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1.
MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.
Zhu, Y, Gu, J, Li, Y, Peng, C, Shi, M, Wang, X, Wei, G, Ge, O, Wang, D, Zhang, B, et al
Cancer letters. 2018;:59-68
Abstract
The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment.
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2.
Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer.
Van Cutsem, E, Hidalgo, M, Canon, JL, Macarulla, T, Bazin, I, Poddubskaya, E, Manojlovic, N, Radenkovic, D, Verslype, C, Raymond, E, et al
International journal of cancer. 2018;(8):2053-2064
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Abstract
The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.
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Diabetes and pancreatic neuroendocrine tumours: Which interplays, if any?
Gallo, M, Ruggeri, RM, Muscogiuri, G, Pizza, G, Faggiano, A, Colao, A, ,
Cancer treatment reviews. 2018;:1-9
Abstract
Pancreatic neuroendocrine tumours (PanNETs) represent an uncommon type of pancreatic neoplasm, whose incidence is increasing worldwide. As per exocrine pancreatic cancer, a relationship seems to exist between PanNETs and glycaemic alterations. Diabetes mellitus (DM) or impaired glucose tolerance often occurs in PanNET patients as a consequence of hormonal hypersecretion by the tumour, specifically affecting glucose metabolism, or due to tumour mass effects. On the other hand, pre-existing DM may represent a risk factor for developing PanNETs and is likely to worsen the prognosis of such patients. Moreover, the surgical and/or pharmacological treatment of the tumour itself may impair glucose tolerance, as well as antidiabetic therapies may impact tumour behaviour and patients outcome. Differently from exocrine pancreatic tumours, few data are available for PanNETs as yet on this issue. In the present review, the bidirectional association between glycaemic disorders and PanNETs has been extensively examined, since the co-existence of both diseases in the same individual represents a further challenge for the clinical management of PanNETs.
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Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'.
Haas, M, Siveke, JT, Schenk, M, Lerch, MM, Caca, K, Freiberg-Richter, J, Fischer von Weikersthal, L, Kullmann, F, Reinacher-Schick, A, Fuchs, M, et al
European journal of cancer (Oxford, England : 1990). 2018;:95-103
Abstract
INTRODUCTION In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).
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Pancreatic cancer: A critical review of dietary risk.
Salem, AA, Mackenzie, GG
Nutrition research (New York, N.Y.). 2018;:1-13
Abstract
Pancreatic cancer is a deadly disease. It is estimated that about 90% of pancreatic cancer cases are due to environmental risk factors. Among these, approximately 50% of pancreatic cancer cases may be attributed to diet, which is largely modifiable. Given this large attribution to diet, there have been numerous epidemiological studies assessing the risk of various dietary factors on the incidence of pancreatic cancer. However, many of these studies present conflicting and/or inconclusive findings. The objective of this review is two-fold: (a) to summarize the current evidence on the association between various dietary factors and the risk of developing pancreatic cancer and (b) to discuss what additional studies are needed to better elucidate the role of diet as a potential risk factor for pancreatic cancer. We summarized the evidence by using data primarily from meta-analyses and pooled analysis when available, focusing on the most studied nutrients, foods, and dietary patterns. We observed that, while the association between individual nutrients and pancreatic cancer risk have been heavily studied, the evidence is mostly conflicting and inconclusive. In contrast, the evidence of certain associations among dietary patterns and pancreatic cancer risk is clearer, has more power, and is less conflicting. Therefore, we propose a shift in the focus of nutritional epidemiological research with regards to pancreatic cancer risk. We discourage further epidemiological research studies that focus on single nutrients, whereas we strongly encourage additional studies that investigate how a combination of diet and other lifestyle factors may promote or prevent pancreatic carcinogenesis.
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6.
The Role of Genetics in Pancreatitis.
Hasan, A, Moscoso, DI, Kastrinos, F
Gastrointestinal endoscopy clinics of North America. 2018;(4):587-603
Abstract
Individuals with acute recurrent and chronic pancreatitis may have an inherited predisposition to the development of the disease. Pancreatitis in the setting of a significant family history of the disease can be classified as hereditary or familial pancreatitis. In this article, the authors closely examine the specific genes implicated in pancreatitis, investigate the role of genetic testing for diagnosis, and describe the impact of genetic testing results on clinical management.
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7.
Is endoscopic ultrasonography more sensitive than magnetic resonance imaging in detecting and localizing pancreatic neuroendocrine tumors?
Kann, PH
Reviews in endocrine & metabolic disorders. 2018;(2):133-137
Abstract
To compare endoscopic ultrasonography (EUS) and magnetic resonance imaging (MRI) in terms of their sensitivities to localize pancreatic neuroendocrine tumors (pNET) preoperatively. Systematic analysis of the literature; sensitivity of EUS and MRI in insulinomas and pancreaticoduodenal NETs in multiple endocrine neoplasia type 1 (MEN1) in series of at least 20 subjects referring to tumors confirmed by surgery and histopathology. Other imaging methods reported were also assessed. Eighteen publications on insulinomas (782 cases) could be analyzed, no study in MEN1 fulfilled the inclusion criteria and compared EUS to MRI. Data quality was moderate: all publications referred to case series. Mean correct detection / localization rates (sensitivity) were calculated: EUS 80%, MRI 66%, computed tomography 63%, angiography 52%, somatostatin receptor scintigraphy 42%, ultrasonography 23%; arterial calcium stimulation with hepatic venous sampling regionalized correctly in 80%. EUS seems to be more sensitive than MRI in localizing pancreatic neuroendocrine tumors. If a specialized endosonographist is available, EUS is the preferable imaging procedure. Otherwise, MRI is a suitable alternative.
