Genetic variability of the ABCC2 gene and clinical outcomes in pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis, caused by various factors, such as the aggressiveness of the disease, the limited therapeutic options and the lack of early detection and risk markers. The ATP binding cassette subfamily C member 2 (ABCC2) protein plays a critical role in response to various drugs and is differentially expressed in gemcitabine sensitive and resistant cells. Moreover, single nucleotide polymorphisms (SNPs) in the gene have been associated with differential outcomes and prognosis in several tumour types. The aim of this study was to investigate the possible association between SNPs in the ABCC2 gene and overall survival (OS) in PDAC patients. We analysed 12 polymorphisms, including tagging-SNPs covering all the genetic variability of the ABCC2 gene and genotyped them in 1415 PDAC patients collected within the Pancreatic Disease ReseArch (PANDoRA) consortium. We tested the association between ABCC2 SNPs and PDAC OS using Cox proportional hazard models. We analysed PDAC patients dividing them by stage and observed that the minor alleles of three SNPs showed an association with worse OS [rs3740067: hazard ratio (HR) = 3.29, 95% confidence interval (CI) = 1.56-6.97, P = 0.002; rs3740073: HR = 3.11, 95% CI = 1.52-6.38, P = 0.002 and rs717620: HR = 2.90, 95% CI = 1.41-5.95, P = 0.004, respectively] in stage I patients. In patients with more advanced PDAC, we did not observe any statistically significant association. Our results suggest that rs3740067, rs3740073 and rs717620 could be promising prognostic markers in stage I PDAC patients

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10−10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10−6, ptrend = 3.27 × 10−7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10−9 for highest vs. lowest quintile; p = 1.82 × 10−10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer

Polygenic and multifactorial scores for pancreatic ductal adenocarcinoma risk prediction

Most cases of pancreatic ductal adenocarcinoma (PDAC) are asymptomatic in early stages, and the disease is typically diagnosed in advanced phases, resulting in very high mortality. Tools to identify individuals at high risk of developing PDAC would be useful to improve chances of early detection

Targeted Sequencing of Pancreatic Adenocarcinomas from Patients with Metachronous Pulmonary Metastases

Mutation spectra of 250 cancer driver, druggable, and actionable genes were analyzed in surgically resected pancreatic ductal adenocarcinoma (PDAC) patients who developed metachronous pulmonary metastases. Targeted sequencing was performed in DNA from blood and archival samples of 15 primary tumors and three paired metastases. Results were complemented with the determination of G12V mutation in KRAS by droplet digital PCR. The median number of protein-changing mutations was 52 per patient. KRAS and TP53 were significantly enriched in fractions of mutations in hotspots. Individual gene mutation frequencies or mutational loads accounting separately for drivers, druggable, or clinically actionable genes, did not significantly associate with patients’ survival. LRP1B was markedly mutated in primaries of patients who generalized (71%) compared to those developing solitary pulmonary metastases (0%). FLG2 was mutated exclusively in primary tumors compared to paired metastases. In conclusion, signatures of prognostically differing subgroups of PDAC patients were generated for further utilization in precision medicine

The short- and long-term outcomes of pancreaticoduodenectomy for distal cholangiocarcinoma

Background. The aim of the study was to calculate the short-term and long-term outcomes of curative-intent surgery in distal cholangiocarcinoma (DCC) patients to identify potential prognostic factors. Patients and Methods. A retrospective cohort study of 32 consecutive DCC patients treated with pancreaticoduodenectomy between 2009-2017. The clinicopathological and histopathological data were evaluated for prognostic factors using the univariable Cox regression analysis. The Overall Survival (OS) was estimated using the Kaplan-Meier analysis. Results. The study comprised a total of 32 patients, with a mean age of 65.8 (± 9.0) years at the time of surgery. R0 resection was achieved in 25 (86.2%) patients, 19 (65.5%) patients received adjuvant oncological therapy. The OS rates at 1, 3 and 5 years were 62.5%, 37.5% and 21.9%, respectively. The 90-day mortality was 3/32 (9.4%) accounting for one-fourth of the first-year mortality rate. The median OS was 28.5 months. The only statistically significant prognostic factor was vascular resection, which was associated with worse OS in the univariable analysis (HR: 3.644; 95%-CI: 1.179-11.216, P=0.025). An age less than 65 years, ASA grade I/II, hospital stay of fewer than 15 days, R0 resection, lymph node ratio less than 0.2 and adjuvant oncological therapy tended to be associated with better OS but without statistically significant relevance. Conclusion. The main factor directly influencing the survival of DCC patients is surgical complications. Surgical mortality comprises a significant group of patients, who die in the first year following pancreaticoduodenectomy. Vascular resection is the most important negative prognostic factor for long-term survival

Minimally invasive therapy of upside-down stomach: A single-center experience

Introduction: The aim of this study is to evaluate short-term and long-term outcomes of minimally invasive therapy in Type IV hiatal hernia (upside-down stomach). Patients and Methods: A retrospective study of 58 consecutively operated patients with Type IV hiatal hernia between 1998 and 2015 was conducted. Short-term outcome was evaluated using Clavien-Dindo classification and long-term outcomes using phone survey and subjective assessment of patients at least 1 year following surgery. Results: Laparoscopic hiatoplasty was performed in all patients, with gastropexy in 55.2%, fundoplication in 39.6%, and combination of fundoplication and gastropexy in 5.2%. Complications were observed in 6.9%. Two early reoperations (within 30 days) due to acute reherniation were necessary. Adverse events occurred in seven cases – pleural opening and peroperative bleeding. Three patients were reoperated laparoscopically 2–17 months after the first surgery due to receiving partial stomach herniation. In 67.2% of patients, long-term subjective quality of life assessment was available. Eighty percent of them were completely satisfied, without recurrence of preoperative symptoms. Conclusion: Elective laparoscopic surgery of hiatal hernia Type IV is a safe procedure, which has all the benefits of minimally invasive therapy with favorable short- and long-term results

Identification and Validation of Circulating Micrornas as Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma Patients Undergoing Surgical Resection

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates