Population-based analysis of treatment patterns and outcomes for pancreas cancer in Victoria.

BACKGROUND: The Victorian Pancreas Cancer summit 2017 analysed state-wide data on management of Victorians with pancreas cancer between 2011 and 2015 to identify variations in care and outcomes. Pancreas cancer remains a formidable disease but systemic therapies are increasingly effective. Surgery remains essential but insufficient alone for cure. Understanding patterns of care and identifying variations in treatment is critical to improving outcomes. METHODS: This population-based study analysed data collected prospectively by Department of Health and Human services (Victorian state government). Data were extracted from Victorian Cancer Registry (covering all Victorian cancer diagnoses), Victorian Admitted-Episodes Dataset (all inpatient data), Victorian Radiotherapy Minimum Dataset and Victorian Death Index providing demographics, tumour and treatment characteristics, age-standardized incidence, overall and median survival. RESULTS: Of 3962 Victorian patients with any form of pancreatic malignancy, 82% were ductal adenocarcinoma (PDAC), of whom 67% had metastases at diagnosis. One-year overall survival for PDAC was 30% (60% non-metastatic, 15% if metastatic). Median survival with metastases increased from 2.7 to 3.9 months, and from 13.3 to 15.9 months for non-metastatic PDAC between 2011 and 2015. Thirty-one percent of non-metastatic patients underwent pancreatectomy. About 1.5% were treated with neoadjuvant chemotherapy/chemoradiation. Of patients undergoing intended curative resection, 77% proceeded to adjuvant therapy. Fifty-one percent of metastatic PDAC patients never received anti-tumour therapy. CONCLUSIONS: Nearly one-fourth of surgically treated patients never received systemic therapy. More than two-thirds of non-metastatic patients never proceeded to surgery. Further consideration of neoadjuvant therapy should be given to borderline resectable patients. Most patients with PDAC still die soon after diagnosis, but median survival is increasing.

Ex vivo comparison of the biomechanical properties of hand-sewn and stapled jejunoileal anastomoses in horses.

OBJECTIVE: To compare bursting strength, construction time, and anastomotic dimensions of 4 jejunoileal anastomotic techniques. STUDY DESIGN: Experimental ex vivo study. ANIMALS: Adult horses (n = 12). METHODS: Jejunoileal anastomoses were constructed from harvested ileal and distal jejunal segments using a single-layer Lembert technique (1HS), double-layer simple continuous/Cushing technique (2HS), stapled side-to-side technique (SS), or stapled functional end-to-end technique (FEE). Anastomotic construction time was recorded. Bursting pressures (BP), bursting wall tension (BWT), percentage of mean anastomotic luminal diameter reduction, percentage of luminal diameter reduction relative to adjacent ileal and jejunal diameters and stomal length, were calculated. RESULTS: FEE had the shortest construction time. BP of 1HS and 2HS was significantly higher than FEE and SS (P < .001), which were not different from each other (P = .67). There were no significant differences in BP (P = .25) and BWT (P = .21) between 1HS and 2HS. Mean luminal diameter reduction was less for 1HS (25.1%) than for 2HS (34.8%), however, not statistically different (P = .12). Luminal diameter reduction relative to ileal diameter was significantly less for 1HS (15.2%) than for 2HS (28.47%; P = .012). Luminal diameter reduction relative to jejunal diameter was less for 1HS (32.4%) than 2HS (44.6%) but not statistically different; P = .07). Stomal length was significantly larger for SS (9.93 cm) than FEE (7.32 cm; P = .0002). CONCLUSION: 1HS and 2HS jejunoileal anastomosis are equal in strength; however, 1HS results in less relative luminal diameter reduction. SS and FEE have comparable strength but fail at significantly lower BPs than hand-sewn jejunoileal anastomoses.

Can single knockouts accurately single out gene functions?

BACKGROUND: When analyzing complex biological systems, a major objective is localization of function - assessing how much each element contributes to the execution of specific tasks. To establish causal relationships, knockout and perturbation studies are commonly executed. The vast majority of studies perturb a single element at a time, yet one may hypothesize that in non-trivial biological systems single-perturbations will fail to reveal the functional organization of the system, owing to interactions and redundancies. RESULTS: We address this fundamental gap between theory and practice by quantifying how misleading the picture arising from classical single-perturbation analysis is, compared with the full multiple-perturbations picture. To this end we use a combination of a novel approach for quantitative, rigorous multiple-knockouts analysis based on the Shapley value from game theory, with an established in-silico model of Saccharomyces cerevisiae metabolism. We find that single-perturbations analysis misses at least 33% of the genes that contribute significantly to the growth potential of this organism, though the essential genes it does find are responsible for most of the growth potential. But when assigning gene contributions for individual metabolic functions, the picture arising from single-perturbations is severely lacking and a multiple-perturbations approach turns out to be essential. CONCLUSION: The multiple-perturbations investigation yields a significantly richer and more biologically plausible functional annotation of the genes comprising the metabolic network of the yeast.

Multiple knockout analysis of genetic robustness in the yeast metabolic network.

Genetic robustness characterizes the constancy of the phenotype in face of heritable perturbations. Previous investigations have used comprehensive single and double gene knockouts to study gene essentiality and pairwise gene interactions in the yeast Saccharomyces cerevisiae. Here we conduct an in silico multiple knockout investigation of a flux balance analysis model of the yeast's metabolic network. Cataloging gene sets that provide mutual functional backup, we identify sets of up to eight interacting genes and characterize the 'k robustness' (the depth of backup interactions) of each gene. We find that 74% (360) of the metabolic genes participate in processes that are essential to growth in a standard laboratory environment, compared with only 13% previously found to be essential using single knockouts. The genes' k robustness is shown to be a solid indicator of their biological buffering capacity and is correlated with both the genes' environmental specificity and their evolutionary retention.