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Ramos MFKP, Pereira MA, Charruf AZ, Victor CR, Gregorio JVAM, Alban LBV, Moniz CMV, Zilberstein B, Mello ESD, Hoff PMG, Ribeiro Junior U, Dias AR. INTRAPERITONEAL CHEMOTHERAPY FOR GASTRIC CANCER WITH PERITONEAL CARCINOMATOSIS: STUDY PROTOCOL OF A PHASE II TRIAL. ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA : ABCD = BRAZILIAN ARCHIVES OF DIGESTIVE SURGERY 2023; 36:e1744. [PMID: 37466566 PMCID: PMC10356002 DOI: 10.1590/0102-672020230026e1744] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/26/2023] [Indexed: 07/20/2023]
Abstract
BACKGROUND Peritoneal carcinomatosis in gastric cancer is considered a fatal disease, without expectation of definitive cure. As systemic chemotherapy is not sufficient to contain the disease, a multimodal approach associating intraperitoneal chemotherapy with surgery may represent an alternative for these cases. AIMS The aim of this study was to investigate the role of intraperitoneal chemotherapy in stage IV gastric cancer patients with peritoneal metastasis. METHODS This study is a single institutional single-arm prospective clinical trial phase II (NCT05541146). Patients with the following inclusion criteria undergo implantation of a peritoneal catheter for intraperitoneal chemotherapy: Stage IV gastric adenocarcinoma; age 18-75 years; Peritoneal carcinomatosis with peritoneal cancer index<12; Eastern Cooperative Oncology Group 0/1; good clinical status; and lab exams within normal limits. The study protocol consists of four cycles of intraperitoneal chemotherapy with paclitaxel associated with systemic chemotherapy. After treatment, patients with peritoneal response assessed by staging laparoscopy undergo conversion gastrectomy. RESULTS The primary outcome is the rate of complete peritoneal response. Progression-free and overall survivals are other outcomes evaluated. The study started in July 2022, and patients will be screened for inclusion until 30 are enrolled. CONCLUSIONS Therapies for advanced gastric cancer patients have been evaluated in clinical trials but without success in patients with peritoneal metastasis. The treatment proposed in this trial can be promising, with easy catheter implantation and ambulatory intraperitoneal chemotherapy regime. Verifying the efficacy and safety of paclitaxel with systemic chemotherapy is an important progress that this study intends to investigate.
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Affiliation(s)
| | - Marina Alessandra Pereira
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Gastroenterology - São Paulo (SP), Brazil
| | - Amir Zeide Charruf
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Gastroenterology - São Paulo (SP), Brazil
| | - Carolina Ribeiro Victor
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Radiology and Oncology - São Paulo (SP), Brazil
| | | | - Luciana Bastos Valente Alban
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Radiology and Oncology - São Paulo (SP), Brazil
| | - Camila Motta Venchiarutti Moniz
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Radiology and Oncology - São Paulo (SP), Brazil
| | - Bruno Zilberstein
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Gastroenterology - São Paulo (SP), Brazil
| | - Evandro Sobroza de Mello
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Pathology - São Paulo (SP), Brazil
| | - Paulo Marcelo Gehm Hoff
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Radiology and Oncology - São Paulo (SP), Brazil
| | - Ulysses Ribeiro Junior
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Gastroenterology - São Paulo (SP), Brazil
| | - Andre Roncon Dias
- Universidade de São Paulo, Cancer Institute, Faculty of Medicine, Department of Gastroenterology - São Paulo (SP), Brazil
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Ouchi A, Kinoshita T, Nakanishi H, Komori K, Oshiro T, Yoshimura M, Fujita N, Hosoda W, Shimizu Y. PCR-based quantitative detection of intraperitoneal free cancer cells for predicting locoregional recurrence after rectal cancer resection. ANZ J Surg 2022; 92:794-800. [PMID: 35018696 DOI: 10.1111/ans.17436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Locoregional recurrence after curative resection remains an important issue in the treatment of colorectal cancer (CRC). The aim of the present study was to investigate the clinical significance of quantitative detection of intraperitoneal free cancer cells by a PCR-based method for predicting locoregional recurrence after CRC resection. METHOD A total of 114 patients with CRC were enrolled between March 2017 and December 2018, and 95 patients with Stage I-III CRC were analyzed. Peritoneal lavage fluid was collected before and after tumour resection and subjected to cytology and quantitative reverse transcription-PCR (qRT-PCR) with carcinoembryonic antigen (CEA) as a genetic marker. RESULTS 2.1% of patients had positive cytology after resection, whereas 9.5% had positive CEA qRT-PCR (PCR+) after resection. Eight of nine PCR+ patients after resection had tumours in the rectum. Fifteen (15.8%) patients developed recurrence during the follow-up period, including three with locoregional recurrence. One of 86 (1.2%) PCR- patients and 2 of 9 (22.2%) PCR+ patients after resection developed locoregional recurrence. Overall and in rectal cancer patients, the 3-year cumulative risk of locoregional recurrence was 25.0% and 28.6% for PCR+ patients, which is significantly higher than PCR- patients (1.3% and 0%, P < 0.001 and P = 0.001, respectively). CONCLUSION Intraperitoneal free cancer cells can serve as a sensitive predictor of locoregional recurrence after rectal cancer resection. qRT-PCR for CEA can be a suitable method for detecting intraperitoneal free cancer cells in peritoneal lavage fluid.
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Affiliation(s)
- Akira Ouchi
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Takashi Kinoshita
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Hayao Nakanishi
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Koji Komori
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Taihei Oshiro
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Mayumi Yoshimura
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Nao Fujita
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Waki Hosoda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
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Hu XY, Ling ZN, Hong LL, Yu QM, Li P, Ling ZQ. Circulating methylated THBS1 DNAs as a novel marker for predicting peritoneal dissemination in gastric cancer. J Clin Lab Anal 2021; 35:e23936. [PMID: 34390026 PMCID: PMC8418496 DOI: 10.1002/jcla.23936] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/13/2021] [Accepted: 07/23/2021] [Indexed: 12/27/2022] Open
Abstract
Objectives Thrombospondin 1 (THBS1) is known to play a key role in tumor metastasis, and aberrant DNA methylation is one of the mechanisms regulating THBS1. The present study investigated whether methylated THBS1 in circulating cell‐free DNA from preoperative peritoneal lavage fluid (PPLF) and peripheral blood could be used as a potential biomarker for predicting peritoneal dissemination in gastric cancer (GC) patients. Methods The status of THBS1 methylation was detected by quantitative methylation‐specific PCR (MSP) in tumor tissues, paired PPLF, and serum from 92 GC patients. The correlation between methylated THBS1 levels and peritoneal dissemination of GC was studied, and its diagnostic value for predicting peritoneal dissemination was clarified by the receiver operating characteristic (ROC) curve. Results Aberrant THBS1 methylation in tumor tissues was significantly higher than that in paracancerous normal tissues (p < 0.0001). No THBS1 methylation was found in 40 healthy controls, and partial methylation was detected in 3 of 48 patients with chronic non‐atrophic gastritis. The frequency of THBS1 methylation in pairing PPLF and serum from 92 GC patients was 52.2% (48/92) and 58.7% (54/92), respectively. The results of methylated THBS1 in pairing PPLF and serum were similar to those of tumor tissues. Aberrant THBS1 methylation in tumor tissues and pairing PPLF or serum was closely related to peritoneal dissemination, tumor progression, and poor prognosis (all p < 0.0001). Conclusion Circulating methylated THBS1 DNAs in PPLF/serum may predict peritoneal dissemination, a potential poor prognostic factor for GC patients.
