Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer.

Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha (PPARA) and retinoid X receptor (RXR)-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that PPARA and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of PPARA messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 µM. According to our results, upregulation of PPARA and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.

Oncologic and Perioperative Outcomes Following Selective Application of Laparoscopic Pancreaticoduodenectomy for Periampullary Malignancies.

BACKGROUND: Data are sparse regarding patient selection criteria or evaluating oncologic outcomes following laparoscopic pancreaticoduodenectomy (LPD). Having prospectively limited LPD to patients with resectable disease defined by National Comprehensive Cancer Network (NCCN) criteria, we evaluated perioperative and long-term oncologic outcomes of LPD compared to a similar cohort of open pancreaticoduodenectomy (OPD). METHODS: Consecutive patients (November 2010-February 2014) undergoing pancreaticoduodenectomy (PD) for periampullary adenocarcinoma were reviewed. Patients were excluded from further analysis for benign pathology, conversion to OPD for portal vein resection, and contraindications for LPD not related to their malignancy. Outcomes of patients undergoing LPD were analyzed in an intention-to-treat manner against a cohort of patients undergoing OPD. RESULTS: These selection criteria resulted in offering LPD to 77 % of all cancer patients. Compared to the OPD cohort, LPD was associated with significant reductions in wound infections (16 vs. 34 %; P = 0.038), pancreatic fistula (17 vs. 36 %; P = 0.032), and median hospital stay (9 vs. 12 days; P = 0.025). Overall survival (OS) was not statistically different between patients undergoing LPD vs. OPD for periampullary adenocarcinoma (median OS 27.9 vs. 23.5 months; P = 0.955) or pancreatic adenocarcinoma (N = 28 vs. 22 patients; median OS 20.7 vs. 21.1 months; P = 0.703). CONCLUSIONS: The selective application of LPD for periampullary malignancies results in a high degree of eligibility as well as significant reductions in length of stay, wound infections, and pancreatic fistula. Overall survival after LPD is similar to OPD.

Prognostic Significance of Nodal Ratio in Patients Undergoing Adjuvant Chemoradiotherapy After Curative Resection for Ampullary Cancer.

OBJECTIVES: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients METHODS: : Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors. RESULTS: There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively). CONCLUSIONS: Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients.

Effects of chewing gum against postoperative ileus after pancreaticoduodenectomy--a randomized controlled trial.

BACKGROUND: Postoperative ileus is common after surgery. One non-pharmacological intervention that has shown promising results in reducing the duration of postoperative ileus is chewing gum after surgery. However, this has not been investigated in upper gastrointestinal surgery such as pancreatic surgery. Hence the aim of this study was to investigate the effects of chewing gum treatment on patients undergoing pancreaticoduodenectomy ad modum whipple due to pancreatic or periampullary cancer. METHODS: This study was conducted as a phase III trial that was terminated early. Patients diagnosed with pancreatic tumours scheduled for pancreaticoduodenectomy ad modum whipple were included. The treatment group received chewing gum postoperatively and standard care. Controls received glucose solution and standard care. Chewing gum and glucose were used four times a day during the whole hospital stay. Time to first flatus and stool was defined as the primary outcome. The secondary outcome was start with clear liquids, start with liquid diet and length of hospital stay. RESULTS: No statistically significant differences could be observed between the chewing gum intervention group and the control group. However, a numerical difference in mean time was observed in first flatus, first stool, start of clear fluids, and start of liquid diet and length of hospital stay in favour of the intervention group. CONCLUSIONS: Although this study did not find statistically significant differences favouring the use of chewing gum for postoperative ileus, a positive trend was observed of a reduction of the impact of postoperative ileus among patients after pancreatic surgery. It also contributes valuable methodological experience that is important for future studies of chewing gum interventions during recovery after pancreatic surgery. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02319512 , publication date 2014-12-17.

Lethal cardiotoxicity, steatohepatitis, chronic pancreatitis, and acute enteritis induced by capecitabine and oxaliplatin in a 36-year-old woman.

A 36-year-old female was hospitalized with symptoms suggesting intestinal occlusion. She was diagnosed with adenocarcinoma of the ampulla of Vater (pT4N0 stage) and underwent cephalic duodenopancreatectomy 8 months ago. Five cycles of postoperative chemotherapy were administrated using capecitabine and oxaliplatin (CAPOX or XELOX), the last one being completed 1 month ago. During the present hospitalization, because of normal computed tomography and ultrasound abdominal examination, rehydration and antibiotherapy were administrated. However, 4 days after hospital admission, the patient died. At autopsy and histological examination, we found a severe myocardial sclerosis with large scarring areas, severe steatohepatitis, chronic pancreatitis with large fibrotic areas, and acute enteritis. Alcohol consumption was denied. The patient died due to associated heart, liver and pancreatic failure. This multiorgan toxicity and death following CAPOX regimen had not yet been reported in the literature. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6472150549833105.

