-53. [PMID: 23836122 DOI: 10.1007/s00464-013-3058-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 06/09/2013] [Indexed: 01/18/2023]
Abstract
BACKGROUND Patients with positive peritoneal cytology from oesophagogastric cancer have a poor prognosis. The purpose of this study was to compare lavage cytology from the pelvis alone with the pelvis and subphrenic areas at staging laparoscopy in patients with potentially resectable oesophagogastric adenocarcinoma. METHODS Between November 2006 and November 2010, all patients with operable oesophagogastric adenocarcinoma on spiral CT considered fit for surgical resection underwent staging laparoscopy. Subphrenic and pelvic peritoneal lavage for cytology was performed followed by laparoscopic biopsy of any visible peritoneal disease. Patients were divided into groups: macroscopic peritoneal metastases (P+), no macroscopic peritoneal disease with negative cytology (P-C-), no macroscopic peritoneal disease with positive pelvic cytology (P-PC+), no macroscopic peritoneal disease with positive subphrenic cytology (P-SC+), or both (P-PSC+). RESULTS A total of 316 staging laparoscopy procedures were performed; 245 patients (78 %) were P-C-, 28 (9 %) were P+, and 43 (14 %) were P-C+, of whom 29 (9 %) were P-PSC+, 10 (3 %) were P-SC+, and 4 (1 %) were P-PC+. Pelvic cytology alone had 76.7 % sensitivity for peritoneal disease, and subphrenic cytology alone had 90.7 % sensitivity. CONCLUSIONS Peritoneal lavage for cytology at staging laparoscopy has an incremental benefit for staging oesophagogastric adenocarcinoma in the absence of macroscopic metastatic disease. Subphrenic washings have the highest yield of positive results. Performing isolated pelvic washings for cytology will understage 23.3 % of patients with microscopic peritoneal disease. The routine use of subphrenic in combination with pelvic lavage for cytology at staging laparoscopy in patients with oesophagogastric adenocarcinoma has an incremental benefit in detecting cytology-positive disease over either pelvic or subphrenic cytology alone.
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Affiliation(s)
- Aruna Munasinghe
- Academic Department of Surgery, University Hospital Birmingham, Edgbaston, Birmingham, B15 2TH, UK,
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Yoneda A, Taniguchi K, Torashima Y, Susumu S, Kanetaka K, Kuroki T, Eguchi S. The detection of gastric cancer cells in intraoperative peritoneal lavage using the reverse transcription--loop-mediated isothermal amplification method. J Surg Res 2013; 187:e1-6. [PMID: 24360119 DOI: 10.1016/j.jss.2013.01.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Revised: 12/29/2012] [Accepted: 01/03/2013] [Indexed: 10/27/2022]
Abstract
INTRODUCTION To detect a small number of malignant cells, we used a highly sensitive detection system that measures the expression levels of cytokeratin (CK) 19 messenger RNA by reverse transcription-loop-mediated isothermal amplification (RT-LAMP). MATERIALS AND METHODS We evaluated the clinical relevance of our novel diagnostic method with an RT-LAMP assay using CK19 as a target gene for the detection of free cancer cells in peritoneal lavage and assessed the clinical significance of the molecular diagnosis by survival analysis and frequency of recurrence, with a median follow-up period of 39 mo. We observed 52 patients with gastric cancer who underwent gastrectomy, bypass operation, and exploratory laparotomy. RESULTS Those 52 patients, who were subjected to both RT-LAMP and cytologic examination, were divided into the following three groups: (1) patients positive by cytology and RT-LAMP (CY+/LAMP+) (n = 9), (2) patients positive by LAMP and negative by cytology (CY-/LAMP+) (n = 12), and (3) patients negative by both cytology and LAMP (CY-/LAMP-) (n = 31). All patients with simultaneous peritoneal dissemination and positive cytology were positive on RT-LAMP. The results of RT-LAMP were statistically significant for recurrence by univariate analysis (P < 0.005). Cytology-positive cases had a very poor prognosis, and RT-LAMP-positive cases had a worse prognosis than RT-LAMP-negative cases. CONCLUSIONS Our findings suggest that CK19 RT-LAMP would be useful as an intraoperative diagnostic modality to detect patients with a high risk of recurrence even after clinically curative surgery, who thus require proper adjuvant therapy.
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Affiliation(s)
- Akira Yoneda
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Ken Taniguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yasuhiro Torashima
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Seiya Susumu
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Kengo Kanetaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tamotsu Kuroki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Griniatsos J, Michail O, Dimitriou N, Karavokyros I. Lymph node, peritoneal and bone marrow micrometastases in gastric cancer: Their clinical significance. World J Gastrointest Oncol 2012; 4:16-21. [PMID: 22403737 PMCID: PMC3296804 DOI: 10.4251/wjgo.v4.i2.16] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Revised: 10/03/2011] [Accepted: 10/12/2011] [Indexed: 02/05/2023] Open
Abstract
The 7th TNM classification clearly states that micrometastases detected by morphological techniques (HE stain and immunohistochemistry) should always be reported and calculated in the staging of the disease (pN1mi or M1), while patients in whom micrometastases are detected by non-morphological techniques (e.g., flow cytometry, reverse-transcriptase polymerase chain reaction) should still be classified as N0 or M0. In gastric cancer patients, micrometastases have been detected in lymph nodes, the peritoneal cavity and bone marrow. However, the clinical implications and/or their prognostic significance are still a matter of debate. Current literature suggests that lymph node micrometastases should be encountered for the loco-regional staging of the disease, while skip lymph node micrometastases should also be encountered in the total number of infiltrated lymph nodes. Peritoneal fluid cytology examination should be obligatorily performed in pT3 or pT4 tumors. A positive cytology classifies gastric cancer patients as stage IV. Although a curative resection is not precluded, these patients face an overall dismal prognosis. Whether patients with a positive cytology should be treated similarly to patients with macroscopic peritoneal recurrence should be evaluated further. Gastric cancer cells are detected with high incidence in the bone marrow. However, the published results make comparison of data between groups almost impossible due to severe methodological problems. If these methodological problems are overcome in the future, specific target therapies may be designed for specific groups of patients.
