Transduodenal surgical ampullectomy: a procedure that requires a multidisciplinary approach.

Trans-duodenal surgical ampullectomy (TSA) was first described in 1899. Nowadays its role in ampullary tumor surgery is still a matter of debate and requires a multidisciplinary approach. The aim of this study is to evaluate the results of TSA as a curative treatment for benign and selected malignant tumors arising from the ampulla in a single-institution experience. Sixteen patients with periampullary tumors that underwent TSA in our surgical units between January 2012 and January 2017 were included in the study. Patient demographic characteristics, pre or postoperative endoscopic interventions, operative procedures, postoperative morbidity and mortality, hospitalization, follow-up time, and quality of life questionnaire were analyzed. Mean operative time was 238.5 min (range 180-390), mean tumor size was 2.3 cm (range 1.5-3.9). The microscopic surgical outcome was R0 for 14 patients. The most frequent findings in terms of histological type were high-grade dysplasia/pTis (43.7%), low-grade dysplasia in 37.5% patients, invasive adenocarcinoma in 2 cases (12.5%), chronic inflammation in 1 case (6.3%). The readmission rate was 18.8% (3/16) and in 2 cases (12.5%) relaparotomy was required. The cumulative median duration of follow-up was 50 months (range 1-96). 90-days mortality was 6.2%. Mean hospital stay was 12 days (range 8-60). Our results confirm that TSA offers good results in terms of morbidity and mortality; still, it remains a challenging procedure that requires particular surgical experience and operative skills. A pre-operative planning in a multidisciplinary board should be carried out prior to the procedure.

End-to-side duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy A comparison trial of small versus larger jejunal incision. A single center experience.

AIM: The rates of post-operative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) are between 5% and 30%. Nowadays, pancreaticojejunostomy (PJ) represents the most common type of reconstruction after PD, but the ideal technique is still debated. Our randomized trial was conceived with the intent to evaluate if two variants of PJ could influence the post-operative outcome in term of early complications. MATERIAL AND METHODS: Forty-eight consecutive patients treated with PD were randomized into 2 groups (Group 1 or Large Jejunal Incision or LJI group and Group 2 or Small Jejunal Incision or SJI group). Outcome measures were the operative time, postoperative complications, length of postoperative hospital stay, amylase content in drains. RESULTS: wenty-two patients were enrolled in the LJI and 26 in the SJI group. Median operative times did not differ between the 2 groups. The groups were homogeneous in respect to the median age of patients, the clinical presentation of jaundice and the presence of percutaneous biliary drainage (PBD). POPF developed in 3/22 (13.6%) and 1/26 (4%) patients among the LJI and SJI group respectively (3 grade B and 1 grade C respectively) (p=0.341). PPH occurred in 8/22 (36%) and 2/26 (8%) patients among the LJI and SJI group, respectively (p=0.018). The Amylase content in the drainage fluid measured at the 5th postoperative day showed a higher value in patients who underwent LJI anastomosis compared to those with SJI anastomosis [LJI group: 26.5 (6-254) U/l vs SJI group: 7 (0-38) U/l; p=0.051]. Delayed Gastric Emptying (DGE) was not different. The multivariate logistic regression analysis demonstrated both LJI anastomosis and DGE as independent predictors for pancreatic fistula (DGE: OR=20.04, CI 95%=1.92-208.83, P=0.012; LJI anastomosis: OR=24.58, CI 95%=1.71-354.32, P=0.019) and PPH (DGE: 30.5, CI 95%=3.02-308.16, P=0.004; LJI anastomosis: OR=12.71, CI 95%=1.23-131.55, P=0.033). CONCLUSIONS: Based on the present results, we suggest to adopt what a "pancreas duct-oriented" approach: if pancreas duct is large a SJI-PJ is recommended; if the duct is < than 3 mm, a LJI must be preferred. Our conclusion is that the association of some surgeons to perform always the techniques with them are more confident is a concept of the past: recent data suggest that the pancreatic surgeon must have the different techniques in his "armamentarium" and varying the technique depending on local characteristic of the pancreas to allow a tailored approach to the patient. KEY WORDS: Pancreaticojejunostomy, Pancreatic fistula, Surgical Sutcome.

Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms.

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.

MicroRNA co-expression networks exhibit increased complexity in pancreatic ductal compared to Vater's papilla adenocarcinoma.