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Affiliation(s)
- Xuan-Yu Hu
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.,Experimental Research Centre, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, China
| | - Zhe-Nan Ling
- Experimental Research Centre, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, China.,Department of Hepatobiliary & Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Shangcheng District, Hangzhou, China
| | - Lian-Lian Hong
- Experimental Research Centre, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, China
| | - Qi-Ming Yu
- Experimental Research Centre, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, China
| | - Pei Li
- Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Zhi-Qiang Ling
- Experimental Research Centre, Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Cancer Hospital of the University of Chinese Academy of Sciences, Gongshu District, Hangzhou, China
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Takebayashi K, Murata S, Kodama H, Kaida S, Yamaguchi T, Ishikawa K, Shimoji M, Miyake T, Ueki T, Kojima M, Iida H, Maehira H, Shimizu T, Tani M. Long-term prognosis of patients with cancer-related genes detected in postoperative peritoneal washings obtained during curative gastrectomy. Eur J Surg Oncol 2021; 48:177-182. [PMID: 34034940 DOI: 10.1016/j.ejso.2021.05.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 04/03/2021] [Accepted: 05/03/2021] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Cancer cells in intraoperative peritoneal washings (PW) indicate increased peritoneal recurrence. Detection of CEA or CK20 genes indicates poor prognosis. We assessed long-term prognosis of patients with amplification of cancer-related genes in PW obtained intraoperatively during curative gastric cancer surgery. METHODS PW was collected before and immediately after curative gastrectomy. CEA, CK20, TFF1, MUC2, and FABP1-mRNA were selected as marker genes for reverse transcription polymerase chain reaction. Peritoneal recurrence-free survival (PRFS) and overall survival (OS) after >7-year follow-up were examined using the Kaplan-Meier method. RESULTS Of 138 patients who underwent gastrectomy with negative cytological findings at laparotomy, 80 patients showed negative cancer-related gene amplification in preoperative PW. Fifty-eight patients were excluded due to positive gene amplification, which suggested presence of preoperative peritoneal cancer cells. The 80 patients had mRNA amplification in PW after surgery. Amplification of multiple and single cancer-related marker genes was observed in 38 and 21 patients; 21 cases had marker-negative results. Five-year PRFS was 69.1%, 95.2%, and 100% in multi-marker-positive, single marker-positive, and marker-negative cases, respectively. Multi-marker-positive patients had significantly worse PRFS than the other groups (p < 0.05). Multivariate analysis in the Cox proportional hazards model identified multi-marker-positivity as an independent prognostic factor for PRFS (hazard ratio, 7.6; 95% confidence interval, 1.07-62.63; p = 0.046), and multi-marker-positive patients had significantly worse OS than other groups (p < 0.01). CONCLUSION Multi-marker cancer-related gene amplification in PW is associated with worse prognosis in PRFS and OS even after a long follow-up; PRFS can be stratified by the number of genes amplified.
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Affiliation(s)
- Katsushi Takebayashi
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Satoshi Murata
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan; Cancer Center, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan.
| | - Hirokazu Kodama
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Sachiko Kaida
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tsuyoshi Yamaguchi
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Ken Ishikawa
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Miyuki Shimoji
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Toru Miyake
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tomoyuki Ueki
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Masatsugu Kojima
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Hiroya Iida
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Hiromitsu Maehira
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Tomoharu Shimizu
- Medical Safety Section, Shiga University of Medical Science Hospital, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
| | - Masaji Tani
- Department of Surgery, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga 520-2192, Japan
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Fujita K, Omori T, Hara H, Shinno N, Yamamoto M, Aoyama Y, Sugimura K, Kanemura T, Takeoka T, Yasui M, Matsuda C, Takahashi H, Wada H, Nishimura J, Haraguchi N, Hasegawa S, Nakai N, Asukai K, Mukai Y, Miyata H, Ohue M, Sakon M. Clinical importance of carcinoembryonic antigen messenger RNA level in peritoneal lavage fluids measured by transcription-reverse transcription concerted reaction for advanced gastric cancer in laparoscopic surgery. Surg Endosc 2021; 36:2514-2523. [PMID: 33999253 DOI: 10.1007/s00464-021-08539-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 04/30/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Transcription-reverse transcription concerted reaction (TRC) is recognized as a useful method for detecting free cancer cells in the peritoneal cavity and predicting peritoneal recurrence in patients with gastric cancer. Nonetheless, the clinical significance of TRC in laparoscopic surgery remains unclear. This study aimed to evaluate the clinical importance of carcinoembryonic antigen (CEA) messenger RNA (mRNA) level in peritoneal lavage fluids measured by TRC in laparoscopic surgery for locally advanced gastric cancer. METHODS We enrolled patients with locally advanced gastric cancer who underwent laparoscopic gastrectomy. Peritoneal lavage fluids were collected prior to gastrectomy, and the TRC method was employed to quantify CEA mRNA in peritoneal washes. Overall survival (OS), recurrence-free survival (RFS), and peritoneal recurrence-free survival (PRFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Adjusted Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) for CEA mRNA positivity. RESULTS A total of 100 patients were analyzed in this study. Overall, 22 patients (22%) exhibited CEA mRNA positivity in peritoneal lavage fluids, as measured by TRC. No significant association between CEA mRNA levels and clinicopathological characteristics was observed. Patients who were CEA mRNA-positive in peritoneal lavage fluids had significantly worse OS, RFS, and PRFS than those who were CEA mRNA-negative (p = 0.0059, p < 0.0001, and p = 0.0022, respectively). In the univariate Cox model, the HR for all-cause mortality in CEA mRNA-positive versus CEA mRNA-negative patients was 3.60 (95% CI, 1.33-9.55; p = 0.0129). Multivariate analysis revealed that CEA mRNA positivity was a significant independent factor for recurrence. CONCLUSIONS TRC enables the detection of free cancer cells in the peritoneal cavity and CEA mRNA levels can help predict the prognosis, even in laparoscopic gastrectomy.
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Affiliation(s)
- Kohei Fujita
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Takeshi Omori
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.
| | - Hisashi Hara
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Naoki Shinno
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masaaki Yamamoto
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Yoshimasa Aoyama
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Keijiro Sugimura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Takashi Kanemura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Tomohira Takeoka
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masayoshi Yasui
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Chu Matsuda
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Junichi Nishimura
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Naotsugu Haraguchi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Shinichiro Hasegawa
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Nozomu Nakai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Kei Asukai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Yosuke Mukai
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Hiroshi Miyata
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masayuki Ohue
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Masato Sakon
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan
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Harris MC, Cockbain AJ, McQuillan PW, Kanhere HA. Survey and literature review on the importance of peritoneal cytology in staging and treatment of gastric cancer: always wash it before you treat it. ANZ J Surg 2021; 91:13-18. [PMID: 33590628 DOI: 10.1111/ans.16295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 08/12/2020] [Accepted: 08/13/2020] [Indexed: 11/28/2022]
Affiliation(s)
- Mark C Harris
- Division of Surgery, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.,School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia
| | - Andrew J Cockbain
- Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Patrick W McQuillan
- Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Harsh A Kanhere
- Division of Surgery, The Queen Elizabeth Hospital, Adelaide, South Australia, Australia.,School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia.,Department of Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
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Predicting Peritoneal Dissemination of Gastric Cancer in the Era of Precision Medicine: Molecular Characterization and Biomarkers. Cancers (Basel) 2020; 12:cancers12082236. [PMID: 32785164 PMCID: PMC7547377 DOI: 10.3390/cancers12082236] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/29/2020] [Accepted: 08/05/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of worldwide cancer-related death. Being a highly heterogeneous disease, the current treatment of GC has been suboptimal due to the lack of subtype-dependent therapies. Peritoneal dissemination (PD) is a common pattern of GC metastasis associated with poor prognosis. Therefore, it is urgently necessary to identify patients at high risk of PD. PD is found to be associated with Lauren diffuse type GC. Molecular profiling of GC, especially diffuse type GC, has been utilized to identify molecular alterations and has given rise to various molecular classifications, shedding light on the underlying mechanism of PD and enabling identification of patients at higher PD risk. In addition, a series of diagnositc and prognostic biomarkers of PD from serum, peritoneal lavages and primary GCs have been reported. This comprehensive review summarizes findings on the multi-omic characteristics of diffuse type GC, the clinical significance of updating molecular classifications of GC in association with PD risk and research advances in PD-associated biomarkers.