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Supportive therapy in gastroenteropancreatic neuroendocrine tumors: Often forgotten but important.
Jin, XF, Spampatti, MP, Spitzweg, C, Auernhammer, CJ
Reviews in endocrine & metabolic disorders. 2018;(2):145-158
Abstract
Neuroendocrine tumors (NETs) are a group of rare and heterogeneous malignancies that can develop in various organs. A significant number of gastroenteropancreatic neuroendocrine tumours (GEP-NETs) is functionally active and presents with symptoms related to the secretion of biologically active substances, leading to the development of distinct clinical syndromes. There are various therapeutic approaches for GEP-NETs, including curative surgery, palliative surgery, local-ablative and loco-regional therapies as well as systemic therapeutic options including peptide receptor radionuclide therapy, cytotoxic therapy, and molecularly targeted therapies. Specific supportive therapy of patients with NETs includes management or prevention of hormone-related clinical syndromes and paraneoplastic states. Supportive therapy plays a key role in NET treatment. Supportive therapy includes debulking surgery and interventional radiologic techniques to reduce tumour bulk or load, as well as systemic medical treatment options to manage or prevent hypersecretion syndromes and treatment-related side effects. Supportive therapies are a type of of comprehensive treatment addressing the patient as a whole person throughout the process of NET treatment. Therefore, supportive therapy also encompasses psychosocial support, expert nursing, nutritional support and management of cancer related pain.
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Toxicity of chemotherapy regimens in advanced and metastatic pancreatic cancer therapy: A network meta-analysis.
Wang, XF, Huang, WF, Nie, J, Zhou, Y, Tan, DW, Jiang, JH
Journal of cellular biochemistry. 2018;(7):5082-5103
Abstract
This network meta-analysis is adopted in order to compare the toxicity of different chemotherapy regimens in the treatment of advanced/metastatic pancreatic cancer (PC). Randomized controlled trials (RCTs) about different chemotherapy regimens for advanced/metastatic PC were included in this network meta-analysis using Cochrane Library and PubMed electronic databases. The network meta-analysis was performed to combine direct and indirect evidence in order to calculate the odd ratios (OR) and draw a surface under the cumulative ranking (SUCRA) curve. A total of 19 RCTs were enrolled in this network meta-analysis including 12 chemotherapy regimens (Gemcitabine, Gemcitabine + S-1 [tegafur], Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin], Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, S-1). The incidence of anemia of Gemcitabine + Capecitabine regimen was higher compared with Gemcitabine regimen, Gemcitabine + pemetrexed regimen exhibited the highest incidence rates of anemia and neutropenia; while Gemcitabine + S-1, Gemcitabine + Cisplatin and FOLFIRINOX regimens exhibited the highest incidence rates of neutropenia. However, S-1 regimen exhibited lower incidence rates of leukopenia and thrombocytopenia. Moreover, the incidence rates of nausea/vomiting and rash of Gemcitabine + S-1 regimen were higher compared with Gemcitabine regimen, while Gemcitabine + Cisplatin regimen had the highest incidence rate of nausea/vomiting. This study demonstrated that the hematologic toxicity of S-1 regimen was the lowest, while Gemcitabine regimen exhibited the lowest incidence rate of non-hematologic toxicity, providing guidance for the treatment of advanced/metastatic PC.
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Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves safety and efficacy of gemcitabine: Results of a prospective phase II trial.
Pastorelli, D, Fabricio, ASC, Giovanis, P, D'Ippolito, S, Fiduccia, P, Soldà, C, Buda, A, Sperti, C, Bardini, R, Da Dalt, G, et al
Pharmacological research. 2018;:72-79
Abstract
A large body of biomedical evidence indicates that activation of Nrf2 by curcumin increases the nucleophilic tone and damps inflammation cumulatively supporting the malignant phenotype. Conversely, genetic analyses suggest a possible oncogenic nature of constitutive Nrf2 activation since an increased nucleophilic tone is alleged increasing chemoresistance of cancer cells. Aiming to contribute to solve this paradox, this study addressed the issue of safety and efficacy of curcumin as complementary therapy of gemcitabine on pancreatic cancer. This was a single centre, single arm prospective phase II trial. Patients received gemcitabine and Meriva®, a patented preparation of curcumin complexed with phospholipids. Primary endpoint was response rate, secondary endpoints were progression free survival, overall survival, tolerability and quality of life. Analysis of inflammatory biomarkers was also carried out. Fifty-two consecutive patients were enrolled. Forty-four (13 locally advanced and 31 metastatic) were suitable for primary endpoint evaluation. Median age was 66 years (range 42-87); 42 patients had Eastern Cooperative Oncology Group performance status 0-1. The median number of treatment cycle was 4.5 (range 2-14). We observed 27.3% of response rate and 34.1% of cases with stable disease, totalizing a disease control rate of 61.4%. The median progression free survival and overall survival were 8.4 and 10.2 months, respectively. Higher IL-6 and sCD40L levels before treatment were associated to a worse overall survival (p < 0.01). Increases in sCD40L levels after 1 cycle of chemotherapy were associated with a reduced response to the therapy. Grade 3/4 toxicity was observed (neutropenia, 38.6%; anemia, 6.8%). There were no significant changes in quality of life during therapy. In conclusion, the complementary therapy to gemcitabine with phytosome complex of curcumin is not only safe but also efficiently translate in a good response rate in first line therapy of advanced pancreatic cancer.