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Miró M, Vives R, Farran L, Secanella L, Varela M, Baixeras N, Estremiana F, Bettonica C, Aranda H, Galán M. Utility of Molecular Analysis of Peritoneal Fluid in Staging Laparoscopy of Advanced Esophagogastric Junction and Gastric Cancer Prior to Neoadjuvant Treatment. J Gastrointest Cancer 2023; 54:651-661. [PMID: 35881277 DOI: 10.1007/s12029-022-00846-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/20/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Molecular analysis of peritoneal fluid in staging laparoscopy of gastric cancer is performed to improve the detection of free intraperitoneal tumor cells. Nevertheless, its significance is controversial, especially in patients with negative cytology but positive molecular analysis. The aim of this study was to analyze the sensitivity of molecular analysis and its prognostic value. METHODS A retrospective analysis from April 2011 to October 2019 was performed. Cytology (Cyt) and molecular analysis were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) of the carcinoembryonic antigen (CEA) and cytokeratin 20 (CK20) tumor makers. RESULTS During the study period, 138 staging laparoscopies were performed. Macroscopic carcinomatosis was found in 12.3%. Of the remaining 87.7%, 9.9% were Cyt + and 11.6% were Cyt- RT-PCR + . Of the latter, 9 responded to chemotherapy and underwent radical surgery. The sensitivity of cytology and molecular analysis was 0.70 and 0.76, respectively (p = 0.67). The 2-year overall survival (OS) of Cyt- RT-PCR + vs. Cyt + was similar (p = 0.1). The 2-year OS of Cyt-RT-PCR + subgroup who underwent radical surgery vs. Cyt-RT-PCR- patients was similar (p = 0.69), but disease-free survival was shorter in the first group (p = 0.005). CONCLUSION Our results show that the sensitivity of molecular analysis is similar to that of cytology. The prognostic value of positive molecular analysis was similar to positive cytology in terms of 2-year overall survival, except in the subgroup of operated patients in whom the overall survival was similar to that of those with a negative molecular analysis, albeit with a shorter disease-free survival.
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Affiliation(s)
- M Miró
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain.
| | - R Vives
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain
| | - L Farran
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain
| | - L Secanella
- General and Digestive Surgery Service, Bellvitge University Hospital, L'Hospitalet del Llobregat, Barcelona, Spain
| | - M Varela
- Pathology Department, Bellvitge University Hospital, L'Hospitalet del Llobregat, Barcelona, Spain
| | - N Baixeras
- Pathology Department, Bellvitge University Hospital, L'Hospitalet del Llobregat, Barcelona, Spain
| | - F Estremiana
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain
| | - C Bettonica
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain
| | - H Aranda
- Unit of Esophagogastric Surgery, General and Digestive Surgery Service, Bellvitge University Hospital, St Feixa Llarga s/n, l'Hospitalet del Llobregat, Barcelona, 08907, Spain
| | - M Galán
- Medical Oncology Service, Institut Catala d'Oncologia, Gran Via de L'Hospitalet 199-203, L'Hospitalet del Llobregat, Barcelona, 08908, Spain
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Mari V, Angerilli V, Munari G, Scarpa M, Bao QR, Pucciarelli S, Fassan M, Spolverato G. Molecular Determinants of Peritoneal Dissemination in Gastric Adenocarcinoma. Dig Dis 2022; 41:49-65. [PMID: 35940137 DOI: 10.1159/000526333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 02/02/2023]
Abstract
BACKGROUND Peritoneal dissemination represents a poor prognostic indicator in gastric cancer. Despite a comprehensive molecular characterization of this disease, no peritoneal dissemination-specific signature has been identified, limiting the tailoring of the surgical and oncological treatments. In this review, we outline the available literature focusing on the role of the different molecular pathways involved in the acquisition of peritoneal metastatic dissemination. SUMMARY According to our results, several molecular determinants are associated with peritoneal carcinomatosis and are involved in several cellular and molecular carcinogenetic processes. However, a comprehensive understanding of the complex molecular landscape of gastric carcinosis is still lacking. KEY MESSAGES More efforts should be made toward the integration of molecular and histologic data to perform a risk prediction assessment of peritoneal dissemination based on molecular profiling and histological evaluation.
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Affiliation(s)
- Valentina Mari
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Valentina Angerilli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
| | - Giada Munari
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Marco Scarpa
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Quoc Riccardo Bao
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Salvatore Pucciarelli
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology (I.O.V. IRCSS), Padua, Italy
| | - Gaya Spolverato
- Department of Surgical, General Surgery 3, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
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Abstract
BACKGROUND Lavage cytology is a method to detect cancer cells released within the abdominal cavity. It has been widely utilized, in particular, for gastric cancer. However, its clinical significance has not yet been determined in colorectal cancer. OBJECTIVE This study aimed to investigate the frequency of lavage cytology positivity and its influence on the prognosis of patients with colorectal cancer. DESIGN This is a single-institution retrospective observational study. SETTING This study was conducted at a comprehensive cancer center. PATIENTS We retrospectively analyzed 3135 colorectal cancer cases from 2007 to 2013 at our institution. Intraoperative peritoneal washing cytology was performed just after the start of the operation. Fluids were centrifuged for 5 minutes at 2500 rotations per minute, cell pellets were smeared on microscope glass slides, and Papanicolaou staining was performed. MAIN OUTCOME MEASURES The primary outcome was the 5-year overall survival rate. The secondary outcome was the 5-year recurrence rate. RESULTS Lavage cytology positivity was detected in 19 (2.0%) and 86 (16.9%) cases of stage III and IV colorectal cancer; however, no positive cases were found in stage I and II colorectal cancer. Lavage cytology positivity was an independent prognostic factor in stage III and IV colorectal cancer in the multivariate analysis (5-year mortality HR 3.59 [1.69-7.64] in stage III, 2.23 [1.15-4.31] in stage IV). The prognosis of the 5-year survival rate was significantly worse in the lavage cytology-positive group in stages III and IV. In terms of recurrence, the results of the lavage cytology-positive group in stage III were similar to those of the lavage cytology-positive/negative group in stage IV (73.7%, 70.0%, and 75.0%). LIMITATIONS This study was limited by its retrospective study design. CONCLUSIONS Lavage cytology positivity is an independent prognostic and regulatory factor of stage IV colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B770.INCIDENCIA Y VALOR PRONÓSTICO EN LA CITOLOGÍA DEL LAVADO PERITONEAL EN CÁNCER COLORECTALANTECEDENTES:La citología del lavado peritoneal es un método para