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Nakanishi K, Kanda M, Umeda S, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Kodera Y. The levels of SYT13 and CEA mRNAs in peritoneal lavages predict the peritoneal recurrence of gastric cancer. Gastric Cancer 2019; 22:1143-1152. [PMID: 31055693 DOI: 10.1007/s10120-019-00967-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 04/25/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although peritoneal lavage cytology often serves as a sensitive method to detect free cancer cells in the abdominal cavity, some patients experience peritoneal recurrence despite negative cytology. The aim of this study was to evaluate mRNAs in peritoneal lavage fluid as potential markers for predicting the peritoneal recurrence of gastric cancer (GC). METHODS Peritoneal lavage fluid samples were obtained during surgery conducted on 187 patients with GC and from 30 patients with non-malignant disease (controls). The mRNA levels of nine candidate markers were quantified, and analysis of a receiver-operating characteristic curve compared their accuracies. The cutoff was defined as the highest value of the controls. RESULTS Synaptotagmin XIII (SYT13) and carcinoembryonic antigen (CEA) mRNA levels were analyzed further. SYT13 levels were significantly associated with shorter peritoneal recurrence-free survival (PRFS) and overall survival. Among patients with negative peritoneal lavage cytology, those positive for either SYT13 or CEA mRNA experienced significantly shorter peritoneal recurrence-free survival compared with those with negative fluid (hazards ratio [HR] 4.21, P = 0.0114; HR 3.53; P = 0.0426, respectively). Univariate analysis revealed that SYT13 and CEA mRNA levels were significant predictors of peritoneal recurrence. Positive levels of both SYT13 and CEA mRNA demonstrated the highest HR for peritoneal recurrence (HR 12.27, P = 0.0064). Multivariable analysis revealed that SYT13 positivity was a significant independent prognostic factor (HR 3.69; 95% confidence interval, 1.18-12.74; P = 0.0246). CONCLUSIONS Combined measurement of SYT13 and CEA mRNA levels in peritoneal lavage fluid could serve as a promising approach to predict peritoneal recurrence of GC.
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Affiliation(s)
- Koki Nakanishi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Shinichi Umeda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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9
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Yamaguchi T, Takashima A, Nagashima K, Makuuchi R, Aizawa M, Ohashi M, Tashiro K, Yamada T, Kinoshita T, Hata H, Kawachi Y, Kawabata R, Tsuji T, Hihara J, Sakamoto T, Fukagawa T, Katai H, Higuchi K, Boku N. Efficacy of Postoperative Chemotherapy After Resection that Leaves No Macroscopically Visible Disease of Gastric Cancer with Positive Peritoneal Lavage Cytology (CY1) or Localized Peritoneum Metastasis (P1a): A Multicenter Retrospective Study. Ann Surg Oncol 2019; 27:284-292. [PMID: 31535301 DOI: 10.1245/s10434-019-07697-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND Gastric cancer (GC) patients with positive peritoneal lavage cytology (CY1) and/or localized peritoneum metastasis (P1a) are defined as stage IV in the 15th edition of the Japanese Classification of Gastric Cancer. In Japan, the most common treatment for patients with CY1 and/or P1a is gastrectomy followed by postoperative chemotherapy. PATIENTS AND METHODS Subjects in this multi-institutional retrospective study were GC patients with CY1 and/or P1a who received surgical resection that leaves no macroscopically visible disease. Patients were selected from 34 institutions in Japan between 2007 and 2012. Selection criteria included adenocarcinoma, no distant metastasis except CY1 and P1a, and no prior treatment for GC before surgery. RESULTS Among 824 patients registered, 506 were identified as eligible, with a background of P0CY1, P1aCY0, or P1aCY1 (72.5%, 16.0%, and 11.5% of subjects, respectively). Sixty-two patients had not received postoperative chemotherapy (no-Cx), whereas 444 patients had received postoperative chemotherapy: S-1 monotherapy (S-1; n = 267, 52.7%), cisplatin plus S-1 (CS; n = 114, 22.5%), and others (n = 63, 12.6%). Overall survival (OS) was 29.5, 24.7, 25.4 and 9.9 months in the S-1, CS, 'others', and no-Cx groups, respectively [CS vs. S-1: hazard ratio (HR) 1.15, 95% confidence interval (CI) 0.89-1.50; p = 0.275]. In multivariate analysis, OS was similar between the S-1 and CS groups (CS vs. S-1: HR 1.19, 95% CI 0.92-1.55; p = 0.18). CONCLUSIONS Postoperative chemotherapy after gastrectomy that leaves no macroscopically visible disease may have some survival benefits for GC patients with CY1 and/or P1a. In contrast, S-1 plus cisplatin seems to have no additional benefit over S-1 treatment alone.
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Affiliation(s)
- Toshifumi Yamaguchi
- Cancer Chemotherapy Center and Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan.,Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Atsuo Takashima
- Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
| | - Kengo Nagashima
- Research Center for Medical and Health Data Science, The Institute of Statistical Mathematics, Tokyo, Japan
| | - Rie Makuuchi
- Division of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Masaki Aizawa
- Department of Gastroenterological Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Manabu Ohashi
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Tokyo, Japan
| | - Keitaro Tashiro
- Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan
| | - Tatsuya Yamada
- Department of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Takahiro Kinoshita
- Gastric Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroaki Hata
- Department of Surgery, National Hospital Organization Kyoto Medical Center, Kyoto, Japan
| | - Yasuyuki Kawachi
- Department of Surgery, Nagaoka Chuo General Hospital, Niigata, Japan
| | | | - Toshikatsu Tsuji
- Department of Gastroenterological Surgery, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Jun Hihara
- Department of Surgery, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - Takeshi Sakamoto
- Department of Gastroenterology, Hyogo Cancer Center, Hyogo, Japan
| | - Takeo Fukagawa
- Department of Surgery, Teikyo University Hospital, Tokyo, Japan
| | - Hitoshi Katai
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuhide Higuchi
- Cancer Chemotherapy Center and Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan
| | - Narikazu Boku
- Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan
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10
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Kim YJ, Chung WC, Choi S, Jung YD, Lee J, Chae SY, Jun KH, Chin HM. The Detection of Messenger RNA for Carcinoembryonic Antigen and Cytokeratin 20 in Peritoneal Washing Fluid in Patients with Advanced Gastric Cancer. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 69:220-225. [PMID: 28449423 DOI: 10.4166/kjg.2017.69.4.220] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Background/Aims Peritoneal micrometastasis is known to play an important role in the recurrence of gastric cancer. However, its effects remain equivocal. Herein, we examine the messenger RNA (mRNA) as tumor markers, carcinoembryonic antigen (CEA), and cytokeratin 20 (CK20), in peritoneal washing fluid. Moreover, we evaluate whether these results could predict the recurrence of gastric cancer following curative resection. Methods We prospectively enrolled 132 patients with gastric cancers, who had received an operation, between January 2010 and January 2013. The peritoneal lavage fluid was collected at the operation field and semi-quantitative PCR was performed using the primers for CEA and CK20. We excluded patients with stage IA (n=28) early gastric cancer, positive cytologic examination of peritoneal washings (n=7), and those who were lost during follow up (n=18). Results A total of 79 patients with gastric cancers were enrolled, and the mean follow-up period was 39.95±19.25 months (range, 5-72 months). According to the multivariate analysis, T4 stage at the initial diagnosis was significantly associated with recurrence. All cases of recurrence were CEA positive and 6 cases were CK20 positive. The positive and negative predictive values of CEA were 32.0% and 100%, respectively, whereas those of CK20 were 37.5% and 71.4%, respectively. Disease free survival of CK20-negative cases was 36.17±20.28 months and that of CK20-positive cases was 32.06±22.95 months (p=0.39). Conclusions It is unlikely that the real time polymerase chain reaction results of mRNA for CEA and CK20 in peritoneal washing fluid can predict recurrence. However, negative results can convince surgeons to perform curative R0 resection.