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Affiliation(s)
- John Griniatsos
- John Griniatsos, Othon Michail, Nikoletta Dimitriou, Ioannis Karavokyros, 1st Department of Surgery, University of Athens, Medical School, GR 115-27, Athens, Greece
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Ozaki H, Matsuzaki H, Ando H, Kaji H, Nakanishi H, Ikehara Y, Narimatsu H. Enhancement of metastatic ability by ectopic expression of ST6GalNAcI on a gastric cancer cell line in a mouse model. Clin Exp Metastasis 2012; 29:229-38. [PMID: 22228572 PMCID: PMC3275730 DOI: 10.1007/s10585-011-9445-1] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2011] [Accepted: 12/09/2011] [Indexed: 11/25/2022]
Abstract
ST6GalNAcI is a sialyltransferase responsible for the synthesis of sialyl Tn (sTn) antigen which is expressed in a variety of adenocarcinomas including gastric cancer especially in advanced cases, but the roles of ST6GalNAcI and sTn in cancer progression are largely unknown. We generated sTn-expressing human gastric cancer cells by ectopic expression of ST6GalNAcI to evaluate metastatic ability of these cells and prognostic effect of ST6GalNAcI and sTn in a mouse model, and identified sTn carrier proteins to gain insight into the function of ST6GalNAcI and sTn in gastric cancer progression. A green fluorescent protein-tagged human gastric cancer cell line was transfected with ST6GalNAcI to produce sTn-expressing cells, which were transplanted into nude mice. STn-positive gastric cancer cells showed higher intraperitoneal metastatic ability in comparison with sTn-negative control, resulting in shortened survival time of the mice, which was mitigated by anti-sTn antibody administration. Then, sTn-carrying proteins were immunoprecipitated from culture supernatants and lysates of these cells, and identified MUC1 and CD44 as major sTn carriers. It was confirmed that MUC1 carries sTn also in human advanced gastric cancer tissues. Identification of sTn carrier proteins will help understand mechanisms of metastatic phenotype acquisition of gastric cancer cells by ST6GalNAcI and sTn.
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Affiliation(s)
- Hidenori Ozaki
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hideki Matsuzaki
- Lectin Application and Analysis Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hidenobu Ando
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
- Glycogene, Inc, Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hiroyuki Kaji
- Glycoproteomics Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hayao Nakanishi
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Kanokoden 1-1, Chikusa, Nagoya, 464-8681 Japan
| | - Yuzuru Ikehara
- Molecular Medicine Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
| | - Hisashi Narimatsu
- Glycogene Function Team, Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), Central 2, Umezono 1-1-1, Tsukuba, Ibaraki 305-8568 Japan
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Satoh Y, Mori K, Kitano K, Kitayama J, Yokota H, Sasaki H, Uozaki H, Fukayama M, Seto Y, Nagawa H, Yatomi Y, Takai D. Analysis for the combination expression of CK20, FABP1 and MUC2 is sensitive for the prediction of peritoneal recurrence in gastric cancer. Jpn J Clin Oncol 2011; 42:148-52. [PMID: 22172348 DOI: 10.1093/jjco/hyr179] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Prediction of peritoneal recurrence in gastric cancer patients is important for application of adjuvant chemotherapy. After surgery, occasional patients have peritoneal recurrence despite negative cytology of the peritoneal washings. Thus, molecular detection of a subliminal number of cancer cells in peritoneal washings may overcome the sensitivity limitation of conventional cytology. In this study, expressions of five specific marker genes, namely, TFF1, TFF2, CK20, FABP1 and MUC2, were evaluated for their usefulness as markers of micro-dissemination. It was found that reverse transcriptase-polymerase chain reaction for these five genes yielded results highly specific for the depth of invasion and disease stage. Furthermore, the expression of CK20, FABP1 and MUC2 was a reliable prognostic indicator of peritoneal metastasis. Our results suggest that evaluation of the expression of CK20, FABP1 and MUC2 in peritoneal washings is a useful tool for identifying patients at high risk of peritoneal recurrence who may need adjuvant chemotherapy.
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Affiliation(s)
- Yumiko Satoh
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
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Okada K, Fujiwara Y, Nakamura Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Takahashi T, Mori M, Doki Y. Oncofetal protein, IMP-3, a potential marker for prediction of postoperative peritoneal dissemination in gastric adenocarcinoma. J Surg Oncol 2011; 105:780-5. [PMID: 22012575 DOI: 10.1002/jso.22108] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2011] [Accepted: 09/10/2011] [Indexed: 01/13/2023]
Abstract
BACKGROUND The aim of this study was to determine the expression of insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP-3) and its clinical significance in gastric cancers, as well the prognostic value of its expression in the peritoneal lavage fluid after surgery. METHODS IMP-3 expression was examined by immunohistochemistry in 96 primary gastric tumors. IMP-3 mRNA expression in peritoneal lavage fluid obtained at laparotomy was determine by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). RESULTS Positive staining for IMP-3 was observed in 74% (71/96) of the tumors. IMP-3 expression in gastric tumors correlated significantly with worst overall survival (OS) and recurrence-free survival. Multivariate analyses identified pathological N stage and IMP-3 expression as significant independent prognostic factors for disease-free survival. Eight (28%) of 36 peritoneal lavage samples were cytologically negative but positive for IMP-3 mRNA expression by RT-PCR. The OS of patients with IMP-3-positive peritoneal lavage was significantly worse than of those with negative expression. CONCLUSIONS IMP-3 expression in primary gastric tumors was an independent poor prognostic factor. IMP-3 mRNA expression in peritoneal lavage fluid was a predictor of recurrence after surgery in gastric cancer and a marker of poor prognosis.
