DNA polymeraseη protein expression predicts treatment response and survival of metastatic gastric adenocarcinoma patients treated with oxaliplatin-based chemotherapy

<p>Abstract</p> <p>Background</p> <p>DNA polymerase η (pol η) is capable of bypassing DNA adducts produced by cisplatin or oxaliplatin and is associated with cellular tolerance to platinum. Previous studies showed that defective pol η resulted in enhanced cisplatin or oxaliplatin sensitivity in some cell lines. The purpose of the present study was to investigate the role of pol η protein expression in metastatic gastric adenocarcinoma.</p> <p>Methods</p> <p>Four gastric adenocarcinoma cell lines were chosen to explore the relationship between pol η protein expression and oxaliplatin sensitivity by western blotting and MTT assay. Eighty metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX regimen as first-line chemotherapy were analyzed, corresponding pretreatment formalin-fixed paraffin-embedded tumor tissues were used to detect pol η protein expression by immunohistochemistry. Relationship between pol η protein expression and clinical features and outcome of these patients was analyzed.</p> <p>Results</p> <p>A positive linear relationship between pol η protein expression and 48 h IC50 values of oxaliplatin in four gastric cancer cell lines was observed. Positivity of pol η protein expression was strongly associated with poor treatment response, as well as shorter survival at both univariate (8 versus 14 months; P < 0.001) and multivariate (hazard ratio, 4.555; 95% confidence interval, 2.461-8.429; P < 0.001) analysis in eighty metastatic gastric adenocarcinoma patients.</p> <p>Conclusions</p> <p>Our study indicates that polη is a predictive factor of treatment response and survival of metastatic gastric adenocarcinoma patients treated with FOLFOX or XELOX as first-line chemotherapy. Therefore confirming the value of polη in studies with prospective design is mandatory.</p

Biologic therapy in esophageal and gastric malignancies: Current therapies and future directions

Biologic agents, including targeted antibodies as well as immunomodulators, are demonstrating unparalleled development and study across the entire spectrum of human malignancy. This review summarizes the current state of biologic therapies for esophageal, esophagogastric, and gastric malignancies, including those that target human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), c-Met, mechanistic target of rapamycin (mTOR) and immunomodulators. We focus primarily on agents that have been included in phase II and III clinical trials in locally advanced, progressive, or metastatic esophageal and gastric malignancies. At this time, only two biologic therapies are recommended by the National Comprehensive Cancer Network (NCCN): trastuzumab for patients with esophageal/esophagogastric or gastric adenocarcinomas with HER2 overexpression and ramucirumab, a VEGFR-2 inhibitor, as a second-line therapy for metastatic disease. However, recent reports of increases in overall and progression-free survival for agents including pertuzumab, apatinib, and pembrolizumab will likely increase the use of targeted biologic therapy in clinical practice for esophageal and gastric malignancies

Low Expression of DYRK2 (Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2) Correlates with Poor Prognosis in Colorectal Cancer.

Dual-specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) is a member of dual-specificity kinase family, which could phosphorylate both Ser/Thr and Tyr substrates. The role of DYRK2 in human cancer remains controversial. For example, overexpression of DYRK2 predicts a better survival in human non-small cell lung cancer. In contrast, amplification of DYRK2 gene occurs in esophageal/lung adenocarcinoma, implying the role of DYRK2 as a potential oncogene. However, its clinical role in colorectal cancer (CRC) has not been explored. In this study, we analyzed the expression of DYRK2 from Oncomine database and found that DYRK2 level is lower in primary or metastatic CRC compared to adjacent normal colon tissue or non-metastatic CRC, respectively, in 6 colorectal carcinoma data sets. The correlation between DYRK2 expression and clinical outcome in 181 CRC patients was also investigated by real-time PCR and IHC. DYRK2 expression was significantly down-regulated in colorectal cancer tissues compared with adjacent non-tumorous tissues. Functional studies confirmed that DYRK2 inhibited cell invasion and migration in both HCT116 and SW480 cells and functioned as a tumor suppressor in CRC cells. Furthermore, the lower DYRK2 levels were correlated with tumor sites (P = 0.023), advanced clinical stages (P = 0.006) and shorter survival in the advanced clinical stages. Univariate and multivariate analyses indicated that DYRK2 expression was an independent prognostic factor (P &lt; 0.001). Taking all, we concluded that DYRK2 a novel prognostic biomarker of human colorectal cancer