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Affiliation(s)
- Yeon Ji Kim
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Sooa Choi
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Yun Duk Jung
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Jaejun Lee
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Seung Yun Chae
- Department of Internal Medicine, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Kyong Hwa Jun
- Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
| | - Hyung Min Chin
- Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Suwon, Korea
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11
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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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12
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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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13
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Kelly KJ, Wong J, Gönen M, Allen P, Brennan M, Coit D, Fong Y. Human Trial of a Genetically Modified Herpes Simplex Virus for Rapid Detection of Positive Peritoneal Cytology in the Staging of Pancreatic Cancer. EBioMedicine 2016; 7:94-9. [PMID: 27322463 PMCID: PMC4909379 DOI: 10.1016/j.ebiom.2016.03.043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 02/29/2016] [Accepted: 03/29/2016] [Indexed: 01/16/2023] Open
Abstract
Introduction Patients with peritoneal dissemination of pancreatic adenocarcinoma do not benefit from surgical resection, but radiologic and cytologic detection of peritoneal cancer lack sensitivity. This trial sought to determine if an oncolytic virus may be used as a diagnostic agent to detect peritoneal cancer. Methods Peritoneal washings from patients with pancreatic adenocarcinoma were incubated with the enhanced green fluorescent protein (eGFP)-expressing oncolytic herpes simplex virus (HSV) NV1066. eGFP-positive or negative status was recorded for each specimen and compared to results obtained by conventional cytologic evaluation. These results were correlated with recurrence and survival for patients who underwent R0 resection. Results Of 82 patients entered in this trial, 12 (15%) had positive cytology and 50 (61%) had virally-mediated eGFP positive cells in peritoneal washings. All cytology-positive patients were also eGFP positive. HSV-mediated fluorescence detection had sensitivities of 94% and 100% for detection of any and peritoneal metastatic disease; respectively. Median recurrence free and disease specific survival were 6.5 and 18.3 months for eGFP positive patients, versus 12.2 and 36.2 months for eGFP negative patients (P = 0.01 and 0.19); respectively. Conclusions A genetically modified HSV can be used as a highly sensitive diagnostic agent for detection of micro-metastatic disease in patients with pancreatic adenocarcinoma and may improve patient selection for surgery.
Oncolytic virus-mediated fluorescence is a sensitive assay for detection of cancer cells in peritoneal fluid. Pancreatic cancer patients with eGFP-positive cells in peritoneal washings had a poor prognosis following surgery. Pancreatic cancer is an aggressive disease. Even with complete surgical removal of a pancreatic tumor, recurrence is common. Patients with microscopic spread of cancer cells into the abdomen, or peritoneum, do not benefit from surgery. Current methods of detection of this kind of spread are not very sensitive. This study utilized a virus that specifically infects cancer cells and expresses a green fluorescent protein within them to detect peritoneal disease. Viral fluorescence was more sensitive than standard methods for detecting peritoneal disease and may help to identify which patients with pancreas cancer will benefit from surgery.
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Affiliation(s)
- Kaitlyn J Kelly
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Joyce Wong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Mithat Gönen
- Department of Epidemiology and Statistics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Peter Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Murray Brennan
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Daniel Coit
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States
| | - Yuman Fong
- Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, United States.
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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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15
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Chae HD. Role of genetic detection in peritoneal washes with gastric carcinoma: The past, present and future. World J Gastrointest Oncol 2016; 8:289-296. [PMID: 26989464 PMCID: PMC4789614 DOI: 10.4251/wjgo.v8.i3.289] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/05/2015] [Accepted: 12/18/2015] [Indexed: 02/05/2023] Open
Abstract
The most frequent cause of treatment failure following surgery for gastric cancer is peritoneal dissemination, mainly caused by the seeding of free cancer cells from the primary gastric cancer, which is the most common type of spread. Unfortunately, there is no standard modality of intraperitoneal free cancer cells detection to predict peritoneal metastasis until now. We reviewed English literature in PubMed was done using the MeSH terms for gastric cancer, peritoneal wash, and reverse transcriptase polymerase chain reaction. All the articles were reviewed and core information was tabulated for reference. After a comprehensive review of all articles, the data was evaluated by clinical implication and predictive value of each marker for peritoneal recurrence. There are still many limitations to overcome before the genetic diagnosis for free cancer cells detection can be considered as routine assay. To make it a reliable diagnostic tool for detecting free cancer cells, the process and method of genetic detection with peritoneal washes should be standardized, and the development of simple diagnostic devices and easily available kits are necessary. Herein, we reviewed the past, present and future perspectives of the peritoneal lavage for the detection of intraperitoneal free cancer cells in patients with gastric cancer.
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16
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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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17
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Sica GS, Fiorani C, Stolfi C, Monteleone G, Candi E, Amelio I, Catani V, Sibio S, Divizia A, Tema G, Iaculli E, Gaspari AL. Peritoneal expression of Matrilysin helps identify early post-operative recurrence of colorectal cancer. Oncotarget 2015; 6:13402-13415. [PMID: 25596746 PMCID: PMC4537023 DOI: 10.18632/oncotarget.2830] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 11/27/2014] [Indexed: 12/20/2022] Open
Abstract
Recurrence of colorectal cancer (CRC) following a potentially curative resection is a challenging clinical problem. Matrix metalloproteinase-7 (MMP-7) is over-expressed by CRC cells and supposed to play a major role in CRC cell diffusion and metastasis. MMP-7 RNA expression was assessed by real-time PCR using specific primers in peritoneal washing fluid obtained during surgical procedure. After surgery, patients underwent a regular follow up for assessing recurrence. transcripts for MMP-7 were detected in 31/57 samples (54%). Patients were followed-up (range 20-48 months) for recurrence prevention. Recurrence was diagnosed in 6 out of 55 patients (11%) and two patients eventually died because of this. Notably, all the six patients who had relapsed were positive for MMP-7. Sensitivity and specificity of the test were 100% and 49% respectively. Data from patients have also been corroborated by computational approaches. Public available coloncarcinoma datasets have been employed to confirm MMP7 clinical impact on the disease. Interestingly, MMP-7 expression appeared correlated to Tgfb-1, and correlation of the two factors represented a poor prognostic factor. This study proposes positivity of MMP-7 in peritoneal cavity as a novel biomarker for predicting disease recurrence in patients with CRC.
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Affiliation(s)
- Giuseppe S. Sica
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
- European Society Degenerative Disease (ESDD). www.esdd.it
| | - Cristina Fiorani
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Carmine Stolfi
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Giovanni Monteleone
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Ivano Amelio
- Medical Research Council, Toxicology Unit, Leicester, UK
| | - Valeria Catani
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Simone Sibio
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Andrea Divizia
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Giorgia Tema
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Edoardo Iaculli
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
| | - Achille L. Gaspari
- Department of Experimental Medicine and Surgery, Tor Vergata University, Rome, Italy
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18
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Kano Y, Kosugi SI, Ishikawa T, Otani T, Muneoka Y, Sato Y, Hanyu T, Hirashima K, Bamba T, Wakai T. Prognostic significance of peritoneal lavage cytology at three cavities in patients with gastric cancer. Surgery 2015; 158:1581-9. [PMID: 25958064 DOI: 10.1016/j.surg.2015.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 03/15/2015] [Accepted: 04/05/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND We sought to determine the prognostic significance of intraoperative peritoneal lavage cytology (CY) at 3 different abdominal cavities and establish the optimal treatment for gastric cancer patients with positive peritoneal cytology (CY1). METHODS A total of 1,039 patients with primary gastric adenocarcinoma who underwent CY at 3 cavities (Douglas' pouch, left subphrenic cavity, and right subhepatic cavity) were enrolled; 116 (11%) patients had at least one positive cavity. We retrospectively analyzed the clinicopathologic characteristics and survival of these 116 patients with CY1. RESULTS Seventeen (15%) of the patients had negative cytology at Douglas' pouch but positive cytology at one or both of the other cavities. The 116 patients' overall 2-year survival rate was 22.9%, with the median survival time of 11 months. The overall 2-year survival rates for the patients with positive cytology at 1, 2, and 3 cavities were 41.9%, 35.8%, and 15%, with median survival times of 17, 18, and 9 months, respectively (P < .01). A multivariate analysis revealed that macroscopic type 4 tumor, R2 resection, lymph node metastasis, and postoperative chemotherapy were independent prognostic factors. Among the CY1 patients with type 4 tumors, there was no substantial difference in survival between the patients who underwent R1 or R2 resection, although the statistical power of this subgroup analysis was low. CONCLUSION CY at 3 cavities might be a useful method to decrease the false-negative rate. Palliative gastrectomy for CY1 patients with type 4 tumors is still controversial.