Zinc deficiency in patients undergoing pancreatoduodenectomy for periampullary tumors is associated with pancreatic exocrine insufficiency.

BACKGROUND AND PURPOSE: The present study was done to investigate the prevalence of zinc deficiency after pancreatoduodenectomy (PD) and its correlation with pancreatic exocrine insufficiency. MATERIALS AND METHODS: Patients were included in this study if they had undergone PD for periampullary tumors without recurrence and had received follow-up for more than 6 months between February 2006 and June 2007. Serum levels of zinc, fasting glucose, albumin, and iron were obtained. The pancreatic exocrine function was evaluated by a fecal elastase-1 assay, stool fat assessment, and a pancreatic duct-parenchymal ratio (DPR) at the L1 level using abdominal computed tomography (CT). The quality of life was estimated with a questionnaire of EORTC QLQ-C30 and PAN26. All of these patients were then supplemented with oral pancreatic enzymes for 4 weeks to evaluate the effect of these enzymes on zinc deficiency. RESULTS: Forty-eight eligible patients, 27 men and 21 women, were included. The mean age was 61.3 ± 1.7 years. Thirty-three (68%) patients had a zinc deficiency with a mean zinc level of 72.3 ± 2.9 mcg/dl (normal range: 80-120 mcg/dl). Patients with lower serum zinc levels tended to have typical presentations of zinc deficiency (P = 0.039, χ(2)). The serum zinc level was significantly negatively correlated with pancreatic duct diameter, DPR, and positive stool fat during the late follow-up period. The most common presentations of patients with lower serum zinc levels were skin rash, photophobia, and glossitis. These gastrointestinal disorders, as well as symptoms of zinc deficiency, improved after pancreatic enzyme supplementation. CONCLUSIONS: Zinc deficiency after PD was a common phenomenon and correlated with pancreatic exocrine insufficiency.

Intraoperative allogeneic red blood cell transfusion in ampullary cancer outcome after curative pancreatoduodenectomy: a clinical study and meta-analysis.

BACKGROUND: Allogeneic blood transfusion (ABT) containing packed red blood cells (RBCs) has a known immunosuppressive effect that may affect cancer metastases and recurrence. This study examined whether intraoperative allogeneic RBC transfusion is an independent risk factor of adverse outcome in patients with ampullary carcinoma after curative pancreatoduodenectomy. METHODS: The clinical data of 67 patients with carcinoma of the ampulla of Vatar underwent pancreatoduodenectomy between 1999 and 2004 were analyzed, and long-term follow-up visits were made for all patients. Kaplan-Meier statistics and Cox proportional hazard methodology were used to perform univariate and multivariate analysis to identify independent risk factors for survival. For the meta-analysis, all English-language studies regarding blood transfusion from carcinoma of the ampulla of Vatar or ampullary carcinoma and prognostic factors or factors for survival from 1995 to 2007 were reviewed, and contingency tables were constructed from which a summary relative risk was calculated. RESULTS: There were 43 patients (64.2%) who received an intraoperative ABT. The amount of intraoperative ABT ranged from 2 to 13 (mean, 4.25) units; there were 18 patients transfused at 2 units, and 25 patients transfused > or =3 units. The follow-up ranged from 2 to 90 (mean, 49) months. Forty-five patients (67.2%) died as a result of tumor progression. For patients transfused > or =3 units, median and cumulative 3-year and 5-year survivals were poorer significantly than that of patients transfused with 2 units and/or nontransfused patients (P < 0.05). After multivariate analysis, except for presence of lymph node metastasis (P = 0.023) and pancreatic invasion (P = 0.024), the intraoperative ABT > or =3 units was found to be an independent poor prognostic factor for those with ampullary cancer after curative pancreatoduodenectomy either (relative risk, 2.082; 95% confidence interval (CI), 1.048-4.135; P = 0.036). Meta-analysis of 346 patients showed the summary relative risk of an adverse outcome after intraoperative ABT in these studies was 2.55 (95% CI, 1.59-4.1). CONCLUSIONS: The amount of intraoperative ABT is one of the important factors that adversely influenced survival in patients with ampullary cancer after curative pancreatoduodenectomy. Healing anemia preoperatively and careful dissection to minimize intraoperative bleeding as much as possible are mandatory for reducing risk of the intraoperative ABT.

Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater.

PURPOSE: The role of adjuvant chemoradiation therapy (CRT) in the treatment of ampullary cancers remains undefined. We retrospectively compared treatment outcomes in patients treated with pancreaticoduodenectomy alone versus those who received additional adjuvant CRT. METHODS AND MATERIALS: Between May 1990 and January 2006, 54 of 96 patients with ampullary adenocarcinoma who underwent potentially curative pancreaticoduodenectomy also received adjuvant CRT. The median preoperative radiation dose was 45 Gy (range, 30-50.4 Gy) and median postoperative dose was 50.4 Gy (range, 45-55.8 Gy). Concurrent chemotherapy included primarily 5-fluorouracil (52%) and capecitabine (43%). Median follow-up was 31 months. Univariate and multivariate statistical methodologies were used to determine significant prognostic factors for local control (LC), distant control (DC), and overall survival (OS). RESULTS: Actuarial 5-year LC, DC, and OS were 77%, 69%, and 64%, respectively. On univariate analysis, age, gender, race/ethnicity, tumor grade, use of adjuvant treatment, and sequencing of adjuvant therapy were not significantly associated with LC, DC, or OS. However, on univariate analysis, T3/T4 tumor stage was prognostic for poorer LC and OS (p = 0.02 and p < 0.001, respectively); node-positive disease was prognostic for poorer LC (p = 0.03). On multivariate analysis, T3/T4 tumor stage was independently prognostic for decreased OS (p = 0.002). Among these patients (n = 34), those who received adjuvant CRT had a trend toward improved OS (median, 35.2 vs. 16.5 months; p = 0.06). CONCLUSIONS: Ampullary cancers have a distinctly better treatment outcome than pancreatic adenocarcinomas. Higher primary tumor stage (T3/T4), an independent adverse risk factor for poorer treatment outcomes, may warrant the addition of adjuvant CRT to pancreaticoduodenectomy.

Missing effect of glutamine supplementation on the surgical outcome after pancreaticoduodenectomy for periampullary tumors: a prospective, randomized, double-blind, controlled clinical trial.

BACKGROUND: The effect of glutamine (Gln) supplementation in patients undergoing a major operation has not been conclusively established. This study was designed to elucidate the effect of Gln supplementation on the surgical outcome after a pancreaticoduodenectomy (PD) for periampullary tumors. METHODS: A prospective, randomized, double-blind, and controlled clinical trial was undertaken for patients who underwent a classical PD or a pylorus-preserving PD for periampullary tumors. The Gln and control groups received isonitrogenous amino acid, with a 0.2 g/kg per day Gln regimen administered to the Gln group. The surgical outcome was compared in light of length of postoperative hospital stay, nutritional and chemical profiles, and complication rate between the Gln and control groups. RESULTS: Sixty of the consecutive 143 patients who were admitted to undergo operation for periampullary tumors were enrolled in our study; 32 were in the Gln group and 28 in the control group. The two groups were comparable prior to and during the operation. The median length of the postoperative hospital stay and the postoperative nutritional and chemical profiles were not different between two groups. The overall and PD-related complication rates of the Gln group (37.5% and 25.0%) and the control group (28.6% and 14.3%) were not statistically different. CONCLUSIONS: No significant beneficial effect of Gln supplementation with a low-dose parenteral regimen was demonstrated on the surgical outcome after a PD for periampullary tumors. Therefore, we should be prudent in using Gln as a routine pharmacologic supplement to the standard nutrition in patients who undergo major operations.

Outcome of surgical treatment of pancreatic, peri-ampullary and ampullary cancer diagnosed in the south of The Netherlands: a cancer registry based study.

AIMS: To gain insight into the quality of pancreatic cancer surgery in 10 low-volume (median sized) hospitals, each serving 150,000-250,000 people, in the Comprehensive Cancer Centre South (CCCS) area and of referred patients to academic centres to determine the need for further regionalization. METHOD: The population-based Eindhoven Cancer Registry was used to select all patients in the CCCS area with pancreatic, peri-ampullary and ampullary cancer diagnosed between January 1, 1995 and April 30, 2000 (N = 1130). Of those, 124 patients (11%) underwent surgical resection (of which 40 were treated in university hospitals outside the region). RESULTS: For all pancreatic carcinoma resections, the 3-month survival rate was 82%, varying from 95% for referred patients to 76% for patients treated within the region (p = 0.014). One- and two-year survival rates showed no difference between both groups (p = 0.36 and p = 0.55, respectively). Surgically treated patients who were referred to university hospitals outside the CCCS area were younger, more often male, more often diagnosed with pTNM stage III, exhibited less comorbidity and had a higher socio-economic status than patients surgically treated within the region. CONCLUSION: Although the results are based on small numbers and patient selection probably influenced these outcomes, these data seem to support further hospital specialisation, to which the surgeons of the CCCS area have committed themselves.

