Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Ventral colporectopexy for overt rectal prolapse and obstructed defaecation syndrome: a systematic review.

AIM: Laparoscopic ventral rectopexy (VR) with the use of prosthesis has been advocated for both overt rectal prolapse (ORP) and obstructed defaecation syndrome (ODS). The present study reviews the short-term and functional results of laparoscopic VR. METHOD: A search was performed of MEDLINE, EMBASE, Ovid and Cochrane databases on all studies reporting on VR for ORP, ODS and other anatomical abnormalities of the pelvic floor from 2004 until February 2013. No language restrictions were made. All studies on VR were reviewed systematically. The main outcomes were intra-operative complications, conversion, procedure duration, short-term mortality and morbidity, length of stay, recurrence of ORP, recurrence of anatomical disorder, faecal incontinence and constipation, quality of life (QoL) score and patient satisfaction. Quality assessment and data extraction were performed independently by three observers. RESULTS: Twenty-three studies including 1460 patients were eligible for analysis. The conversion rate ranged from 0 to 14.3%. No mortality was reported. The immediate postoperative morbidity rate was 8.6%. Length of stay ranged from 1 to 7 days. A significant improvement in constipation and incontinence symptoms was observed in the postoperative period for both ORP and ODS (chi-square test, P < 0.0001). CONCLUSION: Laparoscopic VR is a safe and effective procedure for ORP and ODS. Longer follow-up is required, and studies comparing VR with standard rectopexy and stapled transanal rectal resection are not yet available.

Groove pancreatitis: a diagnostic challenge.

Groove pancreatitis is a distinct form of chronic pancreatitis characterized by inflammation and fibrous tissue formation, affecting the groove area between the head of the pancreas, the duodenum and the common bile duct. It is manifested on imaging by a sheet-like mass in the groove area near the minor papilla. Thickening of the duodenal wall and cystic transformation in the duodenal wall also represent common imaging features. Pathogenesis is still unclear, and clinical presentation is not specific. Endoscopic ultrasonography (EUS), computed tomography (CT) and magnetic resonance imaging (MRI) demonstrate imaging findings consistent with the disease in typical cases, but specific diagnosis is challenging in a number of patients where biopsy is required. The disease may mimic pancreatic, common bile duct or duodenal wall cancer that requires prompt and excessive surgical intervention, as opposed to groove pancreatitis where initial conservative treatment is suggested. The clinical, histopathological and radiological features on cross-sectional imaging of this entity are discussed in this review, and differential diagnostic clues are given.

Can exchange transfusions treat postoperative intrahepatic colestasis in patients with sickle cell anemia?

BACKGROUND: Although the most common cause of liver failure (LF) in hematologic patients is viral hepatitis, several episodes of sickle cell intrahepatic cholestasis (IHC) have been reported as rare but potentially causative of fulminant LF. Reviewing the literature, we have presented a single case of intrahepatic cholestasis after major liver resection, which was effectively treated by exchange transfusion. METHODS: Serial hemoglobin S, D levels and liver enzymes were monitored postoperatively. RESULTS: Although the patient's intra- and postoperative courses were uneventful, an increased serum bilirubin was identified to be due to intrahepatic sinusoid congestion and subsequent cholestasis. Exchange transfusion was required to maintain HbS below 20% and reverse bilirubin levels to normal values. CONCLUSION: Sickle cell anemia is a rare cause of cholestasis after major hepatic surgery. To our knowledge, this case is the only documented incidence of IHC following major hepatectomy that was effectively treated with exchange transfusion.

Development of a disease specific quality of life (QoL) questionnaire module to supplement the EORTC core cancer QoL questionnaire, the QLQ-C30 in patients with pancreatic cancer. EORTC Study Group on Quality of Life.

There is overwhelming consensus that quality of life assessment is urgently required in pancreatic cancer, yet little research has been conducted. We report on the development of a disease specific questionnaire module to supplement the EORTC core cancer module, the QLQ-C30 in patients with pancreatic cancer, using EORTC quality of life study group guidelines for module development. Relevant QoL issues were generated from literature searches and interviews with health professionals and patients with pancreatic cancer. Issues were constructed into items and provisionally translated. The provisional module was pretested in patients in 8 European centres. The resulting module the QLQ-PAN26 includes 26 items related to disease symptoms, treatment side-effects and emotional issues specific to pancreatic cancer. This should ensure that the module will be sensitive to assess the small but important disease and treatment related QoL changes in pancreatic cancer. The use of the QLQ-C30 and QLQ-PAN26 will provide a comprehensive system of QoL assessment in international trials of pancreatic cancer.

Activation of the serine proteinase system in chronic kidney rejection.