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Affiliation(s)
- Yosuke Kano
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shin-ichi Kosugi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Takashi Ishikawa
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takahiro Otani
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yusuke Muneoka
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yu Sato
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takaaki Hanyu
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kotaro Hirashima
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Takeo Bamba
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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Futsukaichi T, Etoh T, Nakajima K, Daa T, Shiroshita H, Shiraishi N, Kitano S, Inomata M. Decreased expression of Bauhinia purpurea lectin is a predictor of gastric cancer recurrence. Surg Today 2015; 45:1299-306. [PMID: 25753302 DOI: 10.1007/s00595-015-1127-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 12/21/2014] [Indexed: 02/06/2023]
Abstract
PURPOSE Molecular markers as indicators for gastric cancer recurrence are urgently required. The aim of this study was to identify lectins that can be used to predict gastric cancer recurrence after gastrectomy. METHODS We created lectin expression profiles by microarray analysis for 60 patients, who underwent surgery for gastric cancer at the Oita University Hospital between January, 2005 and December, 2007. Lectin expression and clinicopathological factors in patients who suffered gastric cancer recurrence and those who did not were compared by univariate and multivariate analyses. RESULTS Thirteen lectins showed a significant increase in binding to cancer tissues, whereas 11 lectins showed a significant decrease in binding to cancer tissues, when compared with binding to normal epithelia. Multivariate analysis revealed that lymph node metastasis and low Bauhinia purpurea lectin (BPL)-binding signals were independent predictive factors for recurrence. All patients with low BPL expression had significantly worse relapse-free survival than those with high BPL expression. CONCLUSIONS Our results using a novel lectin microarray system provide the first solid evidence that BPL expression is a predictor of gastric cancer recurrence.
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Affiliation(s)
- Takuro Futsukaichi
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita, 879-5593, Japan.
| | - Tsuyoshi Etoh
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita, 879-5593, Japan.
| | - Kentaro Nakajima
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Tsutomu Daa
- Department of Diagnostic Pathology, Oita University Faculty of Medicine, Oita, Japan
| | - Hidefumi Shiroshita
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita, 879-5593, Japan
| | - Norio Shiraishi
- Center for Community Medicine, Oita University Faculty of Medicine, Oita, Japan
| | | | - Masafumi Inomata
- Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Hasama-machi, Yufu, Oita, 879-5593, Japan
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Nakabayashi K, Uraoka T, Shibuya M, Matsuura N, Tsujimoto M. Rapid detection of CEA mRNA in peritoneal washes using One-Step Nucleic acid Amplification (OSNA®) for gastric cancer patients. Clin Chim Acta 2015; 439:137-42. [DOI: 10.1016/j.cca.2014.10.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Revised: 09/29/2014] [Accepted: 10/10/2014] [Indexed: 01/12/2023]
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Zhao P, Ding Z, Tang L, Zhou X. Preliminary investigation of intraperitoneal raltitrexed in patients with gastric cancer. World J Surg Oncol 2014; 12:403. [PMID: 25547003 PMCID: PMC4396911 DOI: 10.1186/1477-7819-12-403] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 12/05/2014] [Indexed: 12/12/2022] Open
Abstract
Background Peritoneal implantation metastasis of gastric cancer is the major reason for cancer recurrence after radical operations. As a new chemotherapeutic agent, raltitrexed has been widely used in intravenous chemotherapy for many kinds of cancers. However, no study has reported the efficacy and safety of raltitrexed in intraperitoneal chemotherapy. This study aimed to explore the safety of intraperitoneal chemotherapy with raltitrexed during gastric cancer operation compared to normal saline (NS) rinsing of the abdominal cavity. Methods In this prospective study, 91 gastric cancer patients undergoing surgery and reconstruction were consecutively enrolled and randomly assigned into two groups. Raltitrexed in NS (500 ml) was injected into the abdominopelvic cavity for the patients in the RT group (n = 48), while for the patients in the group NS (n = 43), only NS (500 ml) was injected. The postoperative complications, gas passage time, and adverse effects, according to NCI-CTCAE v3.0, were compared between the two groups. Results There were no significant differences in age, sex, cancer pathological type, clinical stage or operation method between the two groups (all P >0.05). No significant difference was observed in adverse effects and postoperative complications between the two groups (all P >0.05). No significant change was found in the levels of red blood cells, white blood cells, platelets, lactate dehydrogenase, blood urea nitrogen, and alanine aminotransferase before and after the operation for both groups (all P >0.05). All adverse events were mild or moderate by NCI-CTCAE v3.0 (National Cancer Institute common terminology criteria for adverse events) grade. Conclusions The findings of the present study demonstrate that intraperitoneal chemotherapy with raltitrexed after gastric cancer operation is safe and could be used for patients.
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Affiliation(s)
- Ping Zhao
- Division of Gastrointestinal Surgery, Department of abdominal Surgery, Sichuan Cancer Hospital, No.55 of Renmin South Rd., Chengdu, 610041, Sichuan Province, China.
| | - Zhi Ding
- Division of Gastrointestinal Surgery, Department of abdominal Surgery, Sichuan Cancer Hospital, No.55 of Renmin South Rd., Chengdu, 610041, Sichuan Province, China.
| | - Lingchao Tang
- Division of Gastrointestinal Surgery, Department of abdominal Surgery, Sichuan Cancer Hospital, No.55 of Renmin South Rd., Chengdu, 610041, Sichuan Province, China.
| | - Xiang Zhou
- Division of Gastrointestinal Surgery, Department of abdominal Surgery, Sichuan Cancer Hospital, No.55 of Renmin South Rd., Chengdu, 610041, Sichuan Province, China.
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22
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Kagawa S, Shigeyasu K, Ishida M, Watanabe M, Tazawa H, Nagasaka T, Shirakawa Y, Fujiwara T. Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients. World J Gastroenterol 2014; 20:17796-17803. [PMID: 25548478 PMCID: PMC4273130 DOI: 10.3748/wjg.v20.i47.17796] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2014] [Revised: 06/07/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future.
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23
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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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Yabusaki N, Yamada S, Murai T, Kanda M, Kobayashi D, Tanaka C, Fujii T, Nakayama G, Sugimoto H, Koike M, Nomoto S, Fujiwara M, Kodera Y. Clinical significance of zinc-finger E-box binding homeobox 1 mRNA levels in peritoneal washing for gastric cancer. Mol Clin Oncol 2014; 3:435-441. [PMID: 25798282 DOI: 10.3892/mco.2014.462] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2014] [Accepted: 11/10/2014] [Indexed: 12/20/2022] Open
Abstract
Zinc-finger E-box binding homeobox 1 (ZEB1) is an important regulator of epithelial-to-mesenchymal transition and is associated with various types of metastasis. Gastric cancer patients often develop peritoneal carcinomatosis, of which the detection of free cancer cells in the peritoneal washes is an important predictor. We analyzed the correlation of ZEB1 mRNA levels in the peritoneal washing (pZEB1) with clinicopathological variables and survival in 107 gastric cancer patients who underwent surgery and peritoneal washing cytology. Reverse transcription-polymerase chain reaction was performed to quantify pZEB1. The patients were classified into the pZEB1High (n=27) and the pZEB1Low (n=80) groups based on their pZEB1 expression. pZEB1 was statistically correlated with pathological T stage (P=0.03) and vascular involvement (P=0.03). At 5 years, the disease-specific survival was 36.4% for the pZEB1High group and 64.7% for the pZEB1Low group (P=0.02), whereas the disease-free survival rate was 46.9% for the pZEB1High group and 83.0% for the pZEB1Low group (P=0.03). When subclassified into 4 categories based on washing cytology and pZEB1, survival was significantly lower in the pZEB1High compared to the pZEB1Low group (cytology -negative group, P=0.01; cytology -positive group, P=0.13). Therefore, pZEB1 may add valuable information to conventional peritoneal washing cytology as a prognostic determinant in gastric cancer.