MiRNA expression abnormalities in adenocarcinoma arising from pancreatic ductal system (PDAC) and Vater's papilla (PVAC) could be associated with distinctive pathologic features and clinical cancer behaviours. Our previous miRNA expression profiling data on PDAC (n=9) and PVAC (n=4) were revaluated to define differences/similarities in miRNA expression patterns. Afterwards, in order to uncover target genes and core signalling pathways regulated by specific miRNAs in these two tumour entities, miRNA interaction networks were wired for each tumour entity, and experimentally validated target genes underwent pathways enrichment analysis. One hundred and one miRNAs were altered, mainly over-expressed, in PDAC samples. Twenty-six miRNAs were deregulated in PVAC samples, where more miRNAs were down-expressed in tumours compared to normal tissues. Four miRNAs were significantly altered in both subgroups of patients, while 27 miRNAs were differentially expressed between PDAC and PVAC. Although miRNA interaction networks were more complex and dense in PDAC than in PVAC, pathways enrichment analysis uncovered a functional overlapping between PDAC and PVAC. However, shared signalling events were influenced by different miRNA and/or genes in the two tumour entities. Overall, specific miRNA expression patterns were involved in the regulation of a limited core signalling pathways in the biology landscape of PDAC and PVAC.

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

Support Vector Machine Based on microRNA Expression Profiles to Predict Histological Origin of Ampullary Carcinoma: Case Report of a Patient Affected From Adenocarcinoma of the Papilla of Vater With Lynch Syndrome.

Adenocarcinomas of Vater's papilla (PVAC) may originate from either the pancreatic duct or the intestinal epithelium. Conflicting data have been reported about the frequency of the 2 anatomical entities and their influence on patients' prognosis. To ascertain the anatomical origin of PVAC in a family member of a Lynch syndrome kindred, we searched for microRNA (miRNA) expression profiles on resected tumor specimens. The support vector machine was trained on our previous miRNAs expression data sets of pancreatic and colorectal tissue samples and used to classify the site of origin of the tumor in our patient. The support vector machine worked by contrasting the profiles of miRNAs in patients with pancreatic ductal and colorectal cancers to that of our patient, which was finally classified as pancreatic ductal adenocarcinoma accordingly to alterations of 55 miRNAs. The PVAC might be originated from ductal epithelium rather than from the intestinal mucosa of the papilla in the case at issue. Alteration of miR-548b-3p, miR-551a, miR-21, miR-92a, miR-let-7i, and miR-181a* emerged as potentially associated with cancer genetic susceptibility in PVAC.

SIRT1 and circadian gene expression in pancreatic ductal adenocarcinoma: Effect of starvation.

Pancreatic cancer (PC), the fourth leading cause of cancer-related deaths, is characterized by high aggressiveness and resistance to chemotherapy. Pancreatic carcinogenesis is kept going by derangement of essential cell processes, such as proliferation, apoptosis, metabolism and autophagy, characterized by rhythmic variations with 24-h periodicity driven by the biological clock. We assessed the expression of the circadian genes ARNLT, ARNLT2, CLOCK, PER1, PER2, PER3, CRY1, CRY2 and the starvation-activated histone/protein deacetylase SIRT1 in 34 matched tumor and non-tumor tissue specimens of PC patients, and evaluated in PC derived cell lines if the modulation of SIRT1 expression through starvation could influence the temporal pattern of expression of the circadian genes. We found a significant down-regulation of ARNLT (p = 0.015), CRY1 (p = 0.013), CRY2 (p = 0.001), PER1 (p < 0.0001), PER2 (p < 0.001), PER3 (p = 0.001) and SIRT1 (p = 0.017) in PC specimens. PER3 and CRY2 expression levels were lower in patients with jaundice at diagnosis ( < 0.05). Having adjusted for age, adjuvant therapy and tumor stage, we evidenced that patients with higher PER2 and lower SIRT1 expression levels showed lower mortality (p = 0.028). Levels and temporal patterns of expression of many circadian genes and SIRT1 significantly changed upon serum starvation in vitro, with differences among four different PC cell lines examined (BXPC3, CFPAC, MIA-PaCa-2 and PANC-1). Serum deprivation induced changes of the overall mean level of the wave and amplitude, lengthened or shortened the cycle time and phase-advanced or phase-delayed the rhythmic oscillation depending on the gene and the PC cell line examined. In conclusion, a severe deregulation of expression of SIRT1 and circadian genes was evidenced in the cancer specimens of PC patients, and starvation influenced gene expression in PC cell lines, suggesting that the altered interplay between SIRT1 and the core circadian proteins could represent a crucial player in the process of pancreatic carcinogenesis.

Influence of preoperative biliary drainage on surgical outcome after pancreaticoduodenectomy: single centre experience.

