Diabetes mellitus (DM) is known to be associated with pancreatic ductal adenocarcinoma (PDAC), particularly new-onset DM (NODM). Others have developed polygenic risk scores (PRS) associated with PDAC ...risk. We aimed to compare the performance of these PRS in an independent cohort to determine if they can discriminate between NODM and long-standing DM patients with PDAC.
Cases (1042) and matched cancer-free controls (10,420) were drawn from the UK Biobank. Five PRS models were calculated using single nucleotide polymorphisms (SNPs) from previous studies (Nakatochi, Galeotti, Molina, Jia, and Rashkin) and a combination of these. Regression models were used to assess the association between PDAC and PRS adjusted for ancestry, smoking, DM, waist circumference, and family history of digestive cancer. Receiver operator characteristic curves and area under the curve metrics (AUC) were used to assess the performance of each PRS for classifying PDAC risk.
The combined PRS model achieved the highest AUC (0.605), and significantly improved a clinical risk model in this cohort (AUC = 0.83; P = .0002). Individuals within the fifth quintile have a 2.74-fold increased risk of developing PDAC vs those in the first quintile (P < .001), and have a 3.05-fold increased risk of developing PDAC if they have DM vs those without DM (P < .001). The positive predictive value was 11.9% in participants without DM, 23.9% with long-standing DM, and 86.7% with NODM.
The PDAC-related common genetic variants are more strongly associated with DM. This PRS has the potential for targeting individuals with NODM for PDAC secondary screening measures.
Genetic variants associated with risk of pancreatic cancer are more strongly associated with patients with diabetes mellitus compared with patients without diabetes mellitus.
Imbalanced class distribution in the medical dataset is a challenging task that hinders classifying disease correctly. It emerges when the number of healthy class instances being much larger than the ...disease class instances. To solve this problem, we proposed undersampling the healthy class instances to improve disease class classification. This model is named Hellinger Distance Undersampling (HDUS). It employs the Hellinger Distance to measure the resemblance between majority class instance and its neighbouring minority class instances to separate classes effectively and boost the discrimination power for each class. An extensive experiment has been conducted on four imbalanced medical datasets using three classifiers to compare HDUS with a baseline model and three state-of-the-art undersampling models. The outcomes display that HDUS can perform better than other models in terms of sensitivity, F1 measure, and balanced accuracy.
To investigate the influence of clear surgical resection margin width on disease recurrence rate after intentionally curative resection of colorectal liver metastases.
There is consensus that a ...histological positive resection margin is a predictor of disease recurrence after resection of colorectal liver metastases. The dispute, however, over the width of cancer-free resection margin required is ongoing.
Analysis of observational prospectively collected data for 2715 patients who underwent primary resection of colorectal liver metastases from 2 major hepatobiliary units in the United Kingdom. Histological cancer-free resection margin was classified as positive (if cancer cells present at less than 1 mm from the resection margin) or negative (if the distance between the cancer and the margin is 1 mm or more). The negative margin was further classified according to the distance from the tumor in millimeters. Predictors of disease-free survival were analyzed in univariate and multivariate analyses. A case-match analysis by a propensity score method was undertaken to reduce bias.
A 1-mm cancer-free resection margin was sufficient to achieve 33% 5-year overall disease-free survival. Extra margin width did not add disease-free survival advantage (P > 0.05). After the propensity case-match analysis, there is no statistical difference in disease-free survival between patients with negative narrow and wider margin clearance hazard ratio (HR) 1.0; 95% (confidence interval) CI: 0.9-1.2; P = 0.579 at 5-mm cutoff and HR 1.1; 95% CI: 0.96-1.3; P = 0.149 at 10-mm cutoff. Patients with extrahepatic disease and positive lymph node primary tumor did not have disease-free survival advantage despite surgical margin clearance (9 months for <1-mm vs 12 months for ≥1-mm margin clearance; P = 0.062).
One-mm cancer-free resection margin achieved in patients with colorectal liver metastases should now be considered the standard of care.
Human growth factors are potential therapeutic agents for various inflammatory disorders affecting the gastrointestinal tract. However, they are unstable when administered orally and systemic ...administration requires high doses increasing the risk of unwanted side effects. Live microorganism-based delivery systems can overcome these problems although they suffer from the inability to control heterologous protein production and there are concerns regarding biosafety and environmental contamination.
To overcome these limitations we have developed a new live bacteria drug-delivery system using the human commensal gut bacterium Bacteroides ovatus engineered to secrete human growth factors in response to dietary xylan. The anaerobic nature of B ovatus provides an inherent biosafety feature. B ovatus strains expressing human keratinocyte growth factor-2, which plays a central role in intestinal epithelial homeostasis and repair (BO-KGF), were generated by homologous recombination and evaluated using the dextran sodium sulfate (DSS)-induced model of intestinal epithelial injury and colitis.
In response to xylan BO-KGF produced biologically active KGF both in vitro and in vivo. In DSS treated mice administration of xylan and BO-KGF had a significant therapeutic effect in reducing weight loss, improving stool consistency, reducing rectal bleeding, accelerating healing of damaged epithelium, reducing inflammation and neutrophil infiltration, reducing expression of pro-inflammatory cytokines, and accelerating production of goblet cells. BO-KGF and xylan treatment also had a marked prophylactic effect limiting the development of inflammation and disruption of the epithelial barrier.
This novel, diet-regulated, live bacterial drug delivery system may be applicable to treating various bowel disorders.
