Adjuvant and neoadjuvant treatment in pancreatic cancer

Pancreatic adenocarcinoma is one of the most aggressive human malignancies,ranking 4th among causes for cancer-related death in the Western world including the United States.Surgical resection offers the only chance of cure,but only 15 to 20 percent of cases are potentially resectable at presentation.Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy.Currently there is no consensus around the world on what constitutes"standard"adjuvant therapy for pancreatic cancer.This controversy derives from several studies,each fraught with its own limitations.Standards of care also vary somewhat with regard to geography and economy,for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe.Regardless of the efforts in adjuvant and neoadjuvant improved therapy,the major goal to combat pancreatic cancer is to find diagnostic markers,identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients.In this review,authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.

Mouse models of pancreatic cancer

Pancreatic cancer is one of the most lethal of human malignancies ranking 4th among cancer-related death in the western world and in the United States,and potent therapeutic options are lacking.Although during the last few years there have been important advances in the understanding of the molecular events responsible for the development of pancreatic cancer,currently specific mechanisms of treatment resistance remain poorly understood and new effective systemic drugs need to be developed and probed.In vivo models to study pancreatic cancer and approach this issue remain limited and present different molecular features that must be considered in the studies depending on the purpose to fit special research themes.In the last few years,several genetically engineered mouse models of pancreatic exocrine neoplasia have been developed.These models mimic the disease as they reproduce genetic alterations implicated in the progression of pancreatic cancer.Genetic alterations such as activating mutations in KRas,or TGFb and/or inactivation of tumoral suppressors such as p53,INK4A/ARF BRCA2 and Smad4 are the most common drivers to pancreatic carcinogenesis and have been used to create transgenic mice.These mouse models have a spectrum of pathologic changes,from pancreatic intraepithelial neoplasia to lesions that progress histologically culminating in fully invasive and metastatic disease and represent the most useful preclinical model system.These models can characterize the cellular and molecular pathology of pancreatic neoplasia and cancer and constitute the best tool to investigate new therapeutic approaches,chemopreventive and/or anticancer treatments.Here,we review and update the current mouse models that reproduce different stages of human pancreatic ductal adenocarcinoma and will have clinical relevance in future pancreatic cancer developments.

Embryonic stem cell factors and pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC),the most common type of pancreatic tumor,is a highly aggressive human cancer with the lowest five-year survival rate of any human maligancy primarily due to its earlymetastasis and lack of response to chemotherapy and radiation.Recent research suggests that PDAC cells comprise a hierarchy of tumor cells that develop around a population of cancer stem cells(CSCs),a small and distinct population of cancer cells that mediates tumoregenesis,metastasis and resistance to standard treatments.Thus,CSCs could be a target for more effective treatment options.Interestingly,pancreatic CSCs are subject to regulation by some of key embryonic stem cell(ESC)transctiption factors abberently expressed in PDAC,such as SOX2,OCT4 and NANOG.ESC transcription factors are important DNA-binding proteins present in both embryonic and adult somatic cells.The critical role of these factors in reprogramming processes makes them essential not only for embryonic development but also tumorigenesis.Here we provide an overview of stem cell transcription factors,particularly SOX2,OCT4,and NANOG,on their expression and function in pancreatic cancer.In contrast to embryonic stem cells,in which OCT4 and SOX2 are tightly regulated and physically interact to regulate a wide spectrum of target genes,de novo SOX2 expression alone in pancreatic cancer cells is sufficient to promote self-renewal,dedifferentiation and imparting stemness characteristics via impacting specific cell cycle regulatory genes and epithelial-mesnechymal transtion driver genes.Thus,targeting ESC factors,particularly SOX2,could be a worthy strategy for pancreatic cancer therapy.

Alcohol consumption on pancreatic diseases

Although the association between alcohol and pancreatic diseases has been recognized for a long time,the impact of alcohol consumption on pancreatitis and pancreatic cancer(PC)remains poorly defined.Nowadays there is not consensus about the epidemiology and the beverage type,dose and duration of alcohol consumption causing these diseases.The objective of this study was to review the epidemiology described in the literature for pancreatic diseases as a consequence of alcoholic behavior trying to understand the association between dose,type and frequency of alcohol consumption and risk of pancreatitis and PC.The majority of the studies conclude that high alcohol intake was associated with a higher risk of pancreatitis(around 2.5%-3% between heavy drinkers and 1.3%between non drinkers).About 70%of pancreatitis are due to chronic heavy alcohol consumption.Although this incidence rate differs between countries,it is clear that the risk of developing pancreatitis increases with increasing doses of alcohol and the average of alcohol consumption vary since 80 to 150 g/d for 10-15 years.With regard to PC, the role of alcohol consumption remains less clear,and low to moderate alcohol consumption do not appear to be associated with PC risk,and only chronic heavy drinking increase the risk compared with lightly drinkers.In a population of 10%-15%of heavy drinkers, 2%-5%of all PC cases could be attributed to alcohol consumption.However,as only a minority(less than 10%for pancreatitis and 5%for PC)of heavily drinkers develops these pancreatic diseases,there are other predisposing factors besides alcohol involved.Genetic variability and environmental exposures such as smoking and diet modify the risk and should be considered for further investigations.

c-Met in pancreatic cancer stem cells: Therapeutic implications

Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths. Emerging evidence suggests that cancer stem cells (CSCs) play a crucial role in the development and progression of this disease. The identification of CSC markers could lead to the development of new therapeutic targets. In this study, the authors explore the functional role of c-Met in pancreatic CSCs, by analyzing self-renewal with sphere assays and tumorigenicity capacity in NOD SCID mice. They concluded that c-Met is a novel marker for identifying pancreatic CSCs and c-Met high in a higher tumorigenic cancer cell population. Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic CSCs. In pancreatic tumors established in NOD SCID mice, c-Met inhibition slowed tumor growth and reduced the population of CSCs, along with preventing the development of metastases.

