Statin use and survival in resectable pancreatic cancer: confounders and mechanisms.

A first point regards the possible activity of drugs other than statins, such as aspirin or metformin, against pancreatic cancer. As many patients use a combination of these drugs, one might speculate that the association between simvastatin and overall survival in resected pancreatic cancer patients might also be explained by the concomitant use of aspirin or metformin, or that these drugs might result synergistic, as hypothesized for colorectal cancer (3). We wonder whether the authors had access to data on aspirin or metformin use for their population. A second point regards the very high 45% rate of simvastatin or lovastatin users reported by the authors. This figure is different from that of many European countries, thus possibly limiting the attributable fraction of cases for whom the observed findings can be replicated

The use of complementary and alternative medicine is frequent in patients with pancreatic disorder

BACKGROUND: Herbal remedies and other complementary and alternative medicine (CAM) are used by 30% of the patients with liver and inflammatory bowel diseases. However, there are no data regarding CAM use in patients with pancreatic disorders, including potential pancreatotoxicity. AIM OF THE STUDY: The aim of the study was to assess the prevalence of CAM use in patients with pancreatic disorders and screen for pancreatotoxicity. MATERIALS AND METHODS: This was a cross-sectional survey of consecutive outpatients seen at a Pancreas Center. Data were collected in a specific questionnaire. Descriptive statistics were used to analyze the prevalence and the patterns of CAM use. Characteristics associated with CAM use were analyzed by appropriate statistics. RESULTS: Of 108 patients (52% male; mean age, 65±13 years), 47 (43.5%) used CAM. The use of CAM was more frequent among patients with previous acute pancreatitis (47%). Reported reasons for the use of CAM were to help standard therapies and for an overall better feeling. About 61% of the patients reported advantages with treatment. As compared with nonusers, CAM users were more often female (55% vs. 42%), with a higher school degree (43% vs. 36%), more frequently performing physical activity (51% vs. 41%), and reporting anxiety (45% vs. 31%). However, none of these differences were statistically significant. Three patients with previous acute pancreatitis reported the use of Serenoa repens that is potentially pancreatotoxic. DISCUSSION: The rate of CAM use in patients with pancreatic disorders is similar to those reported for other digestive diseases. CAM use seems to be more frequent in women with a higher education level and a "healthier lifestyle." Patients might not be aware of the potential pancreatotoxicity of CAM, which should be carefully considered by physician

Modulation of PKM alternative splicing by PTBP1 promotes gemcitabine resistance in pancreatic cancer cells

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.Oncogene advance online publication, 3 August 2015; doi:10.1038/onc.2015.270

Diagnosis and treatment of acute pancreatitis: The position statement of the Italian Association for the study of the pancreas

BACKGROUND AND AIM: Till now, no Italian studies providing information on acute pancreatitis have been published. The aim of this study was to evaluate the epidemiological and clinical characteristics of acute pancreatitis in Italy. MATERIALS AND METHODS: The study involved 37 Italian centres distributed homogeneously throughout the entire national territory and prospectively collected epidemiological, anamnestic, laboratory, radiological, therapeutic (pharmacological, endoscopic and surgical) data, relevant to each individual case of acute pancreatitis consecutively observed during the period from September 1996 to June 2000. RESULTS: One thousand two hundred and six case report forms were collected, but 201 patients (16.6%) were subsequently eliminated from the final analysis. We therefore studied 1005 patients, 533 (53%) males and 472 (47%) females, mean age 59.6 +/- 20 years. On the basis of the Atlanta classification of acute pancreatitis, 753 patients of the 1005 cases analysed (75%) were mild and 252 patients (25%) severe. The aetiology was biliary in 60% of the patients, related to alcohol abuse in 8.5%, while in 21% of the cases it could not be identified. Over 80% of the patients (83%) were admitted to hospital within 24 h from the onset of clinical symptoms, while only 6% were admitted after 48 h. In particular, 65% of the patients were admitted to hospital within the first 12 h. Antibiotics were used in 85% of the severe and 75% of mild forms. Endoscopic therapy was carried out in 65% of the severe cases, but only in 40% it was carried out prior to 72 h. Eighty-five patients (8.5% of the total, 34% of the severe forms) underwent surgical intervention: 20% on the first day, 38.5% within the fourth day, and the remaining (41.5% of the cases) later on for infected necrosis. The mean duration of hospitalisation for patients with mild pancreatitis was 13 +/- 8 days, while for the severe disease it was of 30 +/- 14 days. The overall mortality rate was 5%, 17% in severe and 1.5% in mild pancreatitis. CONCLUSIONS: Acute pancreatitis in Italy is more commonly a mild disease with a biliary aetiology. The treatment of the disease is not optimal and, on the basis of these data, needs to be standardised. Despite this, the overall mortality rate is low (5%BACKGROUND AND AIM: Till now, no Italian studies providing information on acute pancreatitis have been published. The aim of this study was to evaluate the epidemiological and clinical characteristics of acute pancreatitis in Italy. MATERIALS AND METHODS: The study involved 37 Italian centres distributed homogeneously throughout the entire national territory and prospectively collected epidemiological, anamnestic, laboratory, radiological, therapeutic (pharmacological, endoscopic and surgical) data, relevant to each individual case of acute pancreatitis consecutively observed during the period from September 1996 to June 2000. RESULTS: One thousand two hundred and six case report forms were collected, but 201 patients (16.6%) were subsequently eliminated from the final analysis. We therefore studied 1005 patients, 533 (53%) males and 472 (47%) females, mean age 59.6 +/- 20 years. On the basis of the Atlanta classification of acute pancreatitis, 753 patients of the 10

Results of surveillance in individuals at high-risk of pancreatic cancer: A systematic review and meta-analysis

Background: Data on surveillance for pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs) with “familial pancreatic cancer” (FPC) and specific syndromes are limited and heterogeneous. Objective: We conducted a systematic review and meta-analysis of PDAC surveillance studies in HRIs. Methods: Prevalence of solid/cystic pancreatic lesions and of lesions considered a successful target of surveillance (proven resectable PDAC and high-grade precursors) was pooled across studies. The rate of lesions diagnosed by endoscopic ultrasonography (EUS)/magnetic resonance imaging (MRI) and across different HRI groups was calculated. Results: Sixteen studies incorporating 1588 HRIs were included. The pooled prevalence of pancreatic solid and cystic lesions was 5.8% and 20.2%, respectively. The pooled prevalence of patients with lesions considered a successful target of surveillance was 3.3%, being similar to EUS or MRI and varying across subgroups, being 3% in FPC, 4% in hereditary pancreatitis, 5% in familial melanoma, 6.3% in hereditary breast/ovarian cancer, and 12.2% in Peutz-Jeghers syndrome. The pooled estimated rate of lesions considered a successful target of surveillance during follow-up was 5/1000 person-years. Conclusion: Surveillance programs identify successful target lesions in 3.3% of HRIs with a similar yield of EUS and MRI and an annual risk of 0.5%. A higher rate of target lesions was reported in HRIs with specific DNA mutations

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids

This is an expert consensus from the European Neuroendocrine Tumor Society recommending best practice for the management of pulmonary neuroendocrine tumors including typical and atypical carcinoids. It emphasizes the latest discussion on nomenclature, advances and utility of new diagnostic techniques as well as the limited evidence and difficulties in determining the optimal therapeutic strateg