detectar células cancerosas liberadas dentro de la cavidad abdominal. Se ha utilizado ampliamente, en particular para el cáncer gástrico. Sin embargo, aún no se ha determinado su importancia clínica en el cáncer colorrectal.OBJETIVO:Este estudio tuvo como objetivo investigar la frecuencia de positividad de la citología del lavado y su influencia en el pronóstico de los pacientes con cáncer colorrectal.DISEÑO:Este fue un estudio observacional retrospectivo de una sola institución.DISENTORNO CLÍNICO:El estudio se llevó a cabo en un centro oncológico integral.PACIENTES:Analizamos retrospectivamente 3.135 casos de cáncer colorrectal desde 2007 hasta 2013 en nuestra institución. La citología de lavado peritoneal intraoperatorio se realizó inmediatamente después del inicio de la operación. Los fluidos se centrifugaron durante 5 min a 2.500 rpm, los sedimentos celulares se extendieron sobre portaobjetos de vidrio de microscopio y se realizó la tinción con Papanicolaou.DISPRINCIPALES MEDIDAS DE VALORACIÓN:El primer resultado fueron las tasas de supervivencia general a 5 años. El segundo resultado las tasas de recurrencia a los 5 años.RESULTADOS:Se detectó positividad en la citología de lavado en 19 (2,0%) y 86 (16,9%) casos de cáncer colorrectal en estadio III y IV, respectivamente; sin embargo, no se encontraron casos positivos en el cáncer colorrectal en estadio I y II. La positividad de la citología de lavado fue un factor pronóstico independiente en el cáncer colorrectal en estadio III y IV en el análisis multivariado [cociente de riesgo de mortalidad a 5 años 3,59 (1,69-7,64), en estadio III, 2,23 (1,15-4,31), en estadio IV]. El pronóstico de la tasa de supervivencia a 5 años fue significativamente peor en el grupo con citología de lavado positiva en los estadios III y IV. En cuanto a la recurrencia, los resultados del grupo de lavado con citología positiva en el estadio III fueron similares a los del grupo de lavado con citología positiva / negativa en el estadio IV (73,7%, 70,0% y 75,0%).LIMITACIONES:Este estudio estuvo limitado por su diseño de estudio retrospectivo.CONCLUSIONES:La positividad de la citología de lavado es un factor pronóstico y regulador independiente del cáncer colorrectal en estadio IV. Consulte Video Resumen en http://links.lww.com/DCR/B770. (Traducción- Dr. Ingrid Melo).
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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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Takahashi K, Kurashina K, Saito S, Kanamaru R, Ohzawa H, Yamaguchi H, Miyato H, Hosoya Y, Lefor AK, Sata N, Kitayama J. Flow cytometry-based analysis of tumor-leukocyte ratios in peritoneal fluid from patients with advanced gastric cancer. CYTOMETRY PART B-CLINICAL CYTOMETRY 2020; 100:666-675. [PMID: 33277773 PMCID: PMC9290827 DOI: 10.1002/cyto.b.21978] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/29/2020] [Accepted: 11/19/2020] [Indexed: 01/08/2023]
Abstract
Background The frequency of tumor cell dissemination in the peritoneal cavity is critically related to the progression of peritoneal metastases (PM). Recently, flow cytometry (FCM) has been successfully used to detect tumor cells in malignant effusions. Methods A total of 143 single cell suspensions derived from ascites or peritoneal lavages from patients with advanced gastric cancer (GC) were stained with monoclonal antibodies to CD45 and to CD326 as well as 4,6‐diamidino‐2‐phenylindole (DAPI) and FVS780. Using FCM, tumor‐leukocyte ratio (TLR) were calculated from CD45(−)CD326(+) tumor cell counts/ CD45(+)CD326(+) leukocyte counts in DAPI (+) FVS780(−) gated area. In 54 patients, the ratios of CD11b(+), CD4(+) and CD8(+) cells in CD45(+) leukocytes were evaluated in parallel. Results TLR of 69 patients with PM were significantly higher than those of 74 without PM (p < .001) and log(TLR) showed strong correlation with peritoneal cancer index scores in 51 PM (+) patients (r = 0.439). TLR in PM (+) patients also correlated with the ratio of CD11b (+) myeloid cells (r = 0.547), and correlated inversely with those of CD4(+) (r = −0.490) and CD8(+) T cells (r = −0.648). In PM (−) patients who underwent gastrectomy, TLR never exceeded 0.1% in patients with primary GC without serosal involvement (<T4). However, TLR in patients with T4 GC were significantly higher (p < .05) and peritoneal recurrence occurred in 6/8 patients whose TLR exceeded 0.1%. Conclusion TLR in peritoneal fluid reflects tumor burden and the immune environment in peritoneal cavity. Multicolor FCM may provide additional information which can be used for the treatment of the patients with PM.
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Affiliation(s)
- Kazuya Takahashi
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Kentaro Kurashina
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Shin Saito
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Rihito Kanamaru
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Hideyuki Ohzawa
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Hironori Yamaguchi
- Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan
| | - Hideyo Miyato
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Yoshinori Hosoya
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Alan Kawarai Lefor
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Naohiro Sata
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Joji Kitayama
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
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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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Yepuri N, Bahary N, Jain A, Dhir M. Review and Update on the Role of Peritoneal Cytology in the Treatment of Gastric Cancer. J Surg Res 2018; 235:607-614. [PMID: 30691849 DOI: 10.1016/j.jss.2018.10.049] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 08/12/2018] [Accepted: 10/26/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Positive peritoneal cytology (Cyt+) even in the absence of macroscopic disease is associated with poor prognosis in patients with gastric cancer and deemed as M1 disease. Recent years have seen advancements in the evaluation strategies for peritoneal washings and management of patients with Cyt+. The aim of this review was to describe the newest paradigms in the management of patients with gastric cancer who have Cyt+ without macroscopic peritoneal metastases. METHODS A comprehensive literature review was performed to identify studies on the management of gastric cancer and thereby to summarize relevant information on the accuracy of various diagnostic tests and controversies involved in the treatment of patients with Cyt+. RESULTS Although conventional cytology remains the standard technique for assessment of peritoneal washings, it is limited by low sensitivity. The role of immunohistochemistry and molecular techniques for the assessment of peritoneal washings is evolving. Although systemic chemotherapy remains the standard of care for patients with Cyt+ disease, the role of gastrectomy, intraperitoneal chemotherapy, extensive intraperitoneal saline lavage, and hyperthermic intraperitoneal chemotherapy is being evaluated. CONCLUSIONS Clinical decision-making in patients with Cyt+ remains controversial given the seemingly technical resectable albeit biologically unresectable or aggressive disease that portends an overall poor prognosis. Current management strategies are evolving, and further studies are needed to develop an optimal treatment strategy for these patients.