Fecal immunochemical test accuracy in average-risk colorectal cancer screening

AIM:To assess the fecal immunochemical test(FIT)accuracy for colorectal cancer(CRC)and advanced neoplasia(AN)detection in CRC screening.METHODS:We performed a multicentric,prospective,double blind study of diagnostic tests on asymptomatic average-risk individuals submitted to screening colonoscopy.Two stool samples were collected and the fecal hemoglobin concentration was determined in the first sample(FIT1)and the highest level of both samples(FITmax)using the OC-sensor.Areas under the curve(AUC)for CRC and AN were calculated.The best FIT1and FITmax cut-off values for CRC were determined.At this threshold,number needed to scope(NNS)to detect a CRC and an AN and the cost per lesion detected were calculated.RESULTS:About 779 individuals were included.An AN was found in 97(12.5%)individuals:a CRC in 5(0.6%)and an advanced adenoma(≥10 mm,villous histology or high grade dysplasia)in 92(11.9%)subjects.For CRC diagnosis,FIT1 AUC was 0.96(95%CI:0.95-0.98)and FITmax AUC was 0.95(95%CI:0.93-0.97).For AN,FIT1 and FITmax AUC were similar(0.72,95%CI:0.66-0.78 vs 0.73,95%CI:0.68-0.79,respectively,P=0.34).Depending on the number of determinations and the positivity threshold cut-off used sensitivity for AN detection ranged between 28%and 42%and specificity between 91%and 97%.At the best cut-off point for CRC detection(115 ng/mL),the NNS to detect a CRC were 10.2 and 15.8;and the cost per CRC was 1814€and 2985€on FIT1 and FITmax strategies respectively.At this threshold the sensitivity,NNS and cost per AN detected were 30%,1.76,and 306€,in FIT1 strategy,and 36%,2.26€and 426€,in FITmax strategy,respectively.CONCLUSION:Performing two tests does not improve diagnostic accuracy,but increases cost and NNS to detect a lesion.

Antimicrobial susceptibility testing before first-line treatment for Helicobacter pylori infection in patients with dual or triple antibiotic resistance

AIM To evaluate the efficacy of antimicrobial susceptibilityguided therapy before first-line treatment for infection in patients with dual or triple antibiotic resistance.METHODS A total of 1034 patients infected by Helicobacter pylori(H. pylori) during 2013-2014 were tested for antimicrobial susceptibility. 157 of 1034(15%) patients showed resistance to two(127/1034; 12%) and to three(30/1034; 3%) antibiotics. Sixty-eight patients with dual H. pylori-resistance(clarithromycin, metronidazole or levofloxacin) were treated for 10 d with triple therapies: OAL(omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and levofloxacin 500 mg b.i.d.) 43cases, OAM(omeprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and metronidazole 500 mg b.i.d.) 12 cases and OAC(omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and clarithromycin 500 mg b.i.d.) 13 cases based on the antimicrobial susceptibility testing. Twelve patients showed triple H. pylori-resistance(clarithromycin, metronidazole and levofloxacin) and received for 10 d triple therapy with OAR(omeprazole 20 mg b.id., amoxicillin 1 g b.i.d., and rifabutin 150 mg b.i.d.). Eradication was confirmed by 13C-urea breath test. Adverse effects and compliance were assessed by a questionnaire. RESULTS Intention-to-treat eradication rates were: OAL(97.6%), OAM(91.6%), OAC(92.3%) and OAR(58.3%). Cure rate was significantly higher in na?ve patients treated with OAR-10 compared to patients who had two or three previous treatment failures(83% vs 33%). Adverse events rates for OAL, OAM, OAC and OAR were 22%, 25%, 23% and 17%, respectively, all of them mild-moderate. CONCLUSION Antimicrobial susceptibility-guided triple therapies during 10 d for first-line treatment leads to an eradication rate superior to 90% in patients with dual antibiotic H. pylori resistance.

Spontaneous regression of pancreatic cancer: Real or a misdiagnosis?

Spontaneous tumor regression has been subject of numerous studies and speculations for many years. This phenomenon is exceptional, but well reported, in some types of tumors, but not in pancreatic cancer. Pancreatic cancer has the worst five-year survival rate of any cancer. Despite numerous molecular studies and clinical approaches, using several mouse models, this cancer responds poorly to the existing chemotherapeutic agents and progress on treatment remains elusive. Although pancreatic cancer tumors seldom undergo spontaneous regression, and some authors take that with skepticism, there are some cases reported in the literature. However, the variability in the description of the reports and technical details could make this process susceptible to misdiagnosis. Distinguishing between different types of pancreatic carcinoma should be taken with caution as they have wide differences in malignant potential. Diseases such as pancreatic benign tumors, insulinomas, or autoimmune pancreatitis could be responsible for this misdiagnosis as a pancreatic cancer. Here we review different cases reported, their clinical characteristics, and possible mechanisms leading to spontaneous regression of pancreatic cancer. We also discuss the possibilities of misdiagnosis.