PURPOSE: Controversy prevails on the impact of preoperative biliary drainage (PBD) on postoperative complications and clinical outcome of pancreatic cancer. We determined whether PBD is associated with increased morbidity and mortality rates after pancreaticoduodenectomy. METHODS: A total of 131 consecutive patients who underwent pancreaticoduodenectomy (93 jaundiced, 38 with no jaundice) were included in this study. Overall, 57 % of jaundiced patients underwent PBD, while 43 % were not drained. The impact of PBD on postoperative morbidity and mortality was evaluated by means of logistic regression analysis. The Kaplan-Meier method was applied to determine the effect of PBD on survival of patients with malignant lesions. RESULTS: Mortality and morbidity rate was 3 % and 54.6 %, respectively. PBD was demonstrated to be the unique predictor of complications (odds ration [OR] = 10.18; 95 % confidence interval [CI], 3.65-28.39, p < 0.001). The jaundiced patients who were drained exhibited high frequencies of wound infection (p < 0.001), post-pancreatectomy haemorrhage (p = 0.0185) and hyperglycaemia (p < 0.001). In addition, an increased frequency of pancreatic fistula emerged among drained patients compared to those who were not drained (p = 0.036). PBD did not affect survival of patient with malignant lesions. CONCLUSIONS: With the exception of the classical indications, PBD should be carefully evaluated in patients with resectable pancreatic cancer.

Management of struvite uroliths in dogs.

Urolithiasis is a common clinical problem in dogs. Struvite and calcium oxalate are the predominant mineral types in dog urolithiasis. The aim of the present study was to compare the effect of two commercial dry foods formulated for the management of struvite urolithiasis with different anion-cation balance on urinary pH. For the trial, twelve privately owned adult dogs showing struvite urolithiasis were studied. The dogs were randomly divided into two groups (A and B) and fed two dissolving diets for 3 months. The analyses of urine were repeated six times. In both diets, the anion-cation balance was negative ( - 203 and - 192 for diets A and B, respectively). At the first urine analysis, pH values of all the dogs were close to 8.0, and bacteria were present in about 70 % of the samples and thus an antimicrobial was administered for 1 week. Both groups showed a progressive decrease in pH values, and after 2 months, in both cases, the recommended pH values for stone dissolution were achieved. From the sampling at 30 d, group A showed pH values significantly (P < 0.05) lower than group B, probably due to the lower anion-cation balance of diet A. The combination of antimicrobial and dietary therapy allowed the dissolution of struvite uroliths in both groups, even if the utilisation of the diet characterised by the lower anion-cation balance seems to decrease the urinary pH more rapidly. In this case, it seems necessary to interrupt the dietary treatment in order to avoid the risk of other diseases.

Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family.

To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G>T, located in the MEN1 gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases.

A modified fast-track program for pancreatic surgery: a prospective single-center experience.

OBJECTIVE: The objective of this study is to evaluate the impact of a fast-track protocol in a high-volume center for patients with pancreatic disorders. BACKGROUND: The concept of fast-track surgery allowing accelerated postoperative recovery is accepted in colorectal surgery, but efficacy data are only preliminary for patients undergoing major pancreatic surgery. We aimed to evaluate the impact of a modified fast-track protocol in a high-volume center for patients with pancreatic disorders. METHODS: Between February 2005 and January 2010, 145 subjects had resective pancreatic surgery and were enrolled in the program. Essential features of the program were no preanaesthetic medication, upper and lower air-warming device, avoidance of excessive i.v. fluids perioperatively, effective control of pain, early reinstitution of oral feeding, and immediate mobilization and restoration of bowel function following surgery. Outcome measures were postoperative complications such as pancreatic fistula, delayed gastric emptying, biliary leak, intra-abdominal abscess, post-pancreatectomy hemorrhage, acute pancreatitis, wound infection, 30-day mortality, postoperative hospital stay, and readmission rates. RESULTS: On average, patients were discharged on postoperative day 10 (range 6-69), with a 30-day readmission rate of 6.2%. Percentage of patients with at least one complication was 38.6%. Pancreatic anastomotic leakage occurred in seven of 101 pancreatico-jejunostomies, and biliary leak in three of 109 biliary jejunostomies. Postoperative hemorrhage occurred in ten (6.9%) patients and wound infection in nine (6.2%) cases. In-hospital mortality was 2.7%. Fast-track parameters, such as normal food and first stool, correlated significantly with early discharge (<0.05). At multivariate analysis, lack of jaundice, and resumption of normal diet by the 5th postoperative day were independent factors of early discharge. CONCLUSION: Fast-track programs are feasible, easy, and also applicable for patients undergoing a major surgery such as pancreatic resection.