BACKGROUND: Activation of the serine proteinase system is an important mechanism that contributes to tissue remodeling. In the present study, we analyzed the expression of urokinase plasminogen activator (uPA), urokinase plasminogen activator receptor (uPAR), and plasminogen activator inhibitor type 1 (PAI-1) in samples of chronically rejected human kidneys. METHODS: Using Northern blot analysis, immunohistochemistry, and a uPA activity assay, specimens from 10 chronically rejected kidneys and 10 normal kidney samples were analyzed. RESULTS: By Northern blot analysis, the expression of uPAR and PAI-1 mRNA was 2.9-fold (P<0.05) and 2.3-fold (P<0.05) increased in chronically rejected kidney samples, respectively, compared with normal controls. In contrast, uPA mRNA levels in chronically rejected kidneys were comparable to those in the normal controls. Immunohistochemical analysis in normal kidneys showed weak immunostaining of uPA, moderate to intense uPAR and PAI-1 immunostaining in proximal tubules, and moderate immunostaining in distal tubules, but no signal in the glomeruli or cortical vessels. A similar staining pattern was found in the distal and proximal tubules in rejected kidney tissue samples. However, in the rejected kidneys, the number of tubules was markedly reduced. In addition, within the glomeruli of rejected kidney samples, there was positive immunostaining for uPA, uPAR, and PAI-1 in the mesangial cells, but negative staining in most of the endothelial cells, whereas the normal kidneys revealed no immunoreactivity in these structures. CONCLUSION: The demonstrated up-regulation of uPA/uPAR/PAI-1 in chronic renal rejection is consistent with the plasminogen/plasmin system contributing to tissue remodeling in this disorder. These factors might activate latent transforming growth factor-betas, which have been reported to be enhanced in this disorder, contributing to the generation of the extracellular matrix.

Cystic tumours of the pancreas: a review.

The detection of a cystic tumour of the pancreas is a challenge which puts not only the surgeon's knowledge and expertise to the test, but also those of the team of radiologists and pathologists with whom he works. The diagnosis of a suspected pancreatic cystic tumour is morphological and is based on modern imaging techniques and, in the case of intraductal papillary mucinous tumours, on endoscopic findings. In the search for the correct preoperative diagnosis, however, it is of fundamental importance to bear in mind the limitations of the various instrumental investigations, and particularly those of fine-needle aspiration cytology. In this light the main morphological and clinicopathological features of serous cystadenomas, mucinous adenomas and adenocarcinomas, intraductal papillary mucinous tumours and papillary cystic and solid tumours are analysed as well as the surgical indications. In fact only the surgeon, on the basis of his knowledge of the patient's medical history and symptoms, will be in a position to determine to which nosological "cystic" entity the morphological findings described belong. A deeper knowledge of the natural history of each of these cystic tumours will help the surgeon formulate the most appropriate treatment indication. Providing the patient's condition fulfills the necessary operability criteria, resection will be mandatory whenever there exists a doubt that the tumour may be malignant or whenever its natural history suggests a malignant potential.

Metastatic disease to the pancreas: an imaging challenge.

Metastatic lesions of the pancreas are uncommon, accounting for approximately 2% of pancreatic malignancies. Many tumours involve the pancreas secondarily and may manifest with different clinical and imaging characteristics. Although many patients have widespread disease, isolated metastases can be found. Surgical management is associated with improved survival in these cases. The experience of the pancreatic surgery unit and imaging department of our hospital in many patients presenting with pancreatic metastases is presented, and a review of the recent literature is undertaken. Main Messages • The early recognition of secondary pancreatic tumours on US, CT and MRI is extremely important. • Pancreatic metastases may mimic primary pancreatic adenocarcinoma or induce acute pancreatitis. • Most pancreatic metastases are discovered on a CT examination performed for follow-up.

Sclerosing cholangitis in the era of target chemotherapy: a possible anti-VEGF effect.

Preoperative systemic chemotherapy is generally applied in patients who undergo hepatic resection for colorectal metastases. Although the tumour response rate has been improved recently with the development of new molecular targeted therapies the related hepatic injury is ill defined. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor. It can achieve high response rates and is accepted as a first line treatment in the metastatic colorectal disease. However, the data about its hepatotoxicity profile is still limited. We describe a case of secondary sclerosing cholangitis in a patient with liver metastases treated by Bevacizumab in the neoadjuvant setting and liver resection. It is possible that Bevacizumab may have induced a hypercoagulative condition that was further precipitated by surgery.

One thousand laparoscopic cholecystectomies in a single surgical unit using the "critical view of safety" technique.

INTRODUCTION: Bile duct injuries have been substantially increased after the introduction of laparoscopic cholecystectomy (LC). They are accompanied by major morbidity, occasional mortality, lengthening of hospital stay, additional health costs, and deterioration of patients' quality of life and life expectancy. The aim of this study was to present the method of "critical view of safety" (CVS) as safe and feasible for the prevention of bile duct injuries during laparoscopic cholecystectomy. PATIENTS AND METHODS: During a 6-year period from January 2002 till December 2007, 1,046 LCs (369 men and 677 women) were performed mainly for symptomatic gallstone disease. The CVS technique recommends clearing the triangle of Calot of fat and fibrous tissue and taking the gallbladder off the lowest part of its attachment to the gallbladder bed. The "infundibular" technique (identification of cystic duct and gallbladder junction) was used whenever CVS was not possible to perform. RESULTS: The CVS was performed in 998 patients (95.4%). Overall, 27 patients needed conversion to the open approach (2.6%). This rate was higher in patients with acute inflammation undergoing early operation (nine of 128, 7%) compared with patients operated later or electively (18 of 914, 1.9%). There was no bile duct injury in the 1,046 cholecystectomies. Postoperatively, five patients had bile leaks which were transient and stopped spontaneously after 2-14 days. Two reoperations were performed because of severe bleeding. CONCLUSION: CVS clarifies the relations of the anatomic structures that should be divided, and therefore, it should be ideally and routinely applied in all LCs because of its highly protective role against bile duct injuries.

Solid pseudopapillary tumor of the pancreas: an enigmatic tumor.

Solid pseudopapillary tumor of the pancreas is a rare pancreatic tumor that predominantly occurs in young non-Caucasian women. Although most tumors show benign behavior, malignant degeneration may occur. A case of solid pseudopapillary pancreatic tumor in a Caucasian woman is presented that was investigated by