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Affiliation(s)
- Kaoru Okada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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Piaton E, Villeneuve L, Maurice C, Paulin C, Cottier M, Fontanière B, Salle M, Seigneurin D, Vancina S, Decullier E, Gilly FN, Cotte E. Intraperitoneal free cancer cells in non-gynaecological adenocarcinomas: a reproducibility study. Cytopathology 2011; 23:242-9. [PMID: 21736645 DOI: 10.1111/j.1365-2303.2011.00889.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE In recent years, therapeutic approaches including cytoreductive surgery followed by intraperitoneal chemotherapy have proven effective in peritoneal carcinomatosis of colorectal origin. If cytology is to be used to include patients in aggressive treatment regimens, it is necessary to evaluate its performance, particularly in terms of specificity. The aim of this study was to assess interobserver agreement for the detection of intraperitoneal free cancer cells (IFCCs) in patients with non-gynaecological adenocarcinomas. METHODS Over a 5-year period, 1223 patients were recruited in 19 French surgery departments. Peritoneal samples were examined in 14 dispersed pathology laboratories. Giemsa-stained slides were sent to a control reader blind to the previous diagnosis. Discordant cases, concordant positive results and a random selection of negative concordant cases were reviewed by a panel of seven cytopathologists. The 'final diagnosis' was that of the consensus meetings but took into account locally-processed slides. RESULTS Gathering dubious cases with negative results, a 95.6% concordance was achieved between local readers and the control reader. IFCCs were ascertained by the panel in 85 cases (7.0%). Eight of 873 colorectal cancers cases viewed locally were falsely positive (0.9%). Radiotherapy and neoadjuvant therapy had no impact on the false-positive rate as assessed by final validation by the panel (P > 0.05). Samples initially considered as dubious were reclassified as negative by the panel in 24 of 25 cases (96.0%). CONCLUSIONS The panel consensus allowed reclassification of most dubious/equivocal peritoneal cytology cases, whereas clearcut distinction between benign and malignant cases was correctly achieved in almost all cases.
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Affiliation(s)
- E Piaton
- Hospices Civils de Lyon, Centre de Pathologie Est, Bron Université Lyon 1, Lyon, France.
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Fujiwara Y, Takiguchi S, Nakajima K, Miyata H, Yamasaki M, Kurokawa Y, Okada K, Mori M, Doki Y. Neoadjuvant intraperitoneal and systemic chemotherapy for gastric cancer patients with peritoneal dissemination. Ann Surg Oncol 2011; 18:3726-31. [PMID: 21584835 DOI: 10.1245/s10434-011-1770-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2011] [Indexed: 12/27/2022]
Abstract
BACKGROUND The present study was designed to assess the feasibility and efficiency of intraperitoneal and intravenous neoadjuvant chemotherapy in gastric cancer patients with peritoneal dissemination. METHODS The study subjects were 25 treatment-naïve patients with gastric cancer. Patients with positive cytology or with peritoneal carcinomatosis received neoadjuvant intraperitoneal and systemic chemotherapy (NIPS), comprising intraperitoneal (i.p.) mitomycin C (MMC) and cisplatin (CDDP), followed by two cycles of intravenous triplet chemotherapy of docetaxel, 5-fluorouracil (5-FU), and CDDP. Gastrectomy with lymph node dissection was performed after NIPS in patients free of peritoneal deposits, confirmed by staging laparoscopy. RESULTS Seventeen patients had measurable lymph node metastases by the RECIST criteria. CT examination showed response to the treatment in ten (59%, 0 complete response, 10 partial response). Of the 25 patients, 14 (56%) showed negative results on peritoneal cytology with no macroscopic peritoneal metastasis, whereas the remaining 11 were cancer cell-positive on peritoneal cytology or macroscopic peritoneal metastasis even after NIPS. The median survival time for all 25 patients was 16.7 months. Prognosis was better in patients who showed negative cytology and disappearance of peritoneal cancer metastases after NIPS than in those with positive cytology or existing peritoneal deposits (P < 0.0001). The predominant toxicity was myelosuppression and grade 3-4 leukopenia and neutropenia occurred in 20 (80%) patients, which were manageable. No treatment-related mortality was observed during and after NIPS and surgery. CONCLUSIONS The results of this prospective phase II study indicated that the newly designed NIPS was highly effective and well tolerated in patients with advanced gastric cancer and peritoneal dissemination.
