Evidence Map of Pancreatic Surgery-A living systematic review with meta-analyses by the International Study Group of Pancreatic Surgery (ISGPS)

Background: Pancreatic surgery is associated with considerable morbidity and, consequently, offers a large and complex field for research. To prioritize relevant future scientific projects, it is of utmost importance to identify existing evidence and uncover research gaps. Thus, the aim of this project was to create a systematic and living Evidence Map of Pancreatic Surgery. Methods: PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched for all randomized controlled trials and systematic reviews on pancreatic surgery. Outcomes from every existing randomized controlled trial were extracted, and trial quality was assessed. Systematic reviews were used to identify an absence of randomized controlled trials. Randomized controlled trials and systematic reviews on identical subjects were grouped according to research topics. A web-based evidence map modeled after a mind map was created to visualize existing evidence. Meta-analyses of specific outcomes of pancreatic surgery were performed for all research topics with more than 3 randomized controlled trials. For partial pancreatoduodenectomy and distal pancreatectomy, pooled benchmarks for outcomes were calculated with a 99% confidence interval. The evidence map undergoes regular updates. Results: Out of 30,860 articles reviewed, 328 randomized controlled trials on 35,600 patients and 332 systematic reviews were included and grouped into 76 research topics. Most randomized controlled trials were from Europe (46%) and most systematic reviews were from Asia (51%). A living meta-analysis of 21 out of 76 research topics (28%) was performed and included in the web-based evidence map. Evidence gaps were identified in 11 out of 76 research topics (14%). The benchmark for mortality was 2% (99% confidence interval: 1%–2%) for partial pancreatoduodenectomy and <1% (99% confidence interval: 0%–1%) for distal pancreatectomy. The benchmark for overall complications was 53% (99%confidence interval: 46%–61%) for partial pancreatoduodenectomy and 59% (99% confidence interval: 44%–80%) for distal pancreatectomy. Conclusion: The International Study Group of Pancreatic Surgery Evidence Map of Pancreatic Surgery, which is freely accessible via www.evidencemap.surgery and as a mobile phone app, provides a regularly updated overview of the available literature displayed in an intuitive fashion. Clinical decision making and evidence-based patient information are supported by the primary data provided, as well as by living meta-analyses. Researchers can use the systematic literature search and processed data for their own projects, and funding bodies can base their research priorities on evidence gaps that the map uncovers

Aberrant O-GaINAc glycosylation to enhance AKT/mTOR signaling in pancreatic cancer.

Background: Immature truncated O-GalNAc glycosylation is an important feature of pancreatic ductal adenocarcinomas and is detected with high frequency in premalignant lesions. Differential expression of O-GalNAc glycans Tn antigen and sialyl-Tn antigen is strongly associated with decreased survival and poor prognosis and frequently occurs in pancreatic cancer due to hypermethylation of the COSMC (C1GALT1C1)gene. COSMC knockdown experiments displayed reduced rate of apoptosis and enhanced migratory behavior, thereby promoting oncogenic properties in pancreatic cancer cells. Since the underlying biological processes are not well understood, we investigated the impact of aberrant O-GalNAc glycosylation on AKT/mTOR signaling in Panc-1 and L3.6pl COSMC knockdown cells. Methods: Lentiviral mediated COSMC knockdown cell lines were subjected to stable isotope labeling by amino acids (SILAC) and subsequently analyzed by mass spectromic quantitative proteomics. Immunoprecipitation, Western blot analysis and real time PCR were used to assess glycotype dependent signaling molecule expression and phosphorylation status. Results: In COSMC knockdown cells, quantitative proteomics identified proteins associated to IGF, EGF and PI3K pathways. We could further identify AKT as novel O-GalNAc-modified protein in Panc-1 pancreatic cancer cell line. AKT downstream substrates S6 ribosomal protein and GSK-3b displayed an enhanced phosphorylation and AKT upstream effectors, such as IGF-I receptor and mTORC2 complex showed an enhanced activation in COSMC knockdown cells. Interestingly, aberrant O-glycosylation was able to modify mTOR S2448 phosphorylation in L3.6pl COSMC knockdown cells treated with mTORC inhibitor AZD8055. Conclusions: Our study revealed an enhanced AKT/mTOR signaling in pancreatic cancer COSMC knockdown cells, which is driven by aberrant O-GalNAc glycosylation and substantiates the previously observed enhancement of oncogenic properties

