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.

Patterns of local recurrence in rectal cancer after a multidisciplinary approach

Improvements in surgery and the application of combined approaches to fight rectal cancer have succeeded in reducing the local recurrence (LR) rate and when there is LR it tends to appear later and less often in isolation. Moreover, a subtle change in the distribution of LRs with respect to the pelvis has been observed. In general terms, prior to total mesorectal excision the most common LRs were central types (perianastomotic and anterior) while lateral and posterior forms (presa-cral) have become more common since the growth in the use of combined treatments. No differences have been reported in the current pattern of LRs as a function of the type of approach used, that is, neo-adjuvant therapies (short-term or long-course radiotherapy, orchemoradiotherapy versus extended lymphadenectomy, though there is a trend towards posterior or presacral LR in patients in the Western world and lateral LR in Asia. Nevertheless, both may arise from the same mechanism. Moreover, as well as the mode of treatment, the type of LR is related to the height of the initial tumor. Nowadays most LRs are related to the advanced nature of the disease. Involvement of the circumferential radial margin and spillage of residual tumor cells from lymphatic leakage in the pelvic side wall are two plausible mechanisms for the genesis of LR. The patterns of pelvic recurrence itself (pelvic subsites) also have important implications for prognosis and are related to the potential success of salvage curative approach. The re-operability for cure and prognosis are generally better for anastomotic and anterior types than for presacral and lateral recurrences. Overall survival after LR diagnosis is lower with radio or chemoradiotherapy plus optimal surgery approaches, compared to optimal surgery alone.

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.

Malignant colorectal polyps

Nowadays, the number of cases in which malignant colorectal polyps are removed is increasing due to colorectal cancer screening programmes. Cancerous polyps are classified into non-invasive high grade neoplasia (NHGN), when the cancer has not reached the muscularis mucosa, and malignant polyps, classed as T1, when they have invaded the submucosa. NHGN is considered cured with polypectomy, while the prognosis for malignant polyps depends on various morphological and histological factors. The prognostic factors include, sessile or pedunculated morphology of the polyp, whether partial or en bloc resection is carried out, the degree of differentiation of the carcinoma, vascular or lymphatic involvement, and whether the polypectomy resection margin is tumor free. A malignant polyp at T1 is considered cured with polypectomy ifit is a pedunculated polyp (Ip of the Paris classification), it has been completely resected, it is not poorly differentiated, the resection edge is not affected by the tumor and there is no vascular or lymphatic involvement. The sessile malignant polyp (Is of the Paris classification) at T1 is considered not cured with polypectomy. Only in some cases (e.g. older people with high surgical risk) local excision(polypectomy or endoscopic submucosal dissection or conventional endoscopic mucosal resection) is considered the definitive treatment.

Colorectal and interval cancers of the Colorectal Cancer Screening Program in the Basque Country (Spain)

AIM To assess proportions, related conditions and survival of interval cancer(IC).METHODS The programme has a linkage with different clinical databases and cancer registers to allow suitable evaluation. This evaluation involves the detection of ICs after a negative faecal inmunochemical test(FIT), interval cancer FIT(IC-FIT) prior to a subsequent invitation, and the detection of ICs after a positive FIT and confirmatory diagnosis without colorectal cancer(CRC) detected and before the following recommended c o l o n o s c o p y, I C-c o l o n o s c o p y. W e c o n d u c t e d a retrospective observational study analyzing from January 2009 to December 2015 1193602 invited people onto the Programme(participation rate of 68.6%).RESULTS Two thousand five hundred and eighteen cancers were diagnosed through the programme, 18 cases of IC-colonoscopy were found before the recommended follow-up(43542 colonoscopies performed) and 186 IC-FIT were identified before the following invitation of the 769200 negative FITs. There was no statistically significant relation between the predictor variables of ICs with sex, age and deprivation index, but there was relation between location and stage. Additionally, it was observed that there was less risk when the location was distal rather than proximal(OR = 0.28, 95%CI: 0.20-0.40, P < 0.0001), with no statistical significance when the location was in the rectum as opposed to proximal. When comparing the screen-detected cancers(SCs) with ICs, significant differences in survival were found(P < 0.001); being the 5-years survival for SCs 91.6% and IC-FIT 77.8%.CONCLUSION These findings in a Population Based CRC Screening Programme indicate the need of population-based studies that continue analyzing related factors to improve their detection and reducing harm.

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.

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

To evaluate the efficacy of antimicrobial susceptibility-guided therapy before first-line treatment for infection in patients with dual or triple antibiotic resistance.METHODSA 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.) 43 cases, 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.RESULTSIntention-to-treat eradication rates were: OAL (97.6%), OAM (91.6%), OAC (92.3%) and OAR (58.3%). Cure rate was significantly higher in naïve 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.CONCLUSIONAntimicrobial 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.