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Affiliation(s)
- Yoshiyuki Fujiwara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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Jeong SH, Lee YJ, Park ST, Choi SK, Hong SC, Jung EJ, Joo YT, Jeong CY, Ha WS. Risk of recurrence after laparoscopy-assisted radical gastrectomy for gastric cancer performed by a single surgeon. Surg Endosc 2010; 25:872-8. [PMID: 21072670 DOI: 10.1007/s00464-010-1286-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2010] [Accepted: 07/26/2010] [Indexed: 12/12/2022]
Abstract
BACKGROUND The risk of recurrence after laparoscopy-assisted radical gastrectomy (LAG) was investigated. MATERIALS AND METHODS Clinical data of 398 consecutive patients who underwent radical gastrectomy with R0 resection for gastric cancer at Gyeongsang National University Hospital between January 2005 and December 2007 were reviewed retrospectively. RESULTS Of the patients, 65.4% (n = 261) and 34.6% (n = 138) underwent LAG and open radical gastrectomy (OG), respectively. Of the LAG cases, 73.2% (n = 192), 10.7% (n = 28), 12.6% (n = 33), and 3.1% (n = 8) had stage I, II, III, and IV gastric cancer, respectively. All patients were followed up for a mean of 36.8 ± 13.7 months, and 14.6% (n = 58) had recurrence during the follow-up period. Univariate analysis revealed that tumor size, tumor-node-metastasis (TNM) stage, method of approach (LAG versus OG), and operation type were associated significantly with recurrence. Multivariate analysis revealed that only high TNM stage was significantly associated with recurrence (P = 0.00). While patients who underwent OG had higher incidence of recurrence than patients who underwent LAG, OG was not significantly associated with recurrence on multivariate analysis (P = 0.06). CONCLUSIONS LAG and OG did not differ significantly in terms of recurrence, even when used in advanced gastric cancer cases. Multivariate analysis revealed that high TNM stage was significantly associated with recurrence. Thus, LAG appears to be a safe and feasible procedure that has the potential to be an alternative to open surgery, even for advanced gastric cancer.
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Affiliation(s)
- Sang-Ho Jeong
- Department of Surgery, Gyeongsang National University Hospital, Jinju, Gyeongsang South Province, South Korea
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La Torre M, Ferri M, Giovagnoli MR, Sforza N, Cosenza G, Giarnieri E, Ziparo V. Peritoneal wash cytology in gastric carcinoma. Prognostic significance and therapeutic consequences. Eur J Surg Oncol 2010; 36:982-6. [PMID: 20591604 DOI: 10.1016/j.ejso.2010.06.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Accepted: 06/07/2010] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND AND AIMS The prognosis of patients with gastric cancer is poor, even following curative resection, and is related primarily to the extent of disease at presentation. In locally advanced gastric tumors, peritoneal lavage cytology (PLC) is a relevant prognostic factor. The Authors present their results of peritoneal washing cytology, evaluating the prognostic value of this technique, and discussing the clinical impact. PATIENTS AND METHODS From July 2003 to May 2008, results of PLC in 64 patients with histologically proven primary gastric adenocarcinomas were analyzed. At laparotomy the abdomen was irrigated with 200 ml of normal saline, and ≥50 ml were aspirated and examined by means of cytology and immunocytopathology. RESULTS PLC was positive in 7 cases (11%). Overall, 86% of patients with a positive PLC had a pT3/pT4 tumor and 100% with a positive PLC had an N-positive tumor (p < 0.001); 71% of patients with a positive PLC had a grade G3/G4 tumor (p = 0.001). At a median follow-up of 32 months, the cumulative 5-year survival was 28%. The median survival of patients presenting positive PLC (19 months) was significantly lower than that of patients with negative peritoneal cytology (38 months) (p = 0.0001). Multivariate analysis identified cytology as a significant predictor of outcome (p = 0.018). CONCLUSIONS Results in the present series demonstrated that patients with a positive peritoneal cytology had advanced disease and poor prognosis, thus indicating that patients with locally advanced gastric cancer should undergo staging laparoscopy and PLC examination in order to select those requiring more aggressive treatment. Future therapeutic strategies should include PLC examination in preoperative staging, in order to select patients for more aggressive treatment.
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Affiliation(s)
- M La Torre
- Department of Surgery, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy.
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Detection of micrometastases in peritoneal washings of gastric cancer patients by the reverse transcriptase polymerase chain reaction. Gastric Cancer 2009; 11:206-13. [PMID: 19132482 DOI: 10.1007/s10120-008-0483-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2008] [Accepted: 09/14/2008] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer patients with positive (+) peritoneal cytology have a prognosis similar to stage IV patients. We studied the ability of quantitative reverse transcriptase polymerase chain reaction (RT-PCR) to detect peritoneal micrometastases in patients undergoing staging laparoscopy. METHODS Peritoneal washings were obtained prospectively from 34 patients with gastric adenocarcinoma undergoing staging laparoscopy and 6 patients undergoing laparoscopy for benign disease. Each sample underwent cytologic and RT-PCR analysis for tumor markers: carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), survivin, and MUC2. Markers were evaluated on the basis of their deviance from the ideal marker. RESULTS Pathologic stages for the gastric cancer patients were: stage I, 9 (27%); stage II, 7 (21%); stage III, 15 (44%); and stage IV, 3 (9%). The four cytology (+) patients were: stage II, 1; stage III, 1; and stage IV, 2. Fifteen patients were RT-PCR (+), including all cytology (+) patients. The optimal threshold for cycle amplification was 35, based on a receiver operating characteristic curve. CEA had the smallest deviance. CONCLUSION RT-PCR using a panel of tumor markers, including CEA, detects (+) cytology. The clinical significance of "false-positive" overexpression of CEA, survivin, or CK20 but cytology (-) remains to be defined. RT-PCR could represent a more sensitive method than cytology for detection of subclinical peritoneal tumor dissemination; this may be useful in improving patient selection for operative management and clinical trials.