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Affiliation(s)
- Natesh Yepuri
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York
| | - Nathan Bahary
- Division of Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Ajay Jain
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York
| | - Mashaal Dhir
- Division of Surgical Oncology, Department of Surgery, SUNY Upstate Medical University, Syracuse, New York.
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Watanabe M, Kagawa S, Kuwada K, Hashimoto Y, Shigeyasu K, Ishida M, Sakamoto S, Ito A, Kikuchi S, Kuroda S, Kishimoto H, Tomida S, Yoshida R, Tazawa H, Urata Y, Fujiwara T. Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer. Cancer Sci 2018; 109:3263-3271. [PMID: 30076658 PMCID: PMC6172043 DOI: 10.1111/cas.13760] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 08/01/2018] [Accepted: 08/01/2018] [Indexed: 12/29/2022] Open
Abstract
Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology‐positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology‐positive gastric cancer patients, using a green fluorescent protein (GFP)‐expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP‐401). The fluorescence emitted from TelomeScan‐positive cells was successfully quantified using a multi‐mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology‐positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus‐guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.
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Affiliation(s)
- Megumi Watanabe
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuya Kuwada
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Yuuri Hashimoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Kunitoshi Shigeyasu
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Michihiro Ishida
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuichi Sakamoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Atene Ito
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Satoru Kikuchi
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shinji Kuroda
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroyuki Kishimoto
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Shuta Tomida
- Translational Research Network Project, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Ryuichi Yoshida
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hiroshi Tazawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.,Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | | | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
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RT-PCR of peritoneal washings predicts peritoneal pancreatic cancer recurrence. J Surg Res 2018; 226:122-130. [PMID: 29661277 DOI: 10.1016/j.jss.2017.11.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 10/20/2017] [Accepted: 11/03/2017] [Indexed: 01/29/2023]
Abstract
BACKGROUND Peritoneal recurrence of pancreatic cancer is a frequent and lethal outcome after R0 resection. A method to predict peritoneal recurrence could be helpful in its prevention. MATERIALS AND METHODS Peritoneal washings were prospectively obtained from 29 patients in whom R0 resection was performed. Cytological examination (CY) and real-time reverse transcription polymerase chain reaction (RT-PCR) of the peritoneal washing for the detection of cancer-related genes, CEACAM5, KRT7, KRAS, and MUC1, were performed. Clinicopathological characteristics and real-time RT-PCR results of the peritoneal washing were compared between patients whose pancreatic cancer recurred peritoneally (n = 7) and those patients who it did not recur (n = 22). RESULTS Only one CY-positive (CY+) case was detected, and that patient recurred. MUC1 mRNA expression was significantly higher in the recurrence group (P = 0.015). Cumulative incidence-function analysis demonstrated that peritoneal recurrence rate was significantly higher in MUC1-positive (MUC1+) patients (P = 0.044). MUC1+ patients had significantly decreased disease-free survival (P = 0.009) and disease-specific survival (P = 0.031). MUC1 protein was detected in the primary tumor in 18 of 29 patients. However, no significant difference was observed in the expression of MUC1 protein in peritoneal washings from the primary tumor (P = 0.579). CONCLUSIONS High expression of MUC1 mRNA in peritoneal washings is a significant risk factor for peritoneal recurrence of pancreatic cancer after R0 resection along with poor disease-specific survival. RT-PCR of MUC1 mRNA in peritoneal washing may be useful for individualization of adjuvant chemotherapy.
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Virgilio E, Balducci G, Mercantini P, Giarnieri E, Giovagnoli MR, Montagnini M, Proietti A, D'Urso R, Cavallini M. Preoperative gastric lavage in gastric cancer patients undergoing surgical, endoscopic or minimally invasive treatment: An oncological measure preventing peritoneal spillage of intragastric cancer cells and development of related metastases. Med Hypotheses 2018; 114:30-34. [PMID: 29602460 DOI: 10.1016/j.mehy.2018.02.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 02/19/2018] [Accepted: 02/20/2018] [Indexed: 01/15/2023]
Abstract
In addition to classical metastatic pathways, recently gastric cancer was described having an alternative route called "endoluminal exfoliation". Provisional analyses demonstrated, in fact, this kind of shedding is associated with several clinico-pathological features indicative of aggressive behavior and resulted to be an independent prognostic factor entailing poor prognosis. Compared with non-sowing counterparts, in fact, patients affected with exfoliating early and advanced gastric carcinomas met with shorter overall survival, disease free survival, progression free survival and time to tumor progression. In spite of these interesting results, however, the clinico-pathological and oncological significance of this unconventional metastatic route is still to be clarified. Such an investigation is further urged by the increasing widespread employment of minimally invasive treatments for gastric cancer which include a wide spectrum of intragastric interventions and maneuvers. Indeed, endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic full-thickness resection, intragastric laparoscopic surgery and hybrid procedures all take place inside of the stomach. However, iatrogenic perforations can occur during execution of these treatments leading to spillage of malignant cells from gastric to the peritoneal cavity or trocar insertion sites. Furthermore, many other gastric conditions and interventions can collide with endogastric presence of floating cancer cells: spontaneous ulceration or perforation, laparotomy surgery, gastrointestinal occlusion, diverticula. Viability, migration and intraluminal transportability of the intragastric floating cancer cells represents another original and intriguing topic. All these considerations led us to entertain the hypothesis that removing the exfoliated cancer cells from the gastric lumen could save patients from the dreaded potential risk of spillage. Performing gastric lavage before starting any kind of tumor intervention could be the most appropriate procedure to adopt with prophylactic intent. Should our speculation prove to be clinically significant, preoperative gastric lavage should be pointed out as a simple but cogent method useful for preventing oncological mishaps such as spillage of gastric cancer cells and development of related recurrences or metastases.