Retrospective comparison of flot and modified dcf as first-line chemotherapy in metastatic gastric adenocarcinoma

Background: The aim of our study was to compare the efficacy and the safety of the FLOT and the modified DCF (mDCF) regimens in patients with metastatic gastric (GC) and gastroesophageal junction (GEJ) adenocarcinoma as first-line treatment. Methods: The medical records of 72 patients were retrospectively reviewed. Survivals and hematological adverse events of the patients were examined. Factors affecting survivals were analyzed in univariate analysis. A multivariate analysis was performed with the factors contributing to survivals in univariate analysis. Results: The median PFS (mPFS) was 10.1 months (95% CI, 6.8-13.4) in the FLOT arm (n = 33) and 7.4 months (95% CI, 9.1-21.6) in the mDCF arm (n = 39) (p = 0.041). The median OS (mOS) was 12.9 months (95% CI, 9.7-16.1) in the FLOT arm and 15.4 months (95% CI, 9.1-21.6) in the mDCF arm (p = 0.622). It was found that all grade neutropenia was 51.3% vs. 72.7% (p = 0.063), febrile neutropenia was 8.3% vs. 6.3% (p = 0.743), and thrombocytopenia was 48.7% vs. 51.5% (p = 0.813) in the FLOT and mDCF arms, respectively. Anemia was 59% in the FLOT arm and 100% in the mDCF arm (p < 0.001). Grade 3-4 anemia was 7.7% in the FLOT arm and 24.2% in the mDCF arm (p = 0.052). Discussion: It was shown that the mPFS was significantly increased in the FLOT arm compared to the mDCF arm as the first-line treatment in patients with metastatic GC and GEJC. Hematological adverse events were more favorable in the FLOT arm than in the mDCF arm

Role of cachexia and fragility in the patient candidate for cardiac surgery

Frailty is the major expression of accelerated aging and describes a decreased resistance to stressors, and consequently an increased vulnerability to additional diseases in elderly people. The vascular aging related to frail phenotype reflects the high susceptibility for cardiovascular diseases and negative postoperative outcomes after cardiac surgery. Sarcopenia can be considered a biological substrate of physical frailty. Malnutrition and physical inactivity play a key role in the pathogenesis of sarcopenia. We searched on Medline (PubMed) and Scopus for relevant literature published over the last 10 years and analyzed the strong correlation between frailty, sarcopenia and cardiovascular diseases in elderly patient. In our opinion, a right food intake and moderate intensity resistance exercise are mandatory in order to better prepare patients undergoing cardiac operation

Molecular Prognostic Factors in Gastric Cancer

Gastric cancer represents a major health problem worldwide. Literature data have demonstrated that gastric tumors present a high molecular heterogeneity, responsible for the process of carcinogenesis and dissemination. By revealing the molecular subtype of the tumor, it is possible to assess its behavior, the outcome of the patient, and the treatment approach, according to its genetic and epigenetic profile. This chapter aims to highlight some of the many different genetic mutations, epigenetic alterations, as well as aberrant signaling pathways involved in the pathogenesis of stomach cancers, each of these molecular abnormalities acting in a specific stage of the disease. Moreover, the manuscript describes the novel therapeutic agents that target some of these aberrant molecular signaling pathways. Unfortunately, only a few agents are currently part of the standard treatment of gastric cancer, while most of the others remain to prove their therapeutic efficacy in the setting of clinical trials. By discovering the different molecular subtypes of gastric cancer, as well as numerous classes of targeted molecular agents, in the future, we would be able to perform an individualized treatment, associated with maximum efficiency and less costs

