Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and incurable disease. Poor prognosis is due to multiple reasons, including acquisition of resistance to gemcitabine, the first-line ...chemotherapeutic approach. Thus, there is a strong need for novel therapies, targeting more directly the molecular aberrations of this disease. We found that chronic exposure of PDAC cells to gemcitabine selected a subpopulation of cells that are drug-resistant (DR-PDAC cells). Importantly, alternative splicing (AS) of the pyruvate kinase gene (PKM) was differentially modulated in DR-PDAC cells, resulting in promotion of the cancer-related PKM2 isoform, whose high expression also correlated with shorter recurrence-free survival in PDAC patients. Switching PKM splicing by antisense oligonucleotides to favor the alternative PKM1 variant rescued sensitivity of DR-PDAC cells to gemcitabine and cisplatin, suggesting that PKM2 expression is required to withstand drug-induced genotoxic stress. Mechanistically, upregulation of the polypyrimidine-tract binding protein (PTBP1), a key modulator of PKM splicing, correlated with PKM2 expression in DR-PDAC cell lines. PTBP1 was recruited more efficiently to PKM pre-mRNA in DR- than in parental PDAC cells. Accordingly, knockdown of PTBP1 in DR-PDAC cells reduced its recruitment to the PKM pre-mRNA, promoted splicing of the PKM1 variant and abolished drug resistance. Thus, chronic exposure to gemcitabine leads to upregulation of PTBP1 and modulation of PKM AS in PDAC cells, conferring resistance to the drug. These findings point to PKM2 and PTBP1 as new potential therapeutic targets to improve response of PDAC to chemotherapy.
Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM ...staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.
The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided.
Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio HR of death = 16.23, 95% confidence interval CI = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability.
Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplastic disease. Gemcitabine, the currently used chemotherapeutic drug for PDAC, elicits only minor benefits, because of the development of ...escape pathways leading to chemoresistance. Herein, we aimed at investigating the involvement of the mitogen activating protein kinase interacting kinase (MNK)/eIF4E pathway in the acquired drug resistance of PDAC cells. Screening of a cohort of PDAC patients by immunohistochemistry showed that eIF4E phosphorylation correlated with disease grade, early onset of disease and worse prognosis. In PDAC cell lines, chemotherapeutic drugs induced MNK-dependent phosphorylation of eIF4E. Importantly, pharmacological inhibition of MNK activity synergistically enhanced the cytostatic effect of gemcitabine, by promoting apoptosis. RNA interference (RNAi) experiments indicated that MNK2 is mainly responsible for eIF4E phosphorylation and gemcitabine resistance in PDAC cells. Furthermore, we found that gemcitabine induced the expression of the oncogenic splicing factor SRSF1 and splicing of MNK2b, a splice variant that overrides upstream regulatory pathways and confers increased resistance to the drug. Silencing of SRSF1 by RNAi abolished this splicing event and recapitulated the effects of MNK pharmacological or genetic inhibition on eIF4E phosphorylation and apoptosis in gemcitabine-treated cells. Our results highlight a novel pro-survival pathway triggered by gemcitabine in PDAC cells, which leads to MNK2-dependent phosphorylation of eIF4E, suggesting that the MNK/eIF4E pathway represents an escape route utilized by PDAC cells to withstand chemotherapeutic treatments.
Background
Although consensus guidelines suggest that patients with high‐risk intraductal papillary mucinous neoplasms (IPMNs) should have surgery, a non‐operative strategy is often selected in ...patients who are poor surgical candidates. The aim was to determine the risk of disease‐related death from IPMN in patients with worrisome features or high‐risk stigmata who were kept under observation.
Methods
A PubMed literature search was undertaken of articles published from August 1992 to June 2016 (updated October 2017). The methodology was developed from PRISMA and MOOSE checklists. Incidence proportions and rates of overall and IPMN‐related deaths were calculated, with subgroup analyses for main‐duct/mixed‐type and branch‐duct IPMNs. Quality of the studies, publication bias and heterogeneity were explored.