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Affiliation(s)
- Edoardo Virgilio
- Department of Medical and Surgical Sciences and Translational Medicine, Department of General Surgery, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy.
| | - Genoveffa Balducci
- Department of Medical and Surgical Sciences and Translational Medicine, Department of Emergency Surgery, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Paolo Mercantini
- Department of Medical and Surgical Sciences and Translational Medicine, Department of Emergency Surgery, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Enrico Giarnieri
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Maria Rosaria Giovagnoli
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Monica Montagnini
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Antonella Proietti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Rosaria D'Urso
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
| | - Marco Cavallini
- Department of Medical and Surgical Sciences and Translational Medicine, Department of General Surgery, Faculty of Medicine and Psychology, University "Sapienza", St. Andrea Hospital, via di Grottarossa 1035-39, Rome 00189, Italy
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12
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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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13
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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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14
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Steen W, Blom R, Busch O, Gerhards M, Besselink M, Dijk F, Festen S. Prognostic value of occult tumor cells obtained by peritoneal lavage in patients with resectable pancreatic cancer and no ascites: A systematic review. J Surg Oncol 2016; 114:743-751. [PMID: 27642007 DOI: 10.1002/jso.24402] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 07/29/2016] [Indexed: 01/12/2023]
Abstract
The poor survival of patients with resectable pancreatic cancer might be related to the presence of occult peritoneal tumor cells (OPTC). This systematic review studies the prognostic value of cytology and carcinoembryonic antigen (CEA) by real-time polymerase chain reaction in peritoneal fluid. The results suggest that presence of OPTC is related to a worse survival in patients with resectable pancreatic cancer. Future studies should investigate its possible role in selecting patients for specific treatment strategies. J. Surg. Oncol. 2016;114:743-751. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Willemijn Steen
- Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Rachel Blom
- Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Olivier Busch
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Michael Gerhards
- Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
| | - Marc Besselink
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Frederike Dijk
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Sebastiaan Festen
- Department of Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
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15
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de Mestier L, Lardière-Deguelte S, Volet J, Kianmanesh R, Bouché O. Recent insights in the therapeutic management of patients with gastric cancer. Dig Liver Dis 2016; 48:984-94. [PMID: 27156069 DOI: 10.1016/j.dld.2016.04.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2016] [Revised: 04/14/2016] [Accepted: 04/14/2016] [Indexed: 01/19/2023]
Abstract
Gastric cancer remains frequent and one of the most lethal malignancies worldwide. In this article, we aimed to comprehensively review recent insights in the therapeutic management of gastric cancer, with focus on the surgical and perioperative management of resectable forms, and the latest advances regarding advanced diseases. Surgical improvements comprise the use of laparoscopic surgery including staging laparoscopy, a better definition of nodal dissection, and the development of hyperthermic intraperitoneal chemotherapy. The best individualized perioperative management should be assessed before curative-intent surgery for all patients and can consists in perioperative chemotherapy, adjuvant chemo-radiation therapy or adjuvant chemotherapy alone. The optimal timing and sequence of chemotherapy and radiation therapy with respect to surgery should be further explored. Patients with advanced gastric cancer have a poor prognosis. Nevertheless, they can benefit from doublet or triplet chemotherapy combination, including trastuzumab in HER2-positive patients. Upon progression, second-line therapy can be considered in patients with good performance status. Although anti-HER2 (trastuzumab) and anti-VEGFR (ramucirumab) may yield survival benefit, anti-EGFR and anti-HGFR therapies have failed to improve outcomes. Nevertheless, combination regimens containing cytotoxic drugs and targeted therapies should be further evaluated; keeping in mind that gastric cancer biology is different between Asia and the Western countries.
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Affiliation(s)
- Louis de Mestier
- Service d'Hépato-Gastroentérologie et de Cancérologie Digestive, CHU Robert Debré, Reims, France
| | | | - Julien Volet
- Service d'Hépato-Gastroentérologie et de Cancérologie Digestive, CHU Robert Debré, Reims, France; Unité de Médecine Ambulatoire - Cancérologie-Hématologie, CHU Robert Debré, Reims, France
| | - Reza Kianmanesh
- Service de Chirurgie Générale, Digestive et Endocrinienne, CHU Robert Debré, Reims, France
| | - Olivier Bouché
- Service d'Hépato-Gastroentérologie et de Cancérologie Digestive, CHU Robert Debré, Reims, France; Unité de Médecine Ambulatoire - Cancérologie-Hématologie, CHU Robert Debré, Reims, France.
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16
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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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Shareef MM, Radi DMA, Eid AMM. Tight junction protein claudin 4 in gastric carcinoma and its relation to lymphangiogenic activity. Arab J Gastroenterol 2015; 16:105-12. [PMID: 26526513 DOI: 10.1016/j.ajg.2015.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2015] [Revised: 08/25/2015] [Accepted: 09/28/2015] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND STUDY AIMS Gastric cancer is the second most common cause of cancer-related death worldwide. Claudins are a family of tight junction proteins that are biologically relevant in many cancer progression steps. This study aimed to investigate the expression of the intestinal claudin (claudin 4) in gastric carcinoma and to evaluate its relation to the different clinicopathologic prognostic parameters, especially lymphangiogenesis (production of new lymphatic vessels, measured by lymphovascular density (LVD)) and lymphovascular invasion (LVI). PATIENTS AND METHODS Fifty-five gastric carcinoma specimens were immunohistochemically stained for claudin 4 and D2-40 (for detection of lymphatic vessel endothelium). RESULTS High expression of claudin 4 was detected in 26 of 55 (47.3%) cases. Low expression of claudin 4 was related to poorly differentiated type (p=0.001), non-intestinal (diffuse) type (p=0.001), deeper tumour invasion (p<0.001), lymph node metastasis (p=0.001), and higher stage (p=0.001). In addition, higher LVD was related to poorly differentiated types (p=0.001), non-intestinal type (p=0.001), lymph node metastasis (p=0.015), and higher tumour, node, metastasis (TNM) stage (p=0.001). LVI was related to lymph node metastasis (p=0.025), higher TNM stage (p=0.001), and LVD (p=0.001). Claudin 4 significantly correlated with both LVD (p=0.009) and LVI (p=0.009). CONCLUSIONS High expression of claudin 4 was associated with the more differentiated intestinal-type gastric carcinoma and lost in poorly differentiated diffuse type. So, claudin 4 may be used as one of the differentiating markers between the two major types of gastric carcinoma (intestinal vs. diffuse). LVD and LVI were related to higher incidence of lymph node metastasis and therefore could be used as predictive markers for lymph node metastasis in limited specimens during early gastric carcinoma to determine the need for more invasive surgery. Low expression of claudin 4 was related to lymphangiogenesis. This may shed light on the relation of tight junction protein expression and lymphangiogenesis.