1 Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
2 Fermentation Biotechnology Research, National Center for Agricultural Utilization ...Research, Peoria, IL 61604, USA
3 School of Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK
Correspondence Simon R. Carding Simon.Carding{at}BBSRC.ac.uk
The use of genetically modified bacteria to deliver biologically active molecules directly to the gut has become an increasingly attractive area of investigation. The challenge of regulation of production of the therapeutic molecule and colonization of the bowel led us to investigate Bacteroides ovatus for the production of these molecules, due to its ability to colonize the colon and xylan utilization properties. Here we have identified the putative xylanase promoter. The 5' region of the corresponding mRNA was determined by 5'RACE analysis and the transcription initiation site was identified 216 bp upstream of the ATG start codon. The putative xylanase promoter was regulated by xylan in a dose- and time-dependent manner, and repressed by glucose. This promoter was subsequently used to direct the controlled expression of a gene encoding the human intestinal trefoil factor (TFF-3) after integration as a single copy into the chromosome of B. ovatus . The resulting strain produced biologically active TFF-3 in the presence of xylan. These findings identify the B. ovatus xylanase operon promoter and show that it can be utilized to direct xylan-inducible expression of heterologous eukaryotic genes in B. ovatus .
Abbreviations: IL-2, interleukin-2; 5'RACE, rapid amplification of 5' cDNA ends; TFF-3, trefoil factor 3; TIS, transcription initiation site
The GenBank accession number for the B. ovatus promoter and operon is EU334491.
Adjuvant chemotherapy (AC) can prolong overall survival (OS) after pancreatoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). However, fitness for AC may be influenced by postoperative ...recovery. We aimed to investigate if serious (Clavien-Dindo grade ≥ IIIa) postoperative complications affected AC rates, disease recurrence and OS.
Data were extracted from the Recurrence After Whipple's (RAW) study (n = 1484), a retrospective study of PD outcomes (29 centres from eight countries). Patients who died within 90-days of PD were excluded. The Kaplan-Meier method was used to compare OS in those receiving or not receiving AC, and those with and without serious postoperative complications. The groups were then compared using univariable and multivariable tests.
Patients who commenced AC (vs no AC) had improved OS (median difference: (MD): 201 days), as did those who completed their planned course of AC (MD: 291 days, p < 0.0001). Those who commenced AC were younger (mean difference: 2.7 years, p = 0.0002), more often (preoperative) American Society of Anesthesiologists (ASA) grade I-II (74% vs 63%, p = 0.004) and had less often experienced a serious postoperative complication (10% vs 18%, p = 0.002). Patients who developed a serious postoperative complication were less often ASA grade I-II (52% vs 73%, p = 0.0004) and less often commenced AC (58% vs 74%, p = 0.002).
In our multicentre study of PD outcomes, PDAC patients who received AC had improved OS, and those who experienced a serious postoperative complication commenced AC less frequently. Selected high-risk patients may benefit from targeted preoperative optimisation and/or neoadjuvant chemotherapy.
To analyze results of 70 patients undergoing left hepatic trisectionectomy and to clarify its current role.
Left hepatic trisectionectomy remains a complicated hepatectomy, and few reports have ...described the long-term results of the procedure.
Short-term and long-term outcomes of 70 consecutive patients who underwent left hepatic trisectionectomy from January 1993 to February 2004 were analyzed.
Of the 70 patients, 36 had colorectal liver metastasis, 24 had cholangiocarcinoma, 4 had hepatocellular carcinoma, and the remaining 6 had other tumors. Overall morbidity, 30-day and 90-day mortality rates were 46%, 7%, and 9%, respectively. Multivariate analysis disclosed that preoperative jaundice and intraoperative blood transfusion were positive independent predictors for postoperative morbidity; however, there were no independent predictors for postoperative mortality. Postoperative morbidity (87% versus 35%, P < 0.001) and mortality (20% versus 5%, P = 0.108) were observed more frequently in patients with preoperative obstructive jaundice than in those without jaundice. Each survival according to tumor type was acceptable compared with reported survivals. Survival for patients with colorectal liver metastasis undergoing left hepatic trisectionectomy with concomitant partial resection of the remnant liver was similar to those without this concomitant procedure. This concomitant procedure was not associated with postoperative morbidity and mortality.
Left hepatic trisectionectomy remains a challenging procedure. Preoperative obstructive jaundice considerably increases perioperative risk. Concomitant partial resection of the remaining liver appears to be safe and offers the potential for cure in patients with colorectal metastasis affecting all liver segments.
Pancreatoduodenectomy (PD) is recommended in fit patients with a resectable ampullary adenocarcinoma (AA). We aimed to identify predictors of five-year recurrence/survival.
Data were extracted from ...the Recurrence After Whipple's (RAW) study, a multicentre retrospective study of PD patients with a confirmed head of pancreas or periampullary malignancy (June 1st, 2012–May 31st, 2015). Patients with AA who developed recurrence/died within five-years were compared to those who did not.
394 patients were included and actual five-year survival was 54%. Recurrence affected 45% and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). Among those with recurrence, the most common sites were the liver (32%), local lymph nodes (14%) and lung/pleura (13%). Following multivariable tests, number of resected nodes, histological T stage > II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin correlated with increased recurrence and reduced survival. Furthermore, ≥1 positive margin, PPFI and PNI were all associated with reduced time-to-recurrence.
This multicentre retrospective study of PD outcomes identified numerous histopathological predictors of AA recurrence. Patients with these high-risk features might benefit from adjuvant therapy.
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