Background The aim of this study is to report the experience with conversion surgery from six Gruppo Italiano Ricerca Cancro Gastrico (GIRCG) centers, focusing our analysis on factors affecting survival and the risk of recurrence. Methods A retrospective, multicenter cohort study was performed in patients who had undergone conversion gastrectomy between 2005 and 2017. Data were extracted from a GIRCG database including all metastatic gastric cancer patients submitted to surgery. Only stage IV unresectable tumors/metastases which became resectable after chemotherapy were included in this analysis. Results Forty-five resected M1 patients were included in the analysis. Reasons for being deemed unresectable at diagnosis were peritoneal involvement (PCI > 6) (n = 38, 84.4%), distant metastatic nodes (n = 3, 6.6%) and extensive liver involvement (n = 4, 8.8%). Median follow-up was 25 months (IQR 9-50). Median overall survival from surgery was 15 months and 1-, 3-and 5-year survivals were 57.2, 36.1 and 24%, respectively. Median progression-free survival was 12 months with 1-and 3-year survival of 46.4 and 33.9%, respectively. At cox regression analysis the only independent prognostic factor for OS was the presence of more than one type of metastasis (HR 4.41,, p = 0.002). A positive microscopic resection margin was the only risk factor for recurrence (HR 5.72, 95% CI 1.04-31.4, p = 0.045). Conclusions Unresectable stage IV GC patients could benefit from radical surgery after chemotherapy and achieve long survivals. The main prognostic factor for these patients was the presence of more than one type of extra-gastric metastatic involvement.
GPBAR1 (also known as TGR5) is a bile acid activated receptor expressed in several adenocarcinomas and its activation by secondary bile acids increases intestinal cell proliferation. Here, we have examined the expression of GPBAR1 in human gastric adenocarcinomas and investigated whether its activation promotes the acquisition of a pro-metastatic phenotype. By immunohistochemistry and RT-PCR analysis we found that expression of GPBAR1 associates with advanced gastric cancers (Stage III-IV). GPBAR1 expression in tumors correlates with the expression of N-cadherin, a markers of epithelial-mesenchymal transition (EMT) (r=0.52; P<0.01). Expression of GPBAR1, mRNA and protein, was detected in cancer cell lines, with MKN 45 having the higher expression. Exposure of MKN45 cells to GPBAR1 ligands, TLCA, oleanolic acid or 6-ECDCA (a dual FXR and GPBAR1 ligand) increased the expression of genes associated with EMT including KDKN2A, HRAS, IGB3, MMP10 and MMP13 and downregulated the expression of CD44 and FAT1 (P<0.01 versus control cells). GPBAR1 activation in MKN45 cells associated with EGF-R and ERK1 phosphorylation. These effects were inhibited by DFN406, a GPBAR1 antagonist, and cetuximab. GPBAR1 ligands increase MKN45 migration, adhesion to peritoneum and wound healing. Pretreating MKN45 cells with TLCA increased propensity toward peritoneal dissemination in vivo. These effects were abrogated by cetuximab. In summary, we report that GPBAR1 is expressed in advanced gastric cancers and its expression correlates with markers of EMT. GPBAR1 activation in MKN45 cells promotes EMT. These data suggest that GPBAR1 antagonist might have utility in the treatment of gastric cancers.
Background The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. Methods The Italian Peritoneal Surface Malignancies Oncoteam—S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. Results A total of 91 patients with a median age of 58 years (range 26–75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8–28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4–10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1–16.2; treated patients: 35.3 months, 95% CI 2.8–67.8; p = 0.022). Conclusions In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.
The purpose of the study was to investigate the clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. We conducted a retrospective multicentre review. We evaluated how survival from surgery was influenced by patient-related, tumour-related and treatment-related prognostic factors. We analysed data on 144 patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting. In 117 cases, an R0 resection was achieved, while in 27 an R + hepatic resection was performed. Chemotherapy was administered to 55 patients. Surgical mortality was 2.1% and morbidity 21.5%. One-, 3-, and 5-year OS rates after surgery were 49.9, 19.4 and 11.6%, respectively, with a median OS of 12.0 months. T4 gastric cancer, H3 hepatic involvement, non-curative resection, recurrence after surgery, and abstention from chemotherapy were associated with a worse prognosis. Factor T and H displayed a clear (p < 0.001) cumulative effect. Our data show that R0 resection must be pursued whenever possible. The treatment of T4 gastric cancer with hepatic bilateral and diffuse metastasis (H3) should be considered carefully or it should be probably avoided. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.
Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC.
Background/Aim: This work explored the prognostic role of curative versus non-curative surgery, the prognostic value of the various localizations of metastatic disease, and the possibility of identifying patients to be submitted to aggressive therapies. Patients and Methods: Retrospective chart review of stage IV patients operated on in our institutions. Results: Two hundred and eighty-two patients were considered; 73.4% had a single metastatic presentation. In 117 cases, a curative (R0) resection of primary and metastases was possible; 75 received a R1 resection and 90 a palliative R2 gastrectomy. Surgery was integrated with chemotherapy in multiple forms: conversion therapy, HIPEC, neo-adjuvant and adjuvant treatment. Median overall survival (OS) of the entire cohort was 10.9 months, with 14 months for the R0 subgroup. There was no correlation between metastasis site and survival. At multivariate analysis, several variables associated with the lymphatic sphere showed prognostic value, as well as tumor histology and the curativity of the surgical procedure, with a worse prognosis associated with a low number of resected nodes, D1 lymphectomy, pN3, non-intestinal histology, and R+ surgery. Considering the subgroup of R0 patients, the variables pT, pN and D displayed an independent prognostic role with a cumulative effect, showing that patients with no more than 1 risk factor can reach a median survival of 33 months. Conclusions: Our data show that the possibility of effective care also exists for Western patients with stage IV gastric cancer.
BackgroundThe aim of our study is to analyze survival, treatment-related morbidity, and safety in our experience of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.MethodsSixty-four patients were treated. Survival curves were calculated according to the Kaplan-Meier method. Univariate and multivariate analyses were done, and Cox’s proportional hazard model was used to identify significant factors.ResultsGlobal 5-year overall survival was 55 %. Overall survival was also evaluated according to neutrophils to lymphocytes ratio and neutrophils to platelets ratio. Overall survival according to pre-operative serum albumin level shows a difference in the two groups (P < 0.05). We observed minor or no adverse events in 53 cases (89.8 %), while 3 patients (5.1 %) showed a grade III–IV complication and 3 post-operative deaths (5.1 %). Post-operative complication also influenced overall survival; patients in whom a minor complication occurred had a 3-year overall survival (OS) of 62 % vs. a 3-year OS of 28 % in patients who underwent a major complication (P < 0.1).ConclusionsHyperthermic intraperitoneal chemotherapy (HIPEC) could be a valid and feasible option for selected patients affected by gastrointestinal malignancies’ peritoneal carcinomatosis.Pre-operative parameters could be evaluated to choose patient who could benefit from cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
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