LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases--a randomized, placebo-controlled, multicenter, multinational, double-blinded phase II trial

Background: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 mug once weekly for 8 weeks, followed by s.c. L-BLP25 930 mug maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned. Discussion: The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion. Trial Registration EudraCT Number 2011-000218-2

Genome-wide association study of germline variants and breast cancer-specific mortality

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10

A critical regulatory role of leucin zipper transcription factor c-Maf in Th1-mediated experimental colitis

In this study, we investigated the role of c-Maf, a transcription factor known to induce IL-4 production, in inflammatory bowel diseases and experimental colitis. Although Crohn′s disease (CD) is associated with low IL-4 production by T-bet-expressing Th1 cells in the lamina propria, surprisingly a higher expression of c-Maf in these cells was found as compared with control patients. The relevance of this finding was further evaluated in an animal model of CD induced by adoptive transfer of CD4+CD62L+ T cells in RAG-deficient mice. In this Th1-mediated model, an increase of c-Maf-expressing T lymphocytes in the lamina propria over time was observed. Interestingly, adoptive transfer of c-Maf transgenic CD4+CD62L+ T cells in RAG-1-deficient mice resulted in an IL-4-dependent inability to induce colitis and suppressed colitis activity induced by wild-type CD4+CD62L+ T cells. In contrast, transfer of CD4+CD62L− T cells from c-Maf transgenic, but not wild-type mice induced colitis and augmented colitis induced by CD4+CD62L+ T cells from wild-type mice in an IL-4-independent pathway, as determined by macroscopic, histologic, and endoscopic criteria. This was associated with an accumulation of CD4+ T-bet+ CD25+ effector Th1 cells in the lamina propria of colitic mice. Our results reveal a novel regulatory role of c-Maf in colitis. Although overexpression of c-Maf in naive T cells prevents Th1-mediated colitis, overexpression of c-Maf in memory T-bet+ Th1 cells regulates CD25 expression and augments such colitis. Targeting of c-Maf in memory T cells in CD appears to be an attractive target for therapeutic interventions

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study

Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA.status: publishe

Predicting survival after transarterial chemoembolization for hepatocellular carcinoma using a neural network: A Pilot Study

Background and aims Deciding when to repeat and when to stop transarterial chemoembolization (TACE) in patients with hepatocellular carcinoma (HCC) can be difficult even for experienced investigators. Our aim was to develop a survival prediction model for such patients undergoing TACE using novel machine learning algorithms and to compare it to conventional prediction scores, ART, ABCR and SNACOR. Methods For this retrospective analysis, 282 patients who underwent TACE for HCC at our tertiary referral centre between January 2005 and December 2017 were included in the final analysis. We built an artificial neural network (ANN) including all parameters used by the aforementioned risk scores and other clinically meaningful parameters. Following an 80:20 split, the first 225 patients were used for training; the more recently treated 20% were used for validation. Results The ANN had a promising performance at predicting 1-year survival, with an area under the ROC curve (AUC) of 0.77 +/- 0.13. Internal validation yielded an AUC of 0.83 +/- 0.06, a positive predictive value of 87.5% and a negative predictive value of 68.0%. The sensitivity was 77.8% and specificity 81.0%. In a head-to-head comparison, the ANN outperformed the aforementioned scoring systems, which yielded lower AUCs (SNACOR 0.73 +/- 0.07, ABCR 0.70 +/- 0.07 and ART 0.54 +/- 0.08). This difference reached significance for ART (P < .001); for ABCR and SNACOR significance was not reached (P = .143 and P = .201). Conclusions Artificial neural networks could be better at predicting patient survival after TACE for HCC than traditional scoring systems. Once established, such prediction models could easily be deployed in clinical routine and help determine optimal patient care