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Abstract Background Despite all benefit provided by established therapies prognosis of gastric cancer remains poor. Targeted inhibition of platelet derived growth factor receptor (PDGFR) by imatinib may influence tumor growth and amplify chemotherapeutic effects. Methods This phase I study evaluated dose limiting toxicity (DLT) of imatinib combinated with chemotherapy according to a 3-patient cohort dose-escalating design. Thirty-five patients received cisplatin (60 mg/m2 d1 q 3w)/ capecitabine (1250 mg/m2 bid d1-14 q 21) or cisplatin (50 mg/m2 d1 q 2w)/ 5-fluoruracil (2 g/m2 d1, q 1w). Imatinib was started d - 4 with dose escalation from 300 to 700 mg QD in 100 mg steps. Results At imatinib dose level 1 (300mg) one DLT was observed, three more patients were enrolled without further DLT. At dose level 5 (700 mg) two gastric perforations occurred, so 600 mg imatinib emerged as the maximum tolerated dose. Major grade 3/4 toxicities were nausea (6%), anemia (6%) and fatigue (3%). Response evaluation revealed partial response in 27% and stable disease in 43% of the assessable patients. Conclusions Combination of imatinib and chemotherapy is well tolerated. Response rates were not superior to those of standard therapy. Further investigations of a larger group of patients are required to confirm the amplification of chemotherapy effects by imatinib. Trial registration European Clinical Trials Database: Eudra-CT2006-005792-17 and Clinical Trials Database: NCT00601510

Docking protein-1 (DOK1) is a tumor suppressor frequently lost in malignant cells, however, it retains the ability to control activities of immune receptors in adjacent stroma cells of the tumor microenvironment. We therefore hypothesized that addressing DOK1 may be useful for cancer immunotherapy. DOK1 mRNA and DOK1 protein expression were downregulated in tumor cells of gastric cancer patients (n = 249). Conversely, its expression was up-regulated in cases positive for Epstein Barr Virus (EBV+) together with genes related to macrophage biology and targets of clinical immunotherapy such as programmed-cell-death-ligand-1 (PD-L1). Notably, high DOK1 positivity in stroma cells conferred poor prognosis in patients and correlated with high levels of inducible nitric oxide synthase in CD68+ tumor-associated macrophages. In macrophages derived from human monocytic leukemia cell lines, DOK1 (i) was inducible by agonists of the anti-diabetic transcription factor peroxisome proliferator-activated receptor-gamma (PPARγ), (ii) increased polarization towards an inflammatory phenotype, (iii) augmented nuclear factor-κB-dependent transcription of pro-inflammatory cytokines and (iv) reduced PD-L1 expression. These properties empowered DOK1+ macrophages to decrease the viability of human gastric cancer cells in contact-dependent co-cultures. DOK1 also reduced PD-L1 expression in human primary blood monocytes. Our data propose that the drugability of DOK1 may be exploited to reprogram myeloid cells and enforce the innate immune response against EBV+ human gastric cancer. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancers worldwide, ranking fourth in overall frequency, and accounting for over 870,000 new cases and over 650,000 deaths annually. While the incidence of gastric cancer has decreased, the absolute number of gastric cancer patients has increased due to an aging population. Mortality from gastric cancer is second only to lung cancer, despite the dramatic improvement witnessed over recent decades in the understanding of the epidemiology, pathology and pathogenesis of gastric cancer. Infection with H. pylon or Epstein-Barr virus, dietary and lifestyle factors contribute to the risk of developing gastric cancer. Gene polymorphisms have come to be recognized as crucial factors determining disease susceptibility in patients suffering from chronic gastritis. However, prognosis is still poor, and the search continues for novel diagnostic markers that may enable diagnosis of gastric cancer in its early stages, and novel patient-tailored therapeutic regimens. [ABSTRACT FROM AUTHOR]