Food groups, diet quality and colorectal cancer risk in the Basque Country

BACKGROUND The results obtained to date concerning food groups,diet quality and colorectal cancer(CRC)risk vary according to criteria used and the study populations.AIM To study the relationships between food groups,diet quality and CRC risk,in an adult population of the Basque Country(North of Spain).METHODS This observational study included 308 patients diagnosed with CRC and 308 ageand sex-matched subjects as controls.During recruitment,dietary,anthropometric,lifestyle,socioeconomic,demographic and health status information was collected.Adherence to the dietary recommendations was evaluated utilizing the Healthy Eating Index for the Spanish Diet and the MedDietScore.Conditional logistic regressions were used to evaluate the associations of food group intakes,diet quality scores,categorized in tertiles,with CRC risk.RESULTS The adjusted models for potential confounding factors showed a direct association between milk and dairy products consumption,in particular high-fat cheeses[odds ratio(OR)third tertile vs first tertile=1.87,95%confidence intervals(CI):1.11-3.16],and CRC risk.While the consumption of fiber-containing foods,especially whole grains(OR third tertile vs first tertile=0.62,95%CI:0.39-0.98),and fatty fish(OR third tertile vs first tertile=0.53,95%CI:0.27-0.99)was associated with a lower risk for CRC.Moreover,higher MD adherence was associated with a reduced CRC risk in adjusted models(OR third tertile vs first tertile=0.40,95%CI:0.20-0.80).CONCLUSION Direct associations were found for high-fat cheese,whereas an inverse relation was reported for fiber-containing foods and fatty fish,as well as adherence to a Mediterranean dietary pattern.

New genes emerging for colorectal cancer predisposition

Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

Prognosis and follow-up of 135 patients with ischemic colitis over a five-year period

AIM:To study the prognosis(recurrence and mortality)of patients with ischemic colitis(IC).METHODS:This study was conducted in four Spanish hospitals,participants in the Ischemic Colitis in Spain study We analyzed prospectively 135 consecutive patients who met criteria for definitive or probable IC according to Brandt criteria,and follow up these patients during the next five years,retrospectively.Long-term results(recurrence and mortality)were evaluated retrospectively after a median interval of 62 mo(range54-75 mo).RESULTS:Estimated IC recurrence rates were 2.9%,5.1%,8.1%and 9.7%at years 1,2,3 and 5 years,respectively.Five-year survival was 69%(93 of 135)and 24%(10 of 42 patients)died for causes related to the IC.Among these 10 patients,8 died in their first episode at hospital(4 had gangrenous colitis and 4 fulminant colitis)and 2 due to recurrence.CONCLUSION:The five-year recurrence rate of IC was low.On the other hand,mortality during follow-up was high and was not associated with ischemic colitis.

MicroRNAs in biliary diseases

Cholangiopathies are a group of diseases primarily or secondarily affecting bile duct cells, and result in cholangiocyte proliferation, regression, and/or transformation. Their etiopathogenesis may be associated with a broad variety of causes of different nature, which includes genetic, neoplastic, immune-associated, infectious, vascular, and drug-induced alterations, or being idiopathic. miRNAs, small non-coding endogenous RNAs that post-transcriptionally regulate gene expres sion, have been associated with pathophysiological processes in different organs and cell types, and are postulated as potential targets for diagnosis and therapy. In the current manuscript, knowledge regarding the role of miRNAs in the development and/or progression of cholangiopathies has been reviewed and the most relevant findings in this promising field of hepatology have been highlighted.

Cytomegalovirus hepatitis and myopericarditis

Cytomegalovirus (CMV) infection in inmunocompetent hosts generally is asymptomatic or may present as a mononucleosis syndrome but rarely can lead to severe organ complications. We report a case of simultaneous hepatic and pericardic CMV infection in a 36-year old immunocompetent man. He was admitted to coronary unit with fever, chest pain radiated to shoulders, changes on electrocardiogram with diffuse ST elevation and modest laboratory elevations in the MB fraction of creatine kinase (CK-MB) of 33.77 μg/L (0.1-6.73), serum cardiac troponin T of 0.904 ng/mL (0-0.4), creatine kinase of 454 U/L (20-195) and myoglobin of 480.4 μg/L (28-72). Routine laboratory test detected an elevation of aminotransferase level: alanine aminotransferase 1445 U/L, aspartate aminotransferase 601 U/L. We ruled out other causes of hepatitis with normal results except IgM CMV. The patient was diagnosed with myopericarditis and hepatitis caused by cytomegalovirus and started symptomatic treatment with salicylic acid. In few days the laboratory findings became normal and the patient was discharged.