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Affiliation(s)
- Norimitsu Yabusaki
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Toshifumi Murai
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Shuji Nomoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8550, 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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Circulating methylated MINT2 promoter DNA is a potential poor prognostic factor in gastric cancer. Dig Dis Sci 2014; 59:1160-8. [PMID: 24385013 DOI: 10.1007/s10620-013-3007-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Accepted: 12/17/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Aberrant DNA methylation has been shown to be associated with the growth, development, metastasis, and prognosis of tumors. Methylated DNAs may be suitable biomarkers for cancer patients. Here, we investigated whether circulating methylated MINT2 DNAs represent a potential poor prognostic factor in gastric cancer (GC). METHODS MINT2 methylation was detected by real-time methylation-specific PCR in tumor tissues, pairing preoperative peritoneal lavage fluid (PPLF) and blood from 92 GC patients. The theory meaning and clinical practicality value of MINT2 methylation in different specimens were analyzed. RESULTS The methylation status of the MINT2 gene was found to be significantly higher in tumor tissues (44.6%, 41/92) than in adjacent normal tissues (3.3%, 3/92). No MINT2 methylation was found in healthy controls, and partial MINT2 methylation was observed in three (6.25%, 3/48) patients with chronic atrophic gastritis. The frequency of MINT2 methylation in pairing PPLF and blood samples from 92 GC patients was 40.2% (37/92) and 39.1% (36/92), respectively. Methylated MINT2 in tumor tissues, pairing PPLF, and blood samples were very approximate. Aberrant MINT2 methylation in tumor tissues and pairing PPLF or blood samples were closely related to peritoneal dissemination, tumor progression, and poor prognosis (all P < 0.0001). CONCLUSIONS Aberrant MINT2 methylation in PPLF/blood may predict peritoneal micrometastasis for GC patients, which is a potential poor prognostic factor in GC.
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Takebayashi K, Murata S, Yamamoto H, Ishida M, Yamaguchi T, Kojima M, Shimizu T, Shiomi H, Sonoda H, Naka S, Mekata E, Okabe H, Tani T. Surgery-induced peritoneal cancer cells in patients who have undergone curative gastrectomy for gastric cancer. Ann Surg Oncol 2014; 21:1991-7. [PMID: 24499832 DOI: 10.1245/s10434-014-3525-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Some patients who undergo curative gastrectomy with lymph node dissection (LND) for gastric cancer (GC) show subsequent peritoneal metastasis. The source of these metastatic cells remains unclear. METHODS Curative gastrectomy with LND was performed in 102 patients with GC. Peritoneal washing was collected before and after gastrectomy. Cytology, reverse transcription-polymerase chain reaction, and cell culture were used to determine the presence of cancer cells. The proliferative potential of tumor cells was evaluated using Ki-67 staining. Tumorigenic capacity was assessed by cell injection into the peritoneal cavity of NOD/ShiJic-scid mice. Peritoneal recurrence-free survival (RFS) and peritoneal recurrence rate (RR) were examined to determine the clinical relevance of detected cancer cells. RESULTS Of 102 peritoneal washing samples obtained before gastrectomy, 57 showed no CEA or CK20 mRNA amplification. After gastrectomy, CEA or CK20 mRNA was detected in 35 of these 57 samples, and viable cancer cells were identified in 24. The viable cancer cells in all 24 cases showed Ki-67 positivity, indicating proliferative activity. Cultured viable cancer cells generated peritoneal nodules after spilling over the peritoneal cavity in NOD/ShiJic-scid mice in 4 cases. The peritoneal RFS of patients with CEA or CK20 mRNA amplification after gastrectomy was significantly poorer than that of patients with negative amplification (p < .05). The 24 patients with viable cancer cells in the peritoneal cavity after gastrectomy showed higher peritoneal RR than those without them (p = .033). CONCLUSIONS Viable tumorigenic cancer cells spilled into the peritoneal cavity during surgery, indicating that surgery induces peritoneal metastasis.
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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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30
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Atanackovic D, Reinhard H, Meyer S, Spöck S, Grob T, Luetkens T, Yousef S, Cao Y, Hildebrandt Y, Templin J, Bartels K, Lajmi N, Stoiber H, Kröger N, Atz J, Seimetz D, Izbicki JR, Bokemeyer C. The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting. Hum Vaccin Immunother 2013; 9:2533-42. [PMID: 23955093 DOI: 10.4161/hv.26065] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Patients with gastric cancer benefit from perioperative chemotherapy, however, treatment is toxic and many patients will relapse. The trifunctional antibody catumaxomab targets EpCAM on tumor cells, CD3 on T cells, and the Fcγ-receptor of antigen-presenting cells. While in Europe catumaxomab is approved for treating malignant ascites, it has not been investigated in the perioperative setting and its exact immunological mode of action is unclear. METHODS In our study, gastric cancer patients received neoadjuvant platinum-based chemotherapy, one intraoperative application of catumaxomab, and 4 postoperative doses of intraperitoneal catumaxomab. Immunomonitoring was performed in 6 patients before surgery, after completion of catumaxomab treatment, and one month later. RESULTS Intraperitoneal application of catumaxomab caused an increased expression of activation markers on the patients' T cells. This was accompanied by a transient decrease in numbers of CXCR3(+) effector T cells with a T-helper (Th)-1 phenotype in the peripheral blood. All patients evidenced pre-existing EpCAM-specific CD4(+) and/or CD8(+) T cells. While these cells transiently disappeared from the blood stream after intraperitoneal application of catumaxomab, we detected increased numbers of peripheral EpCAM-specific cells and a modified EpCAM-specific T-cell repertoire 4 weeks after completion of treatment. Finally, catumaxomab also amplified humoral immunity to tumor antigens other than EpCAM. CONCLUSIONS Our findings suggest that catumaxomab exerts its clinical effects by (1) activating peripheral T cells, (2) redistributing effector T cells from the blood into peripheral tissues, (3) expanding and shaping of the pre-existing EpCAM-specific T-cell repertoire, and (4) spreading of anti-tumor immunity to different tumor antigens.
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Affiliation(s)
- Djordje Atanackovic
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Henrike Reinhard
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Sabrina Meyer
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Stefanie Spöck
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Tobias Grob
- Institute for Pathology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Tim Luetkens
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Sara Yousef
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Yanran Cao
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - York Hildebrandt
- Department of Stem Cell Transplantation; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Julia Templin
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Katrin Bartels
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Nesrine Lajmi
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Heribert Stoiber
- Division of Virology; Medical University IBK; Innsbruck, Austria
| | - Nicolaus Kröger
- Department of Stem Cell Transplantation; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | | | | | - Jakob R Izbicki
- Department of General, Visceral, and Thoracic Surgery; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Internal Medicine II; Oncology/Hematology/Bone Marrow Transplantation with the section Pneumology; University Medical Center Hamburg-Eppendorf; Hamburg, Germany
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An isolation technique to prevent the spread of tumor cells during radical gastrectomy for gastric carcinoma located on the anterior wall of the gastric antrum. Eur J Surg Oncol 2013; 39:1136-43. [PMID: 23916474 DOI: 10.1016/j.ejso.2013.07.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 06/03/2013] [Accepted: 07/03/2013] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE To report an isolation technique for reducing the spread of tumor cells during radical gastrectomy for lesions located on the anterior wall of the gastric antrum. METHODS The isolation technique involves using linear cutting staplers and a waterproof membrane to completely "block" and isolate the area to be resected. Blood samples from the portal vein and peritoneal wash samples were obtained immediately after laparotomy and during surgical resection. RT-PCR was used to determine levels of carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20). Carbon nanoparticles were injected into the subserosa of the blocked region before resection to determine lymph flow out of the region. RESULTS A total of 76 patients (median age, 59 years; range, 22-73 years), with tumors on the anterior wall of the gastric antrum were included (blocking group, n = 40; non-blocking group, n = 36). In the blocking group, the carbon nanoparticles did not flow beyond the blocking line. There were no significant differences between the groups in CEA or CK20 mRNA levels in portal vein blood or peritoneal wash fluid immediately after laparotomy. CEA and CK20 levels were significantly lower in portal vein blood in the blocking group during tumor resection. During a median follow-up of 30 months, the incidence of metastasis or recurrence in the blocking group was lower than the non-blocking group, although it did not reach statistical significance (17.9% vs. 25.0%, respectively). CONCLUSION The blocking technique can reduce hematogenous and lymphatic spread of tumor cells into the systemic circulation, and may prevent metastasis or recurrence after radical gastrectomy for gastric carcinoma.