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18
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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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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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20
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Kitayama J, Emoto S, Yamaguchi H, Ishigami H, Onoyama H, Yamashita H, Seto Y, Matsuzaki K, Watanabe T. Flow Cytometric Quantification of Intraperitoneal Free Tumor Cells is a Useful Biomarker in Gastric Cancer Patients with Peritoneal Metastasis. Ann Surg Oncol 2014; 22:2336-42. [PMID: 25404476 DOI: 10.1245/s10434-014-4238-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND The frequency of intraperitoneal free tumor cells (IPTC) is considered to reflect the severity of peritoneal metastasis (PM). We quantified the relative number of IPTC against leukocytes in peritoneal fluid and evaluated its clinical relevance in gastric cancer (GC) patients, particularly those with PM. METHODS Cells recovered from ascites or peritoneal lavage fluid were immunostained with monoclonal antibodies (mAb) to CD45 and CD326 (EpCAM). Using flow cytometry (FACS), CD326(+) and CD45(+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated in a total of 506 samples obtained from 300 patients with GC and 33 patients with liver cirrhosis (LC). RESULTS Median (M) of the TLR of the initial samples obtained from 199 patients with PM(+) GC was 1.32 % (0-1,868.44 %), which was significantly higher than that in patients with PM(-) GC (M = 0 %, 0-0.35 %; n = 101) or LC (M = 0 %, 0-0.031 %; n = 33). In 104 PM(+) patients who received combination chemotherapy including intraperitoneal paclitaxel, the TLR was repeatedly measured in peritoneal fluid obtained from the port. In these patients, the TLR showed a strong correlation with clinical features as well as cytological findings and carcinoembryonic antigen messenger RNA status. Finally, the median survival time of the 11 patients with initial TLR > 10 % was significantly shorter than that of the 52 patients with TLR < 10 % (271 vs. 627 days; p = 0.0002). CONCLUSION The TLR excellently reflected tumor burden in the peritoneal cavity, and could be a reliable biomarker to determine the outcome, as well as the effectiveness, of chemotherapy in patients with PM(+) GC.
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Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan,
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Osayi SN, Bloomston M, Schmidt CM, Ellison EC, Muscarella P. Biomarkers as predictors of recurrence following curative resection for pancreatic ductal adenocarcinoma: a review. BIOMED RESEARCH INTERNATIONAL 2014; 2014:468959. [PMID: 25050350 PMCID: PMC4094702 DOI: 10.1155/2014/468959] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 06/02/2014] [Accepted: 06/03/2014] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is the fourth most common cancer causing death in the United States. Early tumor recurrence is an important contributor to the dismal prognosis. The availability of an accurate prognostic biomarker for predicting disease recurrence following curative resection will be beneficial for patient care. Most of the currently studied biomarkers remain in the investigational phase, with CA 19-9 being the only biomarker currently approved by the FDA. Herein, we review the utility of CA 19-9 and other investigational cellular, gene, and molecular tumor markers for predicting PDA recurrence following curative surgical resection.
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Affiliation(s)
- Sylvester N. Osayi
- Department of Surgery and Center for Minimally Invasive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Mark Bloomston
- Department of Surgery and Center for Minimally Invasive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Carl M. Schmidt
- Department of Surgery and Center for Minimally Invasive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - E. Christopher Ellison
- Department of Surgery and Center for Minimally Invasive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Peter Muscarella
- Department of Surgery and Center for Minimally Invasive Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
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Kitayama J, Emoto S, Yamaguchi H, Ishigami H, Kamei T, Yamashita H, Seto Y, Matsuzaki K, Watanabe T. Flow cytometric quantification of intraperitoneal free tumor cells in patients with peritoneal metastasis. CYTOMETRY PART B-CLINICAL CYTOMETRY 2013; 86:56-62. [PMID: 24115348 DOI: 10.1002/cyto.b.21126] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 07/21/2013] [Accepted: 08/12/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND Peritoneal metastasis (PM) is the most life-threatening type of metastasis in abdominal malignancy. To improve the diagnostic accuracy of cytologic detection (CY) of free tumor cells (FTC) in the peritoneal cavity, we tried to quantify the FTC to leukocyte ratio using flow cytometry in patients with peritoneal metastasis. METHODS Cells were recovered from ascites or peritoneal lavages from 106 patients who underwent abdominal surgery and additional 89 samples which were obtained from peritoneal catheter or access port in patients with PM (+) gastric cancer. The cells were immunostained with monoclonal antibodies to CD45 and to CD326 (EpCAM). Using flow cytometry, CD326 (+) and CD45 (+) cells were classified as either tumor cells (T) or leukocytes (L) and the T/L ratio (TLR) was calculated. RESULTS In 106 samples obtained by laparotomy, Median (M) of the TLR of PM (+) patients was 1.39% (0-807.87%) which was significantly higher than PM (-) patients (M=0%, 0-2.14%, P < 0.001). In PM (+) patients, 86 CY (+) samples showed higher TLR than 61 CY (-) samples (M=2.81%, 0.02-1868.44% vs. M=0%, 0-3.45%, p<0.0001). In all of the 24 patients who were monitored for TLR before and after intraperitoneal (IP) chemotherapy, the TLR was reduced which was more dramatic than the results of the change in cytology. CONCLUSIONS TLR measured with FACS is an excellent reflection of the tumor spread in the peritoneal cavity and could be a reliable diagnostic biomarker to determine the severity of PM as well as effectiveness of IP chemotherapy.
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Affiliation(s)
- Joji Kitayama
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
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Research on the diagnosis of peritoneal micrometastases in tumors of the subdiaphragmatic digestive tract. ARS MEDICA TOMITANA 2013. [DOI: 10.2478/v10307-012-0018-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
This presentation is aimed at analyzing the possibility of detecting the peritoneal micrometastases through multiple peritoneal biopsies to the patients with tumors of the subdiaphragmatic digestive tract.
Nowadays, detection of the micrometastases is performed indirectly through cytological analysis and / PCR analysis of the peritoneal liquid, through the histopathological study of the peritoneal fragments intraoperatively collected and the immunohistochemical study.
This presentation is aimed at analyzing the possibility of detecting the peritoneal micrometastases through multiple peritoneal biopsies and to correlate this with various factors such us: staging neoplasia, the affected organ, histopathological type, tumoral grading.