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al-Shammaa HAH, Li Y, Yonemura Y. Current status and future strategies of cytoreductive surgery plus intraperitoneal hyperthermic chemotherapy for peritoneal carcinomatosis. World J Gastroenterol 2008; 14:1159-66. [PMID: 18300340 PMCID: PMC2690662 DOI: 10.3748/wjg.14.1159] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This article is to offer a concise review on the use of cytoreductive surgery (CRS) plus intraperitoneal hyperthermic chemotherapy (IPHC) for the treatment of peritoneal carcinomatosis (PC). Traditionally, PC was treated with systemic chemotherapy alone with very poor response and a median survival of less than 6 mo. With the establishment of several phase II studies, a new trend has been developed toward the use of CRS plus IPHC as a standard method for treating selected patients with PC, in whom sufficient cytoreduction could be achieved. In spite of the need for more high quality phase III studies, there is now a consensus among many surgical oncology experts throughout the world about the use of this new treatment strategy as standard care for colorectal cancer patients with PC. This review summarizes the current status and possible progress in future.
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Fujiwara Y, Doki Y, Taniguchi H, Sohma I, Takiguchi S, Miyata H, Yamasaki M, Monden M. Genetic detection of free cancer cells in the peritoneal cavity of the patient with gastric cancer: present status and future perspectives. Gastric Cancer 2008; 10:197-204. [PMID: 18095074 DOI: 10.1007/s10120-007-0436-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2007] [Accepted: 08/28/2007] [Indexed: 02/07/2023]
Abstract
The purpose of this review is to examine the current status and future perspectives of the molecular analysis of peritoneal lavage fluid in patients with gastric cancer. During the past 10 years, the polymerase chain reaction (PCR) has been applied for the molecular detection of free cancer cells in the abdominal cavity of patients with gastric cancer, and its clinical significance in establishing the presence of peritoneal dissemination has been assessed by several groups especially in Japan. The majority of these studies have confirmed the predictive value of the molecular detection of peritoneal metastasis and recurrence using peritoneal lavage fluid. Based on these findings, since April 2006, the genetic diagnosis of body fluids has been included in the Japanese Government public health insurance program for patients with solid tumors. However, there are still many obstacles to overcome before the genetic diagnosis of micrometastasis can be considered a routine laboratory assay. Here we review the importance of the molecular detection of cancer cells in the abdominal cavity, and the molecular techniques used for such diagnosis; we also provide some clinical examples to illustrate the value of molecular diagnosis.
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Affiliation(s)
- Yoshiyuki Fujiwara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka (E-2), Suita, 565-0871, Japan
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Choi WH, Kim S, Shen J, Cheong JH, Hyung WJ, Kim YI, Choi SH, Noh SH, Park CI. Prognostic significance of perinodal extension in gastric cancer. J Surg Oncol 2007; 95:540-5. [PMID: 17252555 DOI: 10.1002/jso.20734] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
BACKGROUND The grouping of patients who have a poor prognosis is important in determining a treatment strategy. The aim of this study was to investigate the clinicopathologic features and prognosis in patients with perinodal extension, with a focus on the difference of survival between homogenous groups. METHODS This study included a total of 1,092 patients who underwent curative gastrectomy for gastric adenocarcinoma from 1997 to 2004 at the Department of Surgery, Yongdong Severance Hospital, Yonsei University College of Medicine. RESULTS One hundred sixty-one patients had perinodal extension. The incidence of perinodal extension was positively correlated for T and N stages. Perinodal extension was identified as an independent prognostic factor and had more influence on survival than T and N stages. Patients who had nodal metastasis without serosal exposure and who had serosal exposure without nodal metastasis were selected as homogenous groups, and there was no difference of survival between these groups. However, when the nodal metastasis group was subdivided according to the perinodal extension, perinodal extension subgroup had significant poorer prognosis than no perinodal extension subgroup. CONCLUSIONS The perinodal extension was the most important independent prognostic factor in gastric cancer, and should be included in the TNM gastric cancer staging system.
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Affiliation(s)
- Won Hyuk Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
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Ribeiro U, Safatle-Ribeiro AV, Zilberstein B, Mucerino D, Yagi OK, Bresciani CC, Jacob CE, Iryia K, Gama-Rodrigues J. Does the intraoperative peritoneal lavage cytology add prognostic information in patients with potentially curative gastric resection? J Gastrointest Surg 2006; 10:170-6, discussion 176-7. [PMID: 16455447 DOI: 10.1016/j.gassur.2005.11.001] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2005] [Accepted: 11/03/2005] [Indexed: 01/31/2023]
Abstract
Peritoneal recurrence is the foremost pattern of failure after potentially curative resection for gastric cancer. Our aim was to evaluate the prognostic value of intraperitoneal free cancer cells (IFCCs) in peritoneal lavage of patients who underwent potentially curative resection for gastric carcinoma. Two hundred twenty patients with gastric cancer stage I, II, or III were prospectively evaluated with peritoneal lavage and cytologic examination. Aspirated fluid from the abdominal cavity was centrifuged and subjected to Papanicolaou staining. The mean age was 60.9 years (range, 21-89 years), and 63.6% were men. IFCCs were detected in 6.8% of the patients; suspicious in 2.7%, and negative in 84.5%. No judgment could be given in 5.9% of the cases. Invasion of the gastric serosa (pT3) was observed in all positive cytology patients. Patients with IFCCs had a mean survival time of 10.5 months, while those with negative IFCC had a mean survival time of 61 months (P = 0.00001). There was no correlation between the presence of IFCCs and tumor size, histology, pN, or tumor site. Our conclusions are that (1) positive cytology indicates a poor prognosis in patients who underwent potentially curative gastric resection and (2) peritoneal lavage cytology improves staging in assessing these patients and may alter their therapeutic approach.
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Affiliation(s)
- Ulysses Ribeiro
- Department of Gastroenterology, University of São Paulo, Rua Treze de Maio 1954, Cj. 54, São Paulo-SP 01327-002, Brazil.
