Current standards of surgical management of gastric cancer: an appraisal.

PURPOSE: Gastric cancer (GC) is the fifth most common malignancy worldwide and portends a grim prognosis due to a lack of appreciable improvement in 5-year survival. We aimed to analyze the available literature and summarize the current standards of surgical care for curative and palliative intent treatment of GC. METHODS: We conducted a systematic search on the PubMed database for studies on the management of GC. RESULTS: Endoscopic resection is an acceptable treatment option for T1a tumors. The role of optimal resection margin for GC remains unclear. D2 lymph node dissection remains the standard of care with splenectomy needed selectively for splenic hilum involvement. A distal pancreatic resection should be avoided. The advantage of bursectomy and omentectomy in GC surgery is not clear. Multi-visceral resection may be considered for locally advanced GC in carefully selected patients. Minimally invasive approaches are non-inferior to open surgery. Surgery should be abandoned prior even in metastatic GC within the frame of multimodal therapy approach. CONCLUSION: Various trials have conclusively shown improved patient outcomes when well-established surgical standards are followed.

HSP90 is a promising target in gemcitabine and 5-fluorouracil resistant pancreatic cancer.

Chemotherapy (CT) options in pancreatic cancer (PC) are limited to gemcitabine and 5-fluorouracil (5-FU). Several identified molecular targets in PC represent client proteins of HSP90. HSP90 is a promising target since it interferes with many oncogenic signaling pathways simultaneously. The aim of this study was to evaluate the efficacy of different HSP90 inhibitors in gemcitabine and 5-FU resistant PC. PC cell lines 5061, 5072 and 5156 were isolated and brought in to culture from patients being operated at our institution. L3.6pl cell line served as a control. Anti-proliferative efficacy of three different HSP90 inhibitors (17-AAG, 17-DMAG and 17-AEPGA) was evaluated by the MTT assay. Alterations in signaling pathway effectors and apoptosis upon HSP90 inhibition were determined by western blot analysis and annexin V/PI staining. The cell lines 5061, 5072 and 5156 were resistant to gemcitabine and 5-FU. In contrast 17-AAG and the water-soluble derivates 17-DMAG and 17-AEPGA displayed high anti-proliferative activity in all tested cell lines. The calculated IC50 was below 1 µM. Highly significant down regulation of epidermal-growth-factor-receptor, insulin-like-growth-factor-receptor-1, AKT and MAPK reflected the intracellular molecular signaling-network disruption. Furthermore, besides HSP70 also HSP27 was upregulated in all cell lines. Apoptosis occurred early under HSP90 inhibition and was determined by annexin V/PI staining and CASPASE-3 and PARP assay. In contrast, gemcitabine treated cells did not show any apoptosis. HSP90 inhibition disrupts multiple signaling cascades in gemcitabine and 5-FU resistant PC simultaneously and promotes cancer cell apoptosis. Watersoluble 17-DMAG is equally effective as 17-AAG. HSP27, besides HSP70, may represent an effective response marker of successful HSP90 inhibition.

An A/C germline single-nucleotide polymorphism in the TNFAIP3 gene is associated with advanced disease stage and survival in only surgically treated esophageal cancer.

Prognostication of disease relapse and survival is essential for cancer patients and genetic variations in cancer patients may serve as important indicators. A single-nucleotide polymorphism (SNP) mapping to the tumor necrosis factor, alpha-induced protein 3 (TNFAIP3) gene at position 138241110 displays three genotypes (AA, AC and CC). The aim of this study was to evaluate the potential prognostic value of the TNFAIP3-SNP in esophageal cancer (EC). Genomic DNA was extracted from peripheral blood leukocytes of 173 patients who underwent complete surgical resection for EC and did not receive any neoadjuvant or adjuvant therapy. For SNP detection, a 260- bp fragment was PCR amplified, purified and sequenced with tested primers. The product was analyzed by automatic DNA sequencer.The TNFAIP3 genotypes were correlated with clinico-pathological parameters, tumor cell dissemination in bone marrow and clinical outcome. The C-allele carrier presented with higher disease stage (P<0.001). This was predominantly because of the presence of lymph node metastasis (P<0.001). The recurrence rate was higher in C-allele carriers (AC and CC genotype; P=0.004). Kaplan-Meier plots for disease-free (P=0.017) and overall survival (P<0.001) displayed a gene dosage-associated outcome with AA genotype patients presenting the longest and CC genotype patients the poorest survival. In disease stage-adjusted multivariate analysis the TNFAIP3-SNP was identified as an independent prognostic factor for survival (hazard ratio 1.9; P=0.008). The TNFAIP3-SNP allows risk stratification of EC patients and may be a useful tool to identify patients eligible for multimodal therapy concepts.