Results
Six studies reported data on overall mortality and eight described disease‐specific mortality for 556 patients during follow‐up ranging from 24·9 to 60·0 months. Pooled rates of overall and IPMN‐related mortality were 30·9 (95 per cent c.i. 19·6 to 45·1) and 11·6 (6·0 to 21·2) per cent respectively. The pooled incidence rate for overall mortality was substantially higher than that for IPMN‐related mortality: 78 (95 per cent c.i. 44 to 111) and 23 (9 to 37) per 1000 patient‐years respectively. The pooled incidence rate for disease‐specific mortality was considerably lower for branch‐duct than for main‐duct or mixed‐type IPMNs: 5 (0 to 10) and 32 (12 to 52) per 1000 patient‐years respectively.
Conclusion
In patients unfit for surgery, IPMN‐related mortality among patients with worrisome features and high‐risk stigmata is low, and the risk of death from other causes much higher.
Low disease‐related mortality
Summary
Background Due to suppression of gastric acidity during antisecretory therapy, an impaired absorption of co‐administered drugs may occur.
Aim To review evidence of impaired drug absorption ...related to the use of co‐administered PPIs or H2RAs.
Methods Systematic search of MEDLINE/EMBASE/SCOPUS databases (1980–September 2008) for English articles with keywords: drug malabsorption and absorption, stomach, anti‐secretory/acid inhibitory drugs, histamine H2 antagonists, PPIs, gastric acid, pH, hypochlorhydria, gastric hypoacidity. From 2126 retrieved articles, 16 randomized crossover studies were identified investigating impaired absorption of nine different drugs in association with co‐administration of PPIs or H2RAs. Information on investigated drug, study type, features of investigated subjects, study design, type of intervention, and study results were extracted.
Results The identified studies investigated the absorption kinetics of nine drugs. Acid suppression reduced absorption of ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin and dipyridamole (median Cmax reduction by 66.5%). An increased absorption of nifedipine and digoxin (median AUC increase by 10%) and a 2‐fold‐increase in alendronate bioavailability were observed.
Conclusions Gastric pH appears relevant for absorption of some cardiovascular or infectious disease agents. Antisecretory treatment may significantly modify the absorption of co‐administered drugs.
Background: Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) ...classification and prognostic utility of clinicopathological parameters at diagnosis. Patients and methods: From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models. Results: There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation hazard ratio (HR) 7.3; P = 0.0001, nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), Ki-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality. Conclusion: This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.
This consensus report gives a detailed description of the use of somatostatin analogs in the management of neuroendocrine tumors of the gastroenteropancreatic system. As background information we ...have outlined critical aspects of the pathology, the use of tumor markers, a definition of functional and non-functional digestive neuroendocrine tumors, different imaging modalities, surgical considerations, liver embolization and the use of cytotoxic drugs as well as interferon. Included in the report is an overview of somatostatin, somatostatin analogs and its receptor expression in different neuroendocrine tumors. It will also define the binding affinities of different somatostatin analogs to the five different subtypes of somatostatin receptor. We compare the efficacy of octreotide and lanreotide in reducing diarrhea and flushing. Side-effects are described and we provide practical information on somatostatin analog treatment.
Summary
Background Impaired acid secretion may affect drug absorption and may be consequent to corporal Heliocobacter pylori‐gastritis, which may affect the absorption of orally administered drugs.
...Aim To focus on the evidence of impaired drug absorption associated with H. pylori infection.
Methods Data sources were the systematic search of MEDLINE/EMBASE/SCOPUS databases (1980–April 2008) for English articles using the keywords: drug malabsorption/absorption, stomach, Helicobacter pylori, gastritis, gastric acid, gastric pH, hypochlorhydria, gastric hypoacidity. Study selection was made from 2099 retrieved articles, five studies were identified. Data were extracted from selected papers, investigated drugs, study type, main features of subjects, study design, intervention type and results were extracted.
Results In all, five studies investigated impaired absorption of l‐dopa, thyroxine and delavirdine in H. pylori infection. Eradication treatment led to 21–54% increase in l‐dopa in Parkinon’s disease. Thyroxine requirement was higher in hypochlorhydric goitre with H. pylori‐gastritis and thyrotropin levels decreased by 94% after treatment. In H. pylori‐ and HIV‐positive hypochlorhydric subjects, delavirdine absorption increased by 57% with orange juice administration and by 150% after eradication.
Conclusions A plausible mechanism of impaired drug absorption is decreased acid secretion in H. pylori‐gastritis patients. Helicobacter pylori infection and hypochlorhydria should be considered in prescribing drugs the absorption of which is potentially affected by intragastric pH.
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