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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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Hiraki M, Kitajima Y, Sato S, Nakamura J, Hashiguchi K, Noshiro H, Miyazaki K. Aberrant gene methylation in the peritoneal fluid is a risk factor predicting peritoneal recurrence in gastric cancer. World J Gastroenterol 2010; 16:330-8. [PMID: 20082478 PMCID: PMC2807953 DOI: 10.3748/wjg.v16.i3.330] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [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
AIM: To investigate whether gene methylation in the peritoneal fluid (PF) predicts peritoneal recurrence in gastric cancer patients.
METHODS: The gene methylation of CHFR (checkpoint with forkhead and ring finger domains), p16, RUNX3 (runt-related transcription factor 3), E-cadherin, hMLH1 (mutL homolog 1), ABCG2 (ATP-binding cassette, sub-family G, member 2) and BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) were analyzed in 80 specimens of PF by quantitative methylation-specific polymerase chain reaction (PCR). Eighty patients were divided into 3 groups; Group A (n = 35): the depth of cancer invasion was less than the muscularis propria; Group B (n = 31): the depth of cancer invasion was beyond the muscularis propria. Both group A and B were diagnosed as no cancer cells in peritoneal cytology and histology; Group C (n = 14): disseminated nodule was histologically diagnosed or cancer cells were cytologically defined in the peritoneal cavity.
RESULTS: The positive rates of methylation in CHFR, E-cadherin and BNIP3 were significantly different among the 3 groups and increased in order of group A, B and C (0%, 0% and 21% in CHFR, P < 0.05; 20%, 45% and 50% in E-cadherin, P < 0.05; 26%, 35% and 71% in BNIP3, P < 0.05). In addition, the multigene methylation rate among CHFR, E-cadherin and BNIP3 was correlated with group A, B and C (9%, 19% and 57%, P < 0.001). Moreover, the prognosis was analyzed in group B, excluding 3 patients who underwent a non-curative resection. Two of the 5 patients with multigene methylation showed peritoneal recurrence after surgery, while those without or with a single gene methylation did not experience recurrence (P < 0.05).
CONCLUSION: This study suggested that gene methylation in the PF could detect occult neoplastic cells in the peritoneum and might be a risk factor for peritoneal metastasis.
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Homma Y, Ushida S, Yamada M, Kobayashi H, Suzuki K. Positive peritoneal washing cytology in multiple cavities can predict poor prognosis of advanced gastric cancer patients. Ann Surg Oncol 2009; 17:455-60. [PMID: 19847567 DOI: 10.1245/s10434-009-0764-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2009] [Indexed: 01/02/2023]
Abstract
BACKGROUND Positive peritoneal washing cytology (PWC) has been reported to be a poor prognostic factor for gastric cancer. Japanese gastric cancer classifications recommend PWC in Douglas' pouch for advanced gastric cancer. However, the sensitivity of PWC is relatively low. The goal of this study was to investigate whether PWC in multiple cavities increases its sensitivity to predict prognosis. METHODS Between January 1996 and December 2006, a series of 992 patients with gastric cancer underwent D2 gastrectomy with intraoperative PWC. Of the 992 patients, 62 patients had positive PWC. PWC was conducted in four cavities (left subphrenic cavity, right subhepatic cavity, Douglas' pouch, and inside the omental bursa). The 62 patients were retrospectively analyzed for their background and survival. RESULTS Eleven (17.7%) patients had negative PWC in Douglas' pouch but were positive in the other cavities. The 62 patients were classified into two groups according to the number of positive PWC cavities: 20 patients with one or two and 42 patients with three or four positive PWC cavities. No significant difference in clinicopathological features was observed between these two groups. However, the overall and progression-free survival rates of patients with one or two positive PWC cavities were significantly higher than those for patients with three or more positive PWC cavities. CONCLUSION PWC in multiple cavities was more sensitive than only in one cavity. The number of positive cavities may indicate the grade of tumor spread in the peritoneum and predict the prognosis of patients with positive PWC.
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Affiliation(s)
- Yoichiro Homma
- Department of Gastrointestinal Surgery, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
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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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Shao YS, Peng KQ, Zhang YT, Wu WL, Zhao JG. Histologic detection and significance of distant occult peritoneal metastasis of gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2008; 16:862-868. [DOI: 10.11569/wcjd.v16.i8.862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [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
AIM: To analyze the incidence rate and relative factors of distant occult peritoneal metastasis (DOMP) of gastric carcinoma as well as their influences on prognosis.
METHODS: Fifty-eight patients with gastric carcinoma undergoing radical surgery in our hospital from January 2002 to December 2003 were selected, and distant metastasis was not found by preoperative imaging examination and routine intraoperative physical exploration. Before closing abdomen in operation, two slices of peritoneum from each side of Tau's cavity were cut for HE and cytokeratin immunohistochemical staining. The gender, age of patients, tumor location, size, invasion depth, differentiation degree, Laurén classification and lymph lode metastasis were compared between the DOPM and non-DOMP cases. Logistic multivariable regression analysis was used to distinguish whether the above variables are independent relative factors for DOMP.
RESULTS: Among the 58 cases, there were 12 cases with DOMP, accounting for 20.7%. Single factor analysis showed that DOMP is associated with the gender of patients, tumor size, invasion depth, Laurén classification (diffusing class) and lymph node metastasis, but had nothing to do with the age patients, tumor location and differentiation degree. Logistic multivariable regression analysis showed that the independent relative factors of DOMP were Laurén classification (diffusing class) and tumor size, but not the gender, age of patients, tumor location, invasion depth, differentiation degree and lymph node metastasis. Among 58 cases, the 5-year survival rate of patients was 100% in stageⅠ and Ⅱ, 94.1% in stage Ⅲ and 24.7% in stage Ⅳ (P < 0.001). The 5-year survival rate of DOMP patients was 30.3%, which was similar to that of the stage-N3 patients (22.1%), but significantly different from that of the stage-Ⅲ patients (P < 0.001).
CONCLUSION: DOMP occurs frequently in gastric carcinoma, so routine detection for DOMP should be applied to in patients with advanced gastric carcinoma and diffusing classification (Laurén classification).
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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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Dalal KM, Woo Y, Galanis C, Gonen M, Tang L, Allen P, DeMatteo R, Fong Y, Coit DG. Detection of micrometastases in peritoneal washings of pancreatic cancer patients by the reverse transcriptase polymerase chain reaction. J Gastrointest Surg 2007; 11:1598-605; discussion 1605-6. [PMID: 17879123 DOI: 10.1007/s11605-007-0283-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2007] [Accepted: 07/29/2007] [Indexed: 01/31/2023]
Abstract
OBJECTIVE Pancreatic cancer patients with positive (+) peritoneal cytology have a prognosis similar to stage IV patients. We studied the ability of quantitative real time-polymerase chain reaction (RT-PCR) to detect micrometastases in patients undergoing staging laparoscopy. METHODS Peritoneal washes were obtained prospectively from 35 consecutive patients with pancreatic adenocarcinoma undergoing staging laparoscopy and 16 patients undergoing laparoscopy for benign disease. Each sample was assessed by cytologic examination and RT-PCR analysis for tumor markers: CEA, CK7, Kras2, and MUC1. Markers and their combinations were evaluated on the basis of their deviance from the ideal marker. RESULTS Pathologic stages for pancreatic cancer patients were: 1A-1 (3%), IB-1 (3%), IIA-5 (15%), IIB-13 (38%), III-5 (15%), IV-9 (26%). Eight patients were cytology (+) and stages IIA-1, IIB-2, IV-5. Twenty-five patients were RT-PCR (+). The optimal threshold for cycle amplification was 35 based on a receiver operating characteristic curve. CEA had the best profile of sensitivity, specificity, PPV, NPV, and the smallest deviance. CONCLUSION RT-PCR using a panel of tumor markers, including CEA, was comparable in sensitivity, specificity, PPV, and NPV to cytology. RT-PCR could represent a more sensitive method for detection of subclinical peritoneal tumor dissemination; this may be useful in patient selection for operative management and clinical trials.