Littoral-cell angioma of the spleen:A case report

Littoral-cell angioma （LCA） is a primary splenic vascular tumor that arises from the normal littoral cells lining the sinus channels of the splenic red pulp. We report a case of LCA of the spleen, which has been infrequently communicated in the literature. A 76-year-old man with a 2-wk history of weight loss, abdominal pain and changes in bowel habits was admitted to our hospital. Imaging studies （CT and MR1） showed multiple lesions in the spleen. Splenectomy was performed. Lining cells were positive for CD31/CD68 markers. Our case was associated with a serrated colonic adenoma. LCA is a benign vascular tumor of the spleen that needs to be included in the differential diagnosis of multiple splenic nodules.

Biochemical determination of lipid content in hepatic steatosis by the Soxtec method

AIM:To establish a quantitative method to measure the amount of lipids.METHODS:The livers of 53 male Wistar rats(225 g) with different degrees of hepatic steatosis were studied.This model of hepatic steatosis was based on a high carbohydrate,fat-free modified diet.Biopsies were classified into four grades depending on fat accumulation,using the Kleiner and Brunt classification.Total fat was studied by the Soxtec method(SoxtecTM 2050 Auto Fat Extraction System),and agreement between both assays was assessed by calculating theκ coefficient.RESULTS:According to the histological classification,38% of rats presented grade 0,21% grade 1,22% grade 2 and 20% grade 3.The amount of fat per 100 g tissue was 2.60±0.64 g for grade 0,3.87±1.59 g for grade 1,5.82±1.37 g for grade 2 and 8.68± 2.30 g for grade 3.Statistically significant differences were found between the mean values for each of the histological grades(P<0.05).The correlation for the quantification of fat in the liver between both assays was moderate(κ=0.60).CONCLUSION:The biochemical quantification of fat in liver tissue by the Soxtec method was correlated with the histological classification,although the agreement between the two tests was only moderate.

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.

Somatic second-hit mutations leads to polycystic liver diseases

Polycystic liver diseases(PCLDs) are a heterogeneous group of genetic disorders characterized by the development of multiple fluid-filled cysts in the liver,which derive from cholangiocytes,the epithelial cells lining the bile ducts.When these cysts grow,symptoms such as abdominal distension,nausea,and abdominal pain may occur.PCLDs may exist isolated(i.e.,autosomal dominant polycystic liver disease,ADPLD) or in combination with renal cystogenesis(i.e.,autosomal dominant polycystic kidney disease and autosomal recessive polycystic liver disease).The exact prevalence of PCLDs is unknown,but is estimated to occur in approximately 1:1000 persons.Although the pathogenesis of each form of PCLD appears to be different,increasing evidences indicate that hepatic cystogenesis is a phenomenon that may involve somatic loss of heterozygosity(LOH) in those pathological conditions inherited in a dominant form.A recent report,using highly sophisticated methodology,demonstrated that ADPLD patients with a germline mutation in the protein kinase C substrate 80K-H(PRKCSH) gene mostly develop hepatic cystogenesis through a second somatic mutation.While hepatocystin,the PRKCSH-encoding protein,was absent in the hepatic cysts with LOH,it was still expressed in the heterozygous cysts.On the other hand,no additional trans-heterozygous mutations on the SEC63 homolog(S.cerevisiae /SEC63) gene(also involved in the development of PCLDs) were observed.These data indicate that PCLD is recessive at the cellular level,and point out the important role of hepatocystin loss in cystogenesis.In this commentary,we discuss the knowledge regarding the role of somatic second-hit mutations in the development of PCLDs,and the most relevant findings have been highlighted.

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.

Colorectal cancer prognosis twenty years later

AIM:To evaluate changes in colorectal cancer(CRC) survival over the last 20 years.METHODS:We compared two groups of consecutive CRC patients that were prospectively recruited:Group Ⅰincluded 1990 patients diagnosed between 1980 and 1994.GroupⅡincluded 871 patients diagnosed in 2001.RESULTS:The average follow up time was 21 mo(1-229)for GroupⅠand 50 mo(1-73.4)for GroupⅡ.Overall median survival was significantly longer in Group Ⅱthan in GroupⅠ(73 mo vs 25 mo,P<0.001)and the difference was significant for all tumor stages.Post surgical mortality was 8% for GroupⅠand 2% for Group Ⅱ(P<0.001).Only 17% of GroupⅠpatients received chemotherapy compared with 50% of GroupⅡpatients(P<0.001).CONCLUSION:Survival in colorectal cancer patients has doubled over the past 20 years.This increase seems to be partly due to the generalization in the administration of chemotherapy and to the decrease of post surgical mortality.