Effects of everolimus on oxidative stress in kidney model of ischemia/reperfusion injury.

BACKGROUND/AIMS: Reactive oxygen species play an important role in the pathogenesis of kidney ischemia/reperfusion injury (IRI) which may be influenced by immunosuppressive therapy. Pertinent to this, we investigated the effects of the mTOR inhibitor everolimus on redox settings and the activity of the anti-oxidative system in kidneys exposed to IRI. METHODS: C57BL/6 mice were subjected to IRI by clamping both renal pedicles for 45 min. Everolimus was applied in daily, subcutaneous doses (0.25 mg/kg body weight), starting 1 day before IRI induction. Both everolimus-treated and non-treated mice were sacrificed at several time points, starting 30 min and finishing 7 days after IRI induction. Markers of oxidation such as glutathione and NADPH levels and anti-oxidative enzyme activities were determined in the kidneys. RESULTS: In comparison to both sham and non-treated animals, the treatment with everolimus resulted in an increased level of markers of oxidation, including a lower level of glutathione, increased level of oxidized glutathione and reduced level of NADPH. The activity of superoxide dismutase was reduced in both experimental groups, but the effects were less pronounced in everolimus-treated animals. In the early phase of reperfusion, everolimus-treated animals showed higher activity of glutathione reductase in comparison to non-treated animals, whereas the activities of glutathione peroxidase and catalase were generally similar. The treatment with everolimus significantly reduced heme oxygenase-1 expression and increased iNOS mRNA expression when compared to non-treated animals. CONCLUSION: Our data imply that everolimus treatment may decrease cytoprotective capacity in kidneys exposed to IRI due to promoted oxidative/nitrosative stress.

Interleukin 2 receptor antagonists for liver transplant recipients: a systematic review and meta-analysis of controlled studies.

UNLABELLED: Interleukin 2 receptor antagonists (IL-2Ra) are frequently used as induction therapy in liver transplant recipients to decrease the risk of acute rejection while allowing the reduction of concomitant immunosuppression. We conducted a systematic review of prospective, controlled studies to test the hypothesis that the use of IL-2Ra is associated with a decrease in acute rejection and/or a decrease in the side effects of concomitant medication. We performed a search of all major databases and secondary sources from inception to December 2010. Random effects models were used to assess the incidence of acute rejection, graft loss, patient death, and adverse side effects, with or without IL-2Ra. Subgroup analysis and meta-regression were used to explore differences in effect and sources of heterogeneity. Eighteen studies (13 randomized and 5 nonrandomized) met the inclusion and exclusion criteria. Acute rejection at 12 months or later favored the use of IL-2Ra (relative risk [RR] 0.83; 95% confidence interval [CI] 0.76-0.94) and steroid-resistant rejection was also less frequent in patients receiving IL-2Ra (RR 0.66; CI 0.48-0.91). Graft loss and patient death did not differ significantly between treatments. Patients who received IL-2Ra in addition to reduced or delayed calcineurin inhibitors had better renal function (mean difference of estimated glomerular filtration rate: 6.29 mL/min; CI 1.66-10.91) and a lower incidence of renal dysfunction (RR 0.46; CI 0.27-0.78). The use of IL-2Ra was also associated with a lower incidence of posttransplant diabetes mellitus, whereas the incidence of other adverse events was similar. CONCLUSION: The use of IL-2Ra is associated with a lower incidence of acute rejection after transplantation. Concomitant immunosuppression can be reduced, avoiding long-term side effects of immunosuppression.

A therapeutic exploratory study to determine the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation: CILT.

BACKGROUND: Immunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. METHODS/DESIGN: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT. DISCUSSION: This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase II study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial. TRIAL REGISTRATION NUMBER: NCT00890253 (clinicaltrials.gov).