Inclusion of the patients that find themselves in the early stage of peritoneal carcinomatosis - of peritoneal micrometastases - would allow for the application of an adequate treatment and could greatly increase the patient’s survival chances
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Detection of gastric cancer peritoneal metastases by peritoneal lavage: Current limitations and future perspectives. Surgery 2012; 152:1-4. [PMID: 22703894 DOI: 10.1016/j.surg.2012.03.022] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Accepted: 03/22/2012] [Indexed: 12/16/2022]
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Smyth E, Schöder H, Strong VE, Capanu M, Kelsen DP, Coit DG, Shah MA. A prospective evaluation of the utility of 2-deoxy-2-[(18) F]fluoro-D-glucose positron emission tomography and computed tomography in staging locally advanced gastric cancer. Cancer 2012; 118:5481-8. [PMID: 22549558 DOI: 10.1002/cncr.27550] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 01/16/2012] [Accepted: 01/25/2012] [Indexed: 12/20/2022]
Abstract
BACKGROUND The aim of this study was to examine prospectively the utility of adding preoperative [(18) F]fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) to routine CT, endoscopic ultrasound (EUS), and laparoscopic staging of localized gastric cancer. METHODS Patients with locally advanced gastric/gastroesophageal cancer were screened for 2 institutional review board-approved Memorial Sloan-Kettering Cancer Center neoadjuvant chemotherapy protocols. Locally advanced disease was defined as T3 or T4, or lymph node-positive, based on EUS and high-resolution CT scan. All patients underwent both standard FDG-PET/CT and laparoscopy with cytological examination of washings. The sensitivity and specificity of FDG-PET/CT for the identification of metastatic disease not seen on CT was determined. An economic model using Medicare/Medicaid reimbursement charges was developed to assess the cost-effectiveness of these interventions. RESULTS A total of 113 patients were enrolled from 2003 to 2010. All patients were assessed as having locally advanced disease by CT/EUS. FDG uptake in the primary tumor was associated with male sex, proximal tumors, and nondiffuse Lauren's subtype. 31 (27%) patients had occult metastatic disease detected by PET/CT (n = 11, 10%) and/or laparoscopy (n = 21, 19%), with a single overlap. Economic modeling suggests that the addition of FDG-PET/CT to the standard staging evaluation of patients with locally advanced gastric cancer resulted in an estimated cost savings of ∼US $13,000 per patient. CONCLUSIONS FDG-PET/CT identifies occult metastatic lesions in approximately 10% of patients with locally advanced gastric cancer. Because of reduced morbidity from fewer futile surgeries and lower patient care costs, PET/CT should be considered as a component of the standard staging algorithm for localized gastric cancer.
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Affiliation(s)
- Elizabeth Smyth
- Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center and Weill-Cornell Medical Center, New York, New York, USA
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Wong J, Kelly KJ, Mittra A, Gonen M, Allen P, Fong Y, Coit D. Rt-PCR increases detection of submicroscopic peritoneal metastases in gastric cancer and has prognostic significance. J Gastrointest Surg 2012; 16:889-96; discussion 896. [PMID: 22362071 DOI: 10.1007/s11605-012-1845-2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 02/10/2012] [Indexed: 01/31/2023]
Abstract
BACKGROUND Positive peritoneal cytology confers the same prognosis as clinical stage IV disease in gastric cancer. Conventional cytology examination, however, has low sensitivity. We hypothesize that real-time polymerase chain reaction (RT-PCR) may have increased sensitivity and provide more accurate staging information. METHODS From February 2007 to April 2009, peritoneal lavage samples were collected prospectively from 156 patients with biopsy-proven gastric cancer undergoing staging laparoscopy. These washings were analyzed by both Papanicolaou staining and RT-PCR for the tumor marker carcinoembryonic antigen (CEA). RESULTS Visible peritoneal disease was seen at laparoscopy in 38 patients (LAP+, 24%). Cytology was positive (CYT+) in 23 patients, while RT-PCR was positive (PCR+) in 30. The sensitivity of CYT for the detection of visible disease was 61% compared to 79% for PCR (P = 0.02). No visible peritoneal disease was seen at laparoscopy (LAP-) in 118 (76%) patients. Eight (7%) were CYT+, while 28 (24%) were PCR+. Predictors of PCR positivity included advanced-stage disease (T3-4 vs. T1-2 tumors) and poor pathologic features such as vascular or perineural invasion. Long-term follow-up demonstrated a worse survival of LAP-CYT-PCR+ (P = 0.0003) and LAP-CYT+PCR+ (P = 0.0004) compared to LAP-CYT-PCR- patients. There was no significant difference in survival between CYT-PCR+ and CYT+PCR+ patients. PCR positivity also predicted a higher likelihood of disease recurrence after resection. An R0 resection was performed in 85 LAP- patients (54%): only 1 (1%) was CYT+, while 13 (15%) were PCR+. Of this group, PCR+ demonstrated a worse survival than PCR- patients (P = 0.02). Further analysis showed that, in R0 resection, stage III/IV, CYT- subgroup, PCR+ was associated with a trend towards worse survival (P = 0.09) compared to PCR- patients. CONCLUSION RT-PCR for CEA increases the detection of subclinical peritoneal disease and is more sensitive than cytology. Predictors of positive PCR included advanced-stage disease, vascular invasion, and perineural invasion. PCR positivity was associated with increased disease recurrence and decreased survival. Further follow-up is required to determine if PCR positivity alone is an independent predictor of poor survival in gastric cancer.
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Affiliation(s)
- Joyce Wong
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, 275 York Avenue, New York, NY 10021, USA
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Smyth EC, Shah MA. Role of ( 18F) 2-fluoro-2-deoxyglucose positron emission tomography in upper gastrointestinal malignancies. World J Gastroenterol 2011; 17:5059-74. [PMID: 22171140 PMCID: PMC3235589 DOI: 10.3748/wjg.v17.i46.5059] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2011] [Revised: 06/09/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023] Open
Abstract
The role of whole-body FDG [(18F) 2-fluoro-2-deoxyglucose] positron emission tomography (PET) scanning as an imaging modality in the management of patients with malignancy has evolved enormously over the past two decades. FDG-PET has demonstrated significant efficacy in the staging, prognostication and detection of occult metastatic disease in malignancies of the gastrointestinal tract, in addition to assessment of the response to cytotoxic chemotherapy in a more timely manner than has traditionally been possible by more conventional imaging tools. The sensitivity and specificity of FDG-PET for the detection and staging of malignancy depend not only on the site and size of the primary tumor and metastases, but also on histological cell type, reflecting underlying disparities in glucose metabolism. The metabolic response to neo-adjuvant chemotherapy or to chemo-radiotherapy in cancers of the gastro-esophageal junction or stomach has been demonstrated in several prospective studies to correlate significantly with both the histological tumor response to treatment and with consequent improvements in overall survival. This may offer a future paradigm of personalized treatment based on the PET response to chemotherapy. FDG-PET has been less successful in efforts to screen for and detect recurrent upper gastrointestinal malignancies, and in the detection of low volume metastatic peritoneal disease. Efforts to improve the accuracy of PET include the use of novel radiotracers such as (18F) FLT (3-deoxy-3-fluorothymidine) or 11C-choline, or fusion PET-CT with concurrent high-resolution computed tomography. This review focuses on the role of FDG-PET scanning in staging and response assessment in malignancies of the upper gastrointestinal tract, specifically gastric, esophageal and pancreas carcinoma.