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Kodera Y, Nakanishi H, Ito S, Yamamura Y, Fujiwara M, Koike M, Hibi K, Ito K, Tatematsu M, Nakao A. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: detection of cytokeratin 20 mRNA in peritoneal washes, in addition to detection of carcinoembryonic antigen. Gastric Cancer 2005; 8:142-8. [PMID: 16086116 DOI: 10.1007/s10120-005-0318-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2004] [Accepted: 01/24/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND In patients with gastric cancer, the presence of gastric cancer cells in the peritoneal cavity detected by cytologic examination, is a significant prognostic factor. A more sensitive, reverse transcriptase-polymerase chain reaction (RT-PCR) technique, amplifying carcinoembryonic antigen (CEA), was introduced as a new detection system, but produced some false-positive results. A search for other molecular markers is ongoing. METHODS Peritoneal washes were obtained from 195 patients with gastric carcinoma during surgery. Cytokeratin 20 (CK20) mRNA levels were quantified, in addition to those of CEA, using the LightCycler, and the feasibility of CK20 as a target was evaluated. RESULTS CK20 was limited, in terms of sensitivity, for detecting disseminated cancer cells (sensitivity, 63%; specificity, 91%; positive predictive value, 70%; and negative predictive value, 88%). Multimarker analysis was performed, in which samples positive for either CK20 or CEA mRNA were considered to be positive for cancer cells. Multivariate analysis identified the multimarker analysis as a significant independent prognostic determinant. CONCLUSION CK20 RT-PCR produced information that could add a significant impact to the knowledge obtained by CEA RT-PCR, although detection by CK20 alone was not sufficiently sensitive to replace CEA in the detection system.
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Affiliation(s)
- Yasuhiro Kodera
- Second Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
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Jansen M, Treutner KH, Jansen PL, Zuber S, Otto J, Tietze L, Schumpelick V. Inhibition of gastric cancer cell adhesion in nude mice by inraperitoneal phospholipids. World J Surg 2005; 29:708-14. [PMID: 15895297 DOI: 10.1007/s00268-005-7583-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Adhesion of tumor cells to mesothelial cells or extracellular matrix components is a pivotal step in developing peritoneal dissemination after gastric cancer. As phospholipids were found to reduce adhesion formation, especially at sites of peritoneal lesions, we assessed the inhibition of attachment of NUGC-4 gastric cancer cells by local treatment with phospholipids to the peritoneum in nude mice. Gastric cancer cells (1xl0(6)) suspended in either normal saline (controls) or phospholipid suspension 75 mg/kg body weight (PL75) or 150 mg/kg (PL150) were injected intraperitoneally into 90 female BALB/c nu/nu mice. The treatment groups were subdivided into animals with defined peritoneal lesions and animals without lesions. After 30 days the extent of peritoneal carcinosis and the Peritoneal Cancer Index were evaluated. Statistical analysis was performed with two factorial ANOVAs. The level of significance was adjusted according to Bonferrorni (alpha = 0.00278). During a 90-day observation period the survival rate was determined using the log rank test. After 30 days the intraperitoneal tumor volume was reduced by PL150 up to 0.6 ml (SEM 0.16) and 0.48 ml (SEM 0.09) in mice with peritoneal lesions compared to 0.9 ml (SEM 0.2) and 0.9 ml (SEM 0.1) in the control group (P = 0.04). The mean area of tumor adhesion amounted to 145 mm(2) (SEM 17) (P = 0.08) and 164 mm(2) (SEM 32.8) (P = 0.049) with peritoneal lesions after treatment with PL150 [controls: 216 mm(2) (SEM 28.5) and 245 mm(2) (SEM 29.3)]. The peritoneal cancer index was 16.4 (SEM 1.7) in the control group and 9 (SEM 1.68) with PL150 (P = 0.0002). In the subgroup with peritoneal lesions, the respective values were as follows: controls: 20.8 (SEM 0.85); PL 150:14.3 (SEM 1.07) (P = 0.0001). We found a prolonged survival rate after treatment with PL150. However, this effect was not significantly different to that seen in the control group. Treatment with PL75 had no significant influence. Phospholipids may be an efficacious and economic tool for reducing peritoneal tumor cell adhesion and consequently the development of peritoneal carcinosis after resection of gastric cancer.
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Affiliation(s)
- Marc Jansen
- Department of Surgery, University Clinic, RWTH Aachen Pauwelsstrasse 30, Aachen, 52057, Germany.
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Kim JC, Hong HK, Lee KH, Ka IH, Roh SA, Koo KH, Kim HC, Oh ST, Oh SJ, Kim JS, Park KC. Experimental radioimmunoguided surgery for peritoneal metastases of gastric cancer using anticarcinoembryonic antigen-specific T84.66 F(ab')2. J Cancer Res Clin Oncol 2005; 131:495-503. [PMID: 15887029 DOI: 10.1007/s00432-005-0680-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2004] [Accepted: 02/21/2005] [Indexed: 01/24/2023]
Abstract
PURPOSE In gastric cancer, peritoneal dissemination is the most frequent cause of the noncurative resection and recurrence after curative resection. We therefore evaluated the feasibility of radioimmunoguided surgery (RIGS) in the treatment of peritoneal metastases of gastric cancer and the use of anti-CEA-specific T84.66 F(ab')2 as an efficient immune agent. METHODS Two human gastric cancer cell lines, MKN45 and RF48, were intraperitoneally xenografted into nude mice, which were later injected with 125I-labeled T84.66 F(ab')2. Peritoneal tumors were localized by RIGS 5 days after antibody injection. The minimum number of cells detected by a gamma probe was assayed by in vitro tumor cell localization. RESULTS We observed 37 peritoneal metastases: 8 invisible (long diameter, <1 mm), 6 small (1- < 5 mm), and 23 large (> or =5 mm) tumors. The accuracy, sensitivity and specificity of RIGS in detecting peritoneal metastasis were 82% (69/84), 76% (28/37), and 87% (41/47), respectively. RIGS accuracy did not differ with respect to tumor diameter. Mean labeling indices over minimal and maximal normal counts were 6.1+/-1.2 (mean +/- SEM) and 4.7+/-1, respectively. Mean scores of CEA immunostaining and silver grains in tumors were significantly higher than those in the nontumor-bearing peritoneum (P < 0.001). There was a close correlation among radioactivity, immunostaining and microautoradiography (P < 0.001-0.005). We observed six false-positive and nine false-negatives which may have been due to high blood background and negative radioimmune reactivity, respectively. CONCLUSIONS 125I-labeled T84.66 F(ab')2 efficiently targeted peritoneally disseminated gastric cancer cells, suggesting that RIGS using this immune agent may accurately detect occult peritoneal metastases in patients with gastric cancer.