Syndrome métabolique affectant les survivants de la leucémie lymphoblastique aiguë pédiatrique : rôle et dysfonctions des lipoprotéines « HDL »

La leucémie lymphoblastique aiguë est le cancer le plus fréquent dans la population pédiatrique. L’amélioration des traitements a permis d’atteindre une survie à 5 ans post- diagnostic surpassant les 90%. Cette réussite de la médecine moderne s’accompagne toutefois d’importants effets à long terme. Ainsi, plus de 65% des survivants présentent au moins une complication sévère comme le syndrome métabolique et les maladies cardiovasculaires. Dans ce contexte, une importante proportion de survivants de cancers pédiatriques présente un taux abaissé du contenu en cholestérol des lipoprotéines de haute densité (HDL-Cholestérol). Les causes d’un tel désordre ne sont pas connues. Les HDLs sont des particules multifonctionnelles primordiales pour le maintien de la santé cardiométabolique, entre autres, de par leurs nombreuses actions antioxydantes, anti-athérosclérotiques, anti-inflammatoires et anti- thrombotiques. L’étude de la fonctionnalité des HDLs dans plusieurs pathologies a révélé des dysfonctionnements importants liés à des altérations de leur composition. L’objectif de cette étude était de caractériser les HDLs isolées de survivants de la leucémie lymphoblastique aiguë pédiatrique au niveau de leur composition et fonctionnalité. Les HDLs des survivants contiennent moins de cholestérol que les HDLs de sujets contrôles. L’analyse du protéome a révélé un enrichissement des HDLs des survivants métaboliquement non sains en protéines pro-thrombotiques (ex : fibrinogène) et pro- inflammatoires (ex : amyloïde sérique A). La capacité à promouvoir l’efflux de cholestérol ainsi que la capacité antioxydante de ces HDLs n’en était pas affectée. Les résultats de ces travaux indiquent une altération de la composition et du protéome des HDLs de survivants de la leucémie lymphoblastique aiguë pédiatrique. Bien que plus d’études soient nécessaires pour la validation de la fonctionnalité de ces HDLs, ces travaux semblent pertinents pour la santé des survivants étant donné la révélation de biomarqueurs potentiels du métabolisme et de la fonctionnalité des HDLs, et donc de l’athérosclérose.Acute lymphoblastic leukemia is the most frequent malignancy in children. With the use of more modern, efficient treatments, 5-year survival has reached more than 90% in this population. However, this achievement comes with many long-term effects: more than 65% of the survivors experience at least one severe complication, including the metabolic syndrome and cardiovascular diseases. In this context, a significant proportion of pediatric cancer survivors have low HDL-Cholesterol levels. The causes of such an abnormality remain so far unknown. HDLs are multifunctional particles, which are primordial in maintaining cardiovascular health given their antioxidative, anti-atherosclerosis, anti-inflammatory and anti- thrombotic capacities, to name but a few functions. Accordingly, studies on HDL functionality in diverse pathologies have revealed some important losses of functions linked to an altered composition. The main objective of the present work was to characterize the composition and functionality of HDLs isolated from pediatric acute lymphoblastic leukemia survivors. The HDL fractions from the survivors contained less cholesterol than the controls. In addition, proteomic analyses using mass spectrometry revealed an enrichment of pro-thrombotic (e.g. fibrinogen) and pro-inflammatory (e.g. serum amyloid A) proteins in the HDLs deriving from metabolically unhealthy survivors. The cholesterol efflux and antioxidant capacities of these HDLs were similar to those of the controls. These results indicate an alteration in the composition of lipid and protein content of HDLs from childhood acute lymphoblastic leukemia survivors with metabolic disorders. Although more work is needed to validate the functionality of these HDLs, the data seem relevant for survivor health given the detection of potential biomarkers related to HDL metabolism and functionality in cancer