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Karanicolas PJ, Elkin EB, Jacks LM, Atoria CL, Strong VE, Brennan MF, Coit DG. Staging laparoscopy in the management of gastric cancer: a population-based analysis. J Am Coll Surg 2011; 213:644-651, 651.e1. [PMID: 21872497 DOI: 10.1016/j.jamcollsurg.2011.07.018] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2011] [Revised: 07/20/2011] [Accepted: 07/20/2011] [Indexed: 01/04/2023]
Abstract
BACKGROUND Staging laparoscopy can detect radiographically occult peritoneal metastases and prevent futile laparotomy in patients with gastric adenocarcinoma. We sought to assess the use of staging laparoscopy for gastric adenocarcinoma in a cohort of older patients and to compare outcomes after laparoscopy alone with nontherapeutic laparotomy. STUDY DESIGN Using Surveillance, Epidemiology and End Results (SEER) population-based cancer registry data linked with Medicare claims, we identified patients aged 65 or older diagnosed with gastric adenocarcinoma between 1998 and 2005. We defined staging laparoscopy as a laparoscopic procedure from 1 month before the date of diagnosis until death and futile laparotomy as a laparotomy in the absence of a therapeutic intervention. We examined trends in the use of staging laparoscopy and compared outcomes between patients who underwent staging laparoscopy alone and those who had a futile laparotomy. RESULTS Of 11,759 patients with gastric adenocarcinoma, 6,388 (54.3%) had at least 1 surgical procedure. Staging laparoscopy was performed in 506 (7.9%) patients who had any surgery, and 151 (29.8%) of these patients did not have a subsequent therapeutic intervention. Patients who underwent staging laparoscopy alone had a significantly lower rate of in-hospital mortality (5.3% vs 13.1%, p < 0.001) and shorter length of hospitalization (2 vs 10 days, p < 0.001) than patients who had futile laparotomy. CONCLUSIONS Our findings in this large, population-based cohort suggest that staging laparoscopy is used infrequently in the management of older patients with gastric adenocarcinoma. Increased use of staging laparoscopy could reduce the substantial morbidity and mortality associated with nontherapeutic laparotomy.
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Affiliation(s)
- Paul J Karanicolas
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Liu Y, Liu BA. Enhanced proliferation, invasion, and epithelial-mesenchymal transition of nicotine-promoted gastric cancer by periostin. World J Gastroenterol 2011; 17:2674-80. [PMID: 21677839 PMCID: PMC3110933 DOI: 10.3748/wjg.v17.i21.2674] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Revised: 04/19/2011] [Accepted: 04/26/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the contribution of periostin in nicotine-promoted gastric cancer cell proliferation, survival, invasion, drug resistance, and epithelial-mesenchymal transition (EMT).
METHODS: Gastric cancer cells were treated with nicotine and periostin protein expression was determined by immunoblotting. Periostin mRNA in gastric cancer cells was silenced using small interfering RNA (siRNA) techniques and periostin gene expression was evaluated by quantitative reverse transcription-polymerase chain reaction. Gastric cancer cells transfected with control or periostin siRNA plasmid were compared in terms of cell proliferation using the methylthiazolyldiphenyl-tetrazolium bromide assay. Cell apoptosis was compared using annexin V-fluoresceine isothiocyanate and propidium iodine double staining. Tumor invasion was determined using the Boyden chamber invasion assay, and the EMT marker Snail expression was evaluated by immunoblotting.
RESULTS: Nicotine upregulated periostin in gastric cancer cells through a COX-2 dependent pathway, which was blocked by the COX-2-specific inhibitor NS398. Periostin mRNA expression was decreased by ~87.2% by siRNA in gastric cancer cells, and stable periostin-silenced cells were obtained by G418 screening. Periostin-silenced gastric cancer cells exhibited reduced cell proliferation, elevated sensitivity to chemotherapy with 5-fluorouracil, and decreased cell invasion and Snail expression (P < 0.05).
CONCLUSION: Periostin is a nicotine target gene in gastric cancer and plays a role in gastric cancer cell growth, invasion, drug resistance, and EMT facilitated by nicotine.
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Cao W, Yang W, Li H, Lou G, Jiang J, Geng M, Xi W, Ren R, Qu Q, Jin X, Zhu Y, Jin Y. Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. J Surg Oncol 2010; 103:110-5. [PMID: 21259243 DOI: 10.1002/jso.21777] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 09/15/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVES The present study was designed to investigate the clinicopathological role of survivin-expressing circulating tumor cells (CTCs) and to determine whether the presence of survivin-expressing CTCs is an independent predictor of tumor recurrence following curative resection of gastric cancer. METHODS This study included 98 patients who underwent potentially curative resection. Reverse transcription polymerase chain reaction enzyme linked immunosorbent assay (RT-PCR ELISA) was used to measure survivin mRNA in peripheral blood. RESULTS Of the 98 patients studied, 45 (45.9%) were positive for survivin mRNA. Survivin mRNA expression correlated with Lauren classification (P < 0.001), pathological tumor (pT) stage (P < 0.001), pathological tumor node metastasis (pTNM) stage (P = 0.009), and degree of differentiation (P = 0.001). The pTNM stage and the status of survivin mRNA were independent prognostic factors of disease-free survival (P = 0.007 and <0.001, respectively). CONCLUSIONS The detection of CTCs expressing survivin mRNA could be a good clinical biomarker used to predict the prognosis of patients with curatively resected gastric cancer.