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Affiliation(s)
- Jin C Kim
- Department of Surgery, University of Ulsan College of Medicine and Asan Institute for Life Sciences, 388-1 Poongnap-2-Dong, Songpa-Ku, Seoul, 138-736, Korea.
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Jansen M, Treutner KH, Schmitz B, Otto J, Jansen PL, Neuss S, Schumpelick V. Phospholipids reduce gastric cancer cell adhesion to extracellular matrix in vitro. BMC Gastroenterol 2004; 4:33. [PMID: 15625005 PMCID: PMC544579 DOI: 10.1186/1471-230x-4-33] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2004] [Accepted: 12/29/2004] [Indexed: 12/04/2022] Open
Abstract
Background Nidation of floating tumour cells initiates peritoneal carcinosis and limits prognosis of gastro-intestinal tumours. Adhesion of tumour cells to extracellular matrix components is a pivotal step in developing peritoneal dissemination of intraabdominal malignancies. Since phospholipids efficaciously prevented peritoneal adhesion formation in numerous animal studies we investigated their capacity to reduce adhesions of gastric cancer cells to extracellular matrix components (ECM). Methods Human gastric cancer cells (NUGC-4, Japanese Cancer Research Resources Bank, Tokyo, Japan) were used in this study. Microtiter plates were coated with collagen IV (coll), laminin (ln) and fibronectin (fn). Non-specific protein binding of the coated wells was blocked by adding 1% (w/v) BSA (4°C, 12 h) and rinsing the wells with Hepes buffer. 50.000 tumour cells in 100 μl medium were seeded into each well. Beside the controls, phospholipids were added in concentrations of 0.05, 0.1, 0.5, 0.75 and 1.0/100 μl medium. After an incubation interval of 30 min, attached cells were fixed and stained with 0.1% (w/v) crystal violet. The dye was resuspended with 50 μl of 0.2% (v/v) Triton X-100 per well and colour yields were then measured by an ELISA reader at 590 nm. Optical density (OD) showed a linear relationship to the amount of cells and was corrected for dying of BSA/polystyrene without cells. Results The attachment of gastric cancer cells to collagen IV, laminin, and fibronectin could be significantly reduced up to 53% by phospholipid concentrations of 0.5 mg/100 μl and higher. Conclusion These results, within the scope of additional experimental studies on mice and rats which showed a significant reduction of peritoneal carcinosis, demonstrated the capacity of phospholipids in controlling abdominal nidation of tumour cells to ECM components. Lipid emulsions may be a beneficial adjunct in surgery of gastrointestinal malignancies.
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Affiliation(s)
- Marc Jansen
- Department of Surgery, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - Karl-Heinz Treutner
- Department of Surgery, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - Britta Schmitz
- Department of Surgery, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - Jens Otto
- Department of Surgery, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - Petra Lynen Jansen
- Interdisciplinary Centre of Clinical Research (IZKF) Biomat; University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - S Neuss
- Institute of Pathology, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
| | - Volker Schumpelick
- Department of Surgery, University Clinic, Pauwelsstr. 30, 52057 Aachen, Germany
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Ishii T, Fujiwara Y, Ohnaka S, Hayashi T, Taniguchi H, Takiguchi S, Yasuda T, Yano M, Monden M. Rapid genetic diagnosis with the transcription-reverse transcription concerted reaction system for cancer micrometastasis. Ann Surg Oncol 2004; 11:778-85. [PMID: 15289240 DOI: 10.1245/aso.2004.12.043] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Detection of cancer micrometastases is required for improvement of cancer therapy. The aim of this study was to establish a rapid and practical genetic assay to detect micrometastasis in gastric cancer and to assess its clinical significance with respect to prognosis. METHODS A novel RNA amplification system with transcription-reverse transcription concerted reaction (TRC) was introduced for quantitative detection of cancer-specific carcinoembryonic antigen messenger RNA. The sensitivity and quantitative aspects of the assay were assessed with the full-length carcinoembryonic antigen messenger RNA, a gastric cancer cell line (MKN-45), and metastatic lymph nodes obtained from patients with gastric cancer. Peritoneal lavage fluid specimens that were collected from gastric cancer surgery were subjected to the assay, and the clinical significance of the results was examined for prediction of recurrence and survival. RESULTS The quantification, sensitivity, and reproducibility of the assay with the TRC reaction were equal to those of quantitative reverse transcriptase-polymerase chain reaction with LightCycler. The most important advantages of the assay were its simplicity and rapidity. Molecular diagnosis of peritoneal lavage fluid by the TRC reaction significantly correlated with depth of invasion, peritoneal metastasis, clinical stage, overall survival, and peritoneal recurrence-free survival. CONCLUSIONS Molecular diagnosis of peritoneal lavage fluid with the TRC reaction could be a useful prognostic indicator for peritoneal recurrence and survival. Because the TRC reaction is more rapid and simpler than reverse transcriptase-polymerase chain reaction as a format for detecting RNA sequences, it may enhance the genetic diagnosis of cancer micrometastasis and may improve cancer therapy.