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Affiliation(s)
- Kimberly Moore Dalal
- Department of Surgery, David Grant U.S. Air Force Medical Center, Travis AFB, CA, USA
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Hara M, Nakanishi H, Jun Q, Kanemitsu Y, Ito S, Mochizuki Y, Yamamura Y, Kodera Y, Tatematsu M, Hirai T, Kato T. Comparative analysis of intraperitoneal minimal free cancer cells between colorectal and gastric cancer patients using quantitative RT-PCR: possible reason for rare peritoneal recurrence in colorectal cancer. Clin Exp Metastasis 2007; 24:179-89. [PMID: 17487561 DOI: 10.1007/s10585-007-9067-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2006] [Accepted: 03/09/2007] [Indexed: 01/16/2023]
Abstract
Peritoneal recurrence has a much lower incidence in colorectal cancer (CRC) patients than gastric cancer (GC) patients. The aim of this study is to clarify the reason for the rare peritoneal recurrence in CRC as compared with GC. The incidence and the abundance of free tumor cells in the peritoneal lavages from 102 CRC and 126 GC patients who underwent curative surgery were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) with carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) as genetic markers. Prognostic significance of CEA and CK20 mRNA was also compared between CRC and GC after 2 years of follow-up by Kaplan-Meyer method with overall and peritoneal recurrence-free survival as endpoints. Positivity rate and average values of CEA and CK20 mRNA in peritoneal lavages of CRC patients, which are correlated to the depth of tumor invasion (pT category), were essentially the same as those of GC cases. Overall survival was significantly (marginally) worse in CEA mRNA (CK20 mRNA)-positive CRC patients than negatives like GC. However, peritoneal recurrence-free survival was not different between CEA (CK20) mRNA-positive and -negative CRC patients, in quite contrast to GC cases. Multivariate analysis showed that CEA mRNA was an independent prognostic factor for overall survival in GC patients, but not in CRC patients. These results suggest that the rare peritoneal recurrence in CRC patients is not due to the low incidence or the small number of intraperitoneal free cancer cells, but more likely reflects due to the low-peritoneal metastatic potential of CRC cells.
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Affiliation(s)
- Masayasu Hara
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan
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Yamamura Y, Ito S, Mochizuki Y, Nakanishi H, Tatematsu M, Kodera Y. Distribution of free cancer cells in the abdominal cavity suggests limitations of bursectomy as an essential component of radical surgery for gastric carcinoma. Gastric Cancer 2007; 10:24-8. [PMID: 17334714 DOI: 10.1007/s10120-006-0404-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2006] [Accepted: 10/13/2006] [Indexed: 02/07/2023]
Abstract
BACKGROUND Bursectomy, which has been performed so as to resect peritoneal deposits disseminated within the omental bursa, is considered as an essential component of radical surgery for gastric carcinoma in Japan. Bursectomy has also been described in the Japanese Treatment Guidelines for Gastric Carcinoma as a mandatory procedure for the treatment of serosa-positive cancer. However, no evidence to support the prognostic significance of this procedure has been reported to date. METHODS Cytologic examination and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of the peritoneal washes obtained from the Douglas pouch, left subphrenic cavity, and inside the omental bursa were performed for 136 patients who underwent potentially curative surgery for gastric carcinoma. RESULTS Carcinoembryonic antigen (CEA) or cytokeratin (CK) 20 mRNA was detected in one or more samples from the three different sites of peritoneal washes in 43 of the 136 patients. In 14 patients, the mRNAs were detected in samples obtained from the bursa omentalis (10.3% of all patients and 32.6% of patients with positive RT-PCR results). In 12 of these 14 patients, the mRNAs were also detected in samples taken from either or both of the remaining two sites. Only in the 2 other patients was the sample only from inside the omental bursa positive for CEA. CONCLUSION It is unlikely that viable cancer cells disseminated into the bursa remain restricted to this cavity without migrating into the free abdominal cavity. Routine bursectomy may not be an essential procedure for resecting gastric cancer, from the viewpoint of eliminating microscopic peritoneal deposits within the omental bursa.
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Affiliation(s)
- Yoshitaka Yamamura
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
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Yonemura Y, Endo Y, Obata T, Sasaki T. Recent advances in the treatment of peritoneal dissemination of gastrointestinal cancers by nucleoside antimetabolites. Cancer Sci 2007; 98:11-8. [PMID: 17052255 PMCID: PMC11159699 DOI: 10.1111/j.1349-7006.2006.00350.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Peritoneal dissemination is the most common cause of metastasis from malignancies in the abdominal cavity. There are no standard treatments for peritoneal dissemination and the results are poor. The reasons for this are as follows: (1) no effective chemotherapeutic agents have been identified or developed; (2) surgical cytoreduction has little effect on survival improvement; and (3) the molecular mechanisms of peritoneal dissemination have not been clarified and no therapy against the target molecules has been developed. However, studies on the molecular mechanisms of peritoneal dissemination have elucidated some of the target molecules and the development of new multimodal therapies has also improved survival. Early postoperative intraperitoneal chemotherapy, hyperthermic intraperitoneal perfusion chemotherapy and neoadjuvant intraperitoneal-systemic chemotherapy have been newly developed, and a novel surgical therapy named peritonectomy has been proposed to perform complete cytoreduction of peritoneal dissemination. At present, these approaches appear to be effective therapeutic modalities for peritoneal dissemination. However, TS-1 and capecitabine have shown worthwhile results in recent clinical trials for patients with advanced gastric cancer. We recently found that newly developed antitumor cytosine nucleoside analogs show a survival advantage in peritoneal dissemination models using human cancer cells. These non-fluoropyrimidine nucleosides may potentially help to improve the poor prognosis observed in patients with advanced cancers involving peritoneal dissemination.
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Affiliation(s)
- Yutaka Yonemura
- Peritoneal Dissemination Program, Shizuoka Cancer Center, Suntoh-gun, Japan.
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Kodera Y, Nakanishi H, Ito S, Mochizuki Y, Ohashi N, Yamamura Y, Fujiwara M, Koike M, Tatematsu M, Nakao A. Prognostic significance of intraperitoneal cancer cells in gastric carcinoma: analysis of real time reverse transcriptase-polymerase chain reaction after 5 years of followup. J Am Coll Surg 2005; 202:231-6. [PMID: 16427547 DOI: 10.1016/j.jamcollsurg.2005.09.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2005] [Revised: 08/20/2005] [Accepted: 09/08/2005] [Indexed: 12/23/2022]
Abstract
BACKGROUND The presence of gastric cancer cells in the peritoneal cavity detected by cytologic examination is an important prognostic factor. A reverse transcriptase-polymerase chain reaction (RT-PCR) technique amplifying carcinoembryonic antigen mRNA was recently introduced to detect these cells more sensitively. STUDY DESIGN Five-year followup was completed for 284 gastric carcinoma patients who underwent CEA RT-PCR testing. Analyses to assess the accuracy and prognostic value of this procedure were performed, along with univariate and multivariable analyses to evaluate RT-PCR as a technique with peritoneal carcinomatosis and cancer death as the outcomes variables. RESULTS CEA mRNA levels exceeded the cutoff value defining a positive result in 9.5%, 29%, 66%, and 81% of patients with pT1, pT2, pT3, and pT4 stage disease, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value for peritoneal carcinomatosis within 5 years of surgery were 88.5%, 81.6%, 64.5%, and 94.9%, respectively. Multivariable analysis revealed that a positive CEA mRNA result was an independent risk factor for cancer death (hazard ratio 2.82, 95% CI 1.17 -3.07) among 274 patients (10 patients with no record of nodal status were excluded from the analysis) and for peritoneal carcinomatosis (hazard ratio 1.57, 95% CI 1.07-2.29) among 242 patients who had no peritoneal deposits at operation. CONCLUSIONS CEA RT-PCR is useful as a prognostic marker for increased risk of cancer death and peritoneal carcinomatosis, and might be useful in the clinical setting for selecting patients for various adjuvant treatments.
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Affiliation(s)
- Yasuhiro Kodera
- Department of Surgery II, Nagoya University Graduate School of Medicine, Nagoya, Japan
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