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Affiliation(s)
- Weiguo Cao
- Departments of Oncology, Ruijin Hospital, Medical School of Shanghai, Jiaotong University, Shanghai, People's Republic of China
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Phase II clinical trial of postoperative S-1 monotherapy for gastric cancer patients with free intraperitoneal cancer cells detected by real-time RT-PCR. World J Surg 2010; 34:2083-9. [PMID: 20379713 DOI: 10.1007/s00268-010-0573-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND We have previously reported the molecular detection of peritoneal micrometastases in patients with gastric cancer by quantifying carcinoembryonic antigen (CEA) mRNA in the peritoneal washes. Patients with CEA mRNA exceeding a cutoff value have a significant risk for developing peritoneal carcinomatosis, but optimal treatment for this population remains unknown. METHODS CEA mRNA (+) patients with gastric cancer were treated postoperatively with S-1 monotherapy. Overall survival, the primary endpoint of this phase II trial, was compared with the historical control, which is comprised of CEA mRNA (+) patients who were not given postoperative chemotherapy. RESULTS A total of 32 patients with CEA mRNA (+) gastric cancer were enrolled. Twelve patients (37.5%) relapsed; ten showed peritoneal relapse. Three-year survival was similar between the study population and the historical control (67.3% vs. 67.1%, respectively). CONCLUSIONS S-1 monotherapy, which significantly reduced risk for recurrence in stage II/III gastric carcinoma in another phase III trial, seems not to be as effective in eradicating free cancer cells in the abdominal cavity.
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Hiraki M, Kitajima Y, Sato S, Mitsuno M, Koga Y, Nakamura J, Hashiguchi K, Noshiro H, Miyazaki K. Aberrant gene methylation in the lymph nodes provides a possible marker for diagnosing micrometastasis in gastric cancer. Ann Surg Oncol 2009; 17:1177-86. [PMID: 19957042 DOI: 10.1245/s10434-009-0815-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2009] [Indexed: 01/03/2023]
Abstract
BACKGROUND This study was designed to determine whether gene methylation is a novel diagnostic marker for micrometastasis to the lymph nodes (LNs) in gastric cancer. METHODS The gene methylation of CHFR, p16, RUNX3, E-cadherin, MGMT, hMLH1, and ABCG2 genes were analyzed in 49 primary gastric cancer tissues, corresponding to noncancerous tissues and matched LNs by quantitative methylation-specific PCR (q-MSP). RESULTS CHFR, RUNX3, MGMT, and hMLH1 were more frequently methylated in primary cancer compared with the noncancerous mucosa. Further analyses investigated whether the methylation of the four cancer-specific genes was preserved in LN tissues using the 29 control cases, in which LN metastasis had been histologically confirmed. The methylation of both lesions (M/M pattern) in at least one gene, which was judged to be positive for cancer cells in LNs, was observed in 25 of 29 cases (86%). Quantitative RT-PCR (qRT-PCR) of CEA, CK19, and CK20 mRNA was conducted using the same samples. The mRNA expression of at least one of the three genes was observed in 100% of the specimens. The results of the control analysis were used to attempt to predict micrometastasis by q-MSP and qRT-PCR in the 20 test cases without histological LN metastasis. Six cases (30%) showed the M/M pattern in at least one of the four genes. Three of 20 cases (15%) exhibited both the M/M pattern and positive mRNA. CONCLUSIONS The methylation analysis revealed the clinical feasibility of detecting occult neoplastic cells in the regional LNs.
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Affiliation(s)
- Masatsugu Hiraki
- Department of Surgery, Saga University Faculty of Medicine, 5-1-1 Nabeshima, Saga, 849-8501, Japan
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Kelly KJ, Wong J, Gladdy R, Moore-Dalal K, Woo Y, Gonen M, Brennan M, Allen P, Fong Y, Coit D. Prognostic impact of RT-PCR-based detection of peritoneal micrometastases in patients with pancreatic cancer undergoing curative resection. Ann Surg Oncol 2009; 16:3333-9. [PMID: 19763694 DOI: 10.1245/s10434-009-0683-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2009] [Revised: 07/29/2009] [Accepted: 07/29/2009] [Indexed: 12/21/2022]
Abstract
BACKGROUND Positive peritoneal fluid cytology predicts poor outcome in patients with resected pancreatic cancer. Reverse transcription-polymerase chain reaction (RT-PCR) has been proposed as a more sensitive means of detection of peritoneal micrometastases than conventional cytology. The clinical significance of RT-PCR positivity in the absence of other evidence of peritoneal disease is unknown. The purpose of the current study was to determine the outcome RT-PCR positive/cytology-negative patients who underwent potentially curative resection. METHODS Peritoneal washings were collected prospectively from 115 patients with pancreatic cancer undergoing diagnostic laparoscopy at a single institution. Specimens were analyzed by a cytopathologist and by RT-PCR for carcinoembryonic antigen (CEA). RESULTS Of the 115 patients, 62 (54%) underwent R0 resection. Eleven of the 62 patients (18%) had peritoneal washings that were negative by conventional cytology but positive for CEA by RT-PCR. Those 11 patients experienced early peritoneal and overall disease recurrence versus those who were RT-PCR negative (P = 0.001, P = 0.003, respectively) independent of nodal status. CONCLUSIONS RT-PCR for CEA is a sensitive and specific method for the detection of clinically significant peritoneal micrometastases from pancreatic cancer and it might identify a subgroup of patients with otherwise negative findings at staging laparoscopy who might respond better to treatment other than primary surgical resection.
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Affiliation(s)
- Kaitlyn J Kelly
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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Hu X, Wu H, Zhang S, Yuan H, Cao L. Clinical Significance of Telomerase Activity in Gastric Carcinoma and Peritoneal Dissemination. J Int Med Res 2009; 37:1127-38. [PMID: 19761695 DOI: 10.1177/147323000903700417] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Telomerase activity is responsible for telomere maintenance and is believed to be crucial in most cancer cells, but its significance in gastric cancer remains unknown. This observational study investigated whether there is a relationship between telomerase activity and the development of gastric cancer, and between telomerase activity and peritoneal dissemination. Telomerase activity was measured in primary gastric cancers and in peritoneal washings from the same patients, and findings were compared with those of conventional cytology and an immunoassay for cancer antigen 125 (CA125). Positive cytological examination and telomerase activity in peritoneal washings both correlated with the histological grade, depth of tumour invasion, area of serosal invasion and peritoneal metastasis. The detection of free cancer cells in peritoneal washings by the telomeric repeat amplification protocol/enzyme-linked immunosorbent assay (TRAP–ELISA) was significantly more sensitive than cytology or the CA125 immunoassay, suggesting that this could be used to diagnose early peritoneal dissemination.
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Affiliation(s)
- X Hu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - H Wu
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - S Zhang
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - H Yuan
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - L Cao
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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