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Affiliation(s)
- Takaaki Ishii
- Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2 E2 Yamadaoka, Suita-City, Osaka 565-0871, Japan
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Jansen M, Treutner KH, Jansen PL, Otto J, Schmitz B, Mueller S, Weiss C, Tietze L, Schumpelick V. Phospholipids reduce the intraperitoneal adhesion of colonic tumor cells in rats and adhesion on extracellular matrix in vitro. Int J Colorectal Dis 2004; 19:525-32. [PMID: 15309464 DOI: 10.1007/s00384-004-0611-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2004] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To evaluate the influence of intraperitoneal treatment with phospholipids on the formation of peritoneal carcinosis after inoculation of colonic tumor cells in rats. The presence of tumor cells in the peritoneal cavity serves as a prognostic marker for postoperative survival after resection of gastrointestinal cancer. Intraperitoneal tumor cell attachment is a pivotal step in developing peritoneal carcinosis. Intraabdominal application of phospholipids resulted in a significant decrease of adhesion formation, especially at sites of peritoneal lesions. METHODS 2x10(6) colonic tumor cells (DHD/K12/TRb) were injected intraperitonely in female BD-IX rats. A total of 90 rats were divided into three groups with treatments of phospholipids at 75 mg/kg or 150 mg/kg bodyweight or sodium chloride at 0.9% in the control group. The treatment groups were subdivided into animals with defined peritoneal lesions and animals without lesions. After 30 days, the extent of peritoneal carcinosis was determined by measuring the tumor volume, the area of tumor attachment and the Peritoneal Cancer Index. Over a 90-day observation period, the survival rate was analyzed. In vitro, we examined the reduction of tumor cell adhesion on extracellular matrix components after treatment with phospholipids. Microtiter plates were coated with laminin, fibronectin or collagen IV for adhesion experiments. RESULTS In our study, we found a significant reduction of peritoneal dissemination with respect to all evaluation methods after treatment with phospholipids at 150 mg/kg in animals without peritoneal lesions. This could not be achieved using the lower concentration of phospholipids (75 mg/kg). In vitro, the maximum reductions of tumor cell adhesion by phospholipids compared with the control values for laminin and fibronectin were 46% and 37%, respectively, whereas for collagen IV the reduction was only 24% ( p<0.0001). CONCLUSIONS A new method of prevention of intraperitoneal tumor cell adhesion, possibly leading to a reduced incidence of peritoneal carcinosis after surgery of gastrointestinal tumors, is introduced.
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Affiliation(s)
- Marc Jansen
- Department of Surgery, University Clinic Aachen, Pauwelsstrasse 30, 52057 Aachen, Germany.
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Ueda K, Iwahashi M, Matsuura I, Nakamori M, Nakamura M, Ojima T, Naka T, Ishida K, Matsumoto K, Nakamura T, Yamaue H. Adenoviral-mediated gene transduction of the hepatocyte growth factor (HGF) antagonist, NK4, suppresses peritoneal metastases of gastric cancer in nude mice. Eur J Cancer 2004; 40:2135-42. [PMID: 15341989 DOI: 10.1016/j.ejca.2004.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2003] [Revised: 04/27/2004] [Accepted: 05/07/2004] [Indexed: 02/07/2023]
Abstract
The competitive inhibitory effects of NK4 (a specific hepatocyte growth factor (HGF)-antagonist) on the interaction between HGF and the c-Met/HGF receptor has been shown in HGF-mediated invasion of some distinct types of human cancer cells. Furthermore, NK4 has inhibitory effects on the angiogenic pathways driven by basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), as well as by HGF. In this study, to evaluate the therapeutic efficacy of adenoviral-mediated NK4 gene treatment, we employed animal models of peritoneal metastasis using two gastric cancer cell lines, the strongly c-Met expressing MKN45 cell line and the weakly c-Met-expressing cell line, TMK1. In both models, the total number and weight of peritoneal tumours per mouse and ascites treated early with AxCANK4 (administered 3 times 2, 7 and 12 days after the tumour inoculation) were significantly reduced compared with those treated with phosphate-buffered solution (PBS) and AxCALacZ (P < 0.05). In Factor-VIII-related-antigen-stained sections from peritoneal metastatic tumours, the inhibition of intratumour vessels was observed in tissues from tumours of MKN45 and TMK1 treated with AxCANK4. We also compared the therapeutic effect of early AxCANK4 treatment with that of late treatment (at 7, 12 and 17 days). Peritoneal metastases and ascites treated late with AxCANK4 showed less of an improvement than those treated early with AxCANK4 in both models. In addition, the inhibitory effect of cisplatin (CDDP) on peritoneal metastasis was significantly enhanced by AxCANK4, suggesting that the combination of intraperitoneal (i.p.) chemotherapy with NK4 gene therapy might be effective, even in cases of advanced peritoneal metastasis from gastric cancer. To conclude, these results show clearly that NK4 gene therapy inhibits peritoneal metastases from gastric cancer, regardless of the level of c-Met/HGF receptor expression in the tumour cells, and especially in the early stages of peritoneal metastasis.
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Affiliation(s)
- Kentaro Ueda
- Second Department of Surgery, School of Medicine, Wakayama Medical University, 811-1 Kimiidera, 641-8510, Japan
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