Approximately 1 million individuals develop gastric cancer every year and the mortality of gastric cancer is only second to lung cancer. The poor prognosis is caused by late diagnosis of most cancers in advanced stages and the limited therapeutic options in these stages. Apart from the elucidation of underlying molecular and genetic changes in the development and progression of gastric cancers, the development of new treatment strategies is critical for the improvement of the treatment and prognosis of these patients. In this review we have summarized and critically assessed recent studies dealing with the chemotherapy of advanced gastric cancer. While the efficacy of most treatment regimens is only limited, new developments may indicate that treatment with chemotherapy may confer some benefit in the future. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is a tumour entity with highly variant outcomes. Lymph node metastasis is a prognostically adverse biomarker. We hypothesised that GC primary tissue contains information that is predictive of lymph node status and patient prognosis and that this information can be extracted using deep learning (DL). Using three patient cohorts comprising 1146 patients, we trained and validated a DL system to predict lymph node status directly from haematoxylin and eosin–stained GC tissue sections. We investigated the concordance between the DL-based prediction from the primary tumour slides (aiN score) and the histopathological lymph node status (pN). Furthermore, we assessed the prognostic value of the aiN score alone and when combined with the pN status. The aiN score predicted the pN status reaching area under the receiver operating characteristic curves of 0.71 in the training cohort and 0.69 and 0.65 in the two test cohorts. In a multivariate Cox analysis, the aiN score was an independent predictor of patient survival with hazard ratios of 1.5 in the training cohort and of 1.3 and 2.2 in the two test cohorts. A combination of the aiN score and the pN status prognostically stratified patients by survival with p -values <0.05 in logrank tests. GC primary tumour tissue contains additional prognostic information that is accessible using the aiN score. In combination with the pN status, this can be used for personalised management of GC patients after prospective validation. • Gastric cancer (GC) patients with the same pN status show variant outcomes. • Deep learning (DL) trained on primary tumour tissue can predict survival. • A combination of the DL score and the pN status can stratify GC patients. • This can identify patients at risk of poor outcome. [ABSTRACT FROM AUTHOR]

Abstract: Multiple studies have reported an association between disturbances of folate metabolism and increased risk of gastric cancer, including low intake of folate, low levels of folate in blood or genetic factors affecting folate metabolism. Among the genetic factors, in particular a common polymorphism in the gene encoding for 5,10-methylenetetrahydrofolate reductase (MTHFR C677T) has been linked to gastric cancer. Other polymorphisms in folate-metabolising genes have been less frequently investigated. Therefore, we analyzed this polymorphism, the glutamate carboxypeptidase (GCP) II C1561T and the reduced folate carrier (RFC) G80A in a case-control study involving 106 patients with histologically confirmed and characterized gastric cancer with adjustment for other established risk factors for gastric cancer in comparison to 106 age- and sex-matched controls. Neither the MTHFR nor the GCP gene polymorphisms showed an association to cancer diagnosis, to tumor stage, grade of differentiation or Lauren type. However, non-cardia cancers were more likely to exhibit the 80GA and 80AA RFC genotypes, compared to cancers of the gastric cardia (adjusted OR 0.28; 95% CI=0.11–0.71). Thus, gene polymorphisms of the RFC gene might contribute to an increased risk of developing distal gastric cancer. [Copyright &y& Elsevier]

Abstract: Peroxisome proliferator-activated receptor δ (PPARδ) is ligand-activated transcription factor of the nuclear receptor superfamily which is recently implicated in carcinogenesis. We examined the expression profiles of PPARδ in human gastric cancer, normal gastric mucosa and gastric cancer cell lines by RT-PCR, Western blot and immunohistochemistry. PPARδ mRNA and protein was found to be ubiquitously expressed in all 5 gastric cancer cell lines, 40 gastric cancer samples and 10 normal gastric mucosa from non-cancer patients. Positive immunoreactivity was detected in the nuclei of normal and malignant gastric epithelium. Treatment of gastric cell line MKN45 that overexpressed cyclooxygenase-2 (COX-2) with specific COX-2 inhibitor NS398 resulted in a time- and dose-dependent suppression of PPARδ expression. In contrast, there was no suppression of PPARδ in MKN28 gastric cell line with low COX-2 expression. Our results demonstrated the ubiquitous expression of PPARδ in normal and cancer gastric epithelium. Suppression of PPARδ may be one of the mechanisms underlying the chemopreventive effects of COX-2 inhibitor. [Copyright &y& Elsevier]