Papiloduodenectomia como alternativa terapêutica para tumores papilares / Papiloduodenectomy as an alternative treatment for papillary tumors

The papiloduodenectomy is a procedure that, although accomplished rarely, has its validity in selected cases of papillary tumors. It is included in this group the patients with important diseases that doesn`t have conditions of supporting the surgery of Whipple, the standard procedure for these pathologies. The authors review its experience with four patient carriers of malign neoplasia of the duodenal papila submitted to papiloduodenectomy. All the patients came jaundiced to the admission. The age varied of 62 to 82 years. The ultrassonography, the computed tomography and the endoscopy with biopsy were used for diagnosis and staging, and all the patients presented with initial stages (T1 or T2). Two patients were classified as ASA3 and the other two as ASA4, according to the American Society of Anesthesiology. All the diagnoses were proven by the pathological exam of the surgical piece. It is ended that this procedure facilitates to obtain appropriate margins and satisfactory results when indicated of appropriate way

[The surgical treatment of malignant tumors of the head of the pancreas and of the periampullary area]. / Khirurgicheskoe lechenie zlokachestvennykh opukholei golovki podzheludochnoi zhelezy i periampuliarnoi oblasti.

Under analysis are results of pancreatoduodenal resections in 71 patients. In patients with mechanical jaundice lymph drainage with sorption and return of lymph into the vascular bed was used during the preoperative preparation. Occlusion of the duct system of the pancreas stump with glue KL-3 was performed on 62 patients, in 9 patients choledochocholecysto-anastomosis was used in order to improve the quality of the biliodigestive opening. A cryoprocedure on the nonremoved portion of the tumor was performed in 3 cases on the posterolateral surface of the portal vein. These measures allowed the postoperative lethality to be reduced up to 11.2%.

Pancreatic exocrine function after a sutureless pancreatico-jejunostomy following pancreaticoduodenectomy.

Exocrine pancreatic function was measured in 14 patients after pancreaticoduodenectomy for periampullary neoplasms in order to assess the patency of a sutureless pancreatico-enteric anastomosis. Pancreatic function was examined by the p-aminobenzoic acid/p-aminosalicylic acid (PABA/PAS) test 3-160 months after operation and compared with age- and sex-matched controls. There were no significant differences between mean (s.e.m.) serum PABA concentrations 3 h after ingestion of N-benzoyl-L-tyrosyl-PABA (25.5 (3.6)) mumol/l for patients, 26.1 (2.0) mumol/l for controls). However, the mean (s.e.m.) PABA excretion index was significantly lower in the patients (0.58 (0.08)) than in the controls (0.76 (0.04)). Four patients required pancreatic enzyme supplements for control of diarrhoea. Self-limiting pancreatic leaks occurred in two patients. The results suggests that the sutureless pancreatico-enteric anastomosis has an acceptably low leakage rate but that pancreatic exocrine function is diminished following pancreaticoduodenectomy with this technique. However, the majority of patients require no enzyme supplements and no significant tendency to late stenosis of the anastomosis was demonstrated.

Endoscopic therapy of biliary calculi.

Since 1973, biliary calculi can be extracted from the common bile duct after endoscopic papillotomy (EPT). The success rate amounts to 90%. Complications occur in 7%, and 1% of the patients will die. The most frequent complication is haemorrhage (30%), but only 10% of these cases require surgery. Results of EPT are more favourable than those of surgery. Prophylactic antibiotics are not necessary, but in the event of fever, beta-lactam antibiotics or modern cephalosporins are indicated. When stone extraction fails, several different methods of lithotripsy can be employed: endoscopic mechanic, endoscopic electrohydraulic, and the recently developed extracorporeally generated shock-waves. Lithotripsy will succeed in 80-90% of cases. As late sequelae after EPT cannot be completely excluded, dilatation of the papilla by balloon catheter was developed. However, the number of patients treated is still very small. When these methods fail or are not available, common bile duct stones can be chemically dissolved. Irrigation media are infused into the biliary tree via a nasobiliary tube after EPT or percutaneous transhepatic cholangiography. The substances used are cholesterol solvents such as mono-octanoin, GMOC or MTBE. A buffered 1% EDTA solution is used for calcium bilirubinate stones. Stone dissolution will succeed in 50-70% of cases. Side-effects include cholangitis and duodenitis.