Extent of liver resection modulates the activation of transcription factors and the production of cytokines involved in liver regeneration

AIM: To investigate the molecular events involved in liver regeneration following subtotal hepatectomy (SH) as previous studies have largely focused on partial hepatectomy (PH)

Loss of 4q21.23-22.1 is a prognostic marker for disease free and overall survival in non-small cell lung cancer.

This study was performed to assess the prognostic relevance of genomic aberrations at chromosome 4q in NSCLC patients. We have previously identified copy number changes at 4q12-q32 to be significantly associated with the early hematogenous dissemination of non-small cell lung cancer (NSCLC), and now aim to narrow down potential hot-spots within this 107 Mb spanning region. Using eight microsatellite markers at position 4q12-35, allelic imbalance (AI) analyses were performed on a preliminary study cohort (n = 86). Positions indicating clinicopathological and prognostic associations in AI analyses were further validated in a larger study cohort using fluorescence in situ hybridization (FISH) in 209 NSCLC patients. Losses at positions 4q21.23 and 4q22.1 were shown to be associated with advanced clinicopathological characteristics as well as with shortened disease free (DFS) and overall survival (OS) (DFS: P = 0.019; OS: P = 0.002). Multivariate analyses identified the losses of 4q21.23-22.1 to be an independent prognostic marker for both DFS and OS in NSCLC (HR 1.64-2.20, all P<0.04), and especially in squamous cell lung cancer (P<0.05). A case report study of a lung cancer patient further revealed a loss of 4q21.23 in disseminated tumor cells (DTCs). Neither gains at the latter positions, nor genomic aberrations at 4q12, 4q31.2 and 4q35.1, indicated a prognostic relevance. In conclusion, our data indicate that loss at 4q21.23-22.1 in NSCLC is of prognostic relevance in NSCLC patients and thus, includes potential new tumor suppressor genes with clinical relevance

p53 overexpression is a prognosticator of poor outcome in esophageal cancer

Immunohistochemistry studies on p53 inactivation in esophageal cancer are available with inconclusive results. Data on the combined effect of p53 protein accumulation and TP53 genomic deactivation in large scale studies for esophageal cancer are currently lacking. A tissue microarray with 691 esophageal cancer samples was analyzed by p53 immunohistochemistry and fluorescence in situ hybridization (FISH). Nuclear p53 accumulation was observed in 45.9% of patients with adenocarcinoma (AC) and in 40.0% in squamous cell carcinoma (SCC). Heterozygous TP53 deletions occurred in 40.9% in AC and in 19.4% in SCC. Homozygous deletions did not occur at all. High-level p53 immunostaining was associated with shortened overall survival in AC and SCC while TP53 deletions alone showed no correlation with survival. High-level p53 immunostaining in patients with AC was associated with advanced tumor (P=0.019) and Union for International Cancer Control stages (P=0.004), grading (P=0.027) and the resection margin status (P=0.006). Associations between p53 immunostaining and SCC were not found. TP53 deletions were found to be associated with advanced tumor stages (P=0.028) and the presence of lymph node metastasis (P=0.009) in SCC. In conclusion, strong p53 immunostaining, but not TP53 deletion alone, is associated with unfavorable outcomes and may therefore represent a clinically useful molecular marker in esophageal cancer

Multivariate analysis RP11-1053C2.

<p>Cox regression hazard model was used for multivariate analysis to assess the prognostic value of aberrations.</p><p>HR, hazard ratio; CI, confidence interval; UICC, Union for International Cancer Control.</p><p>Multivariate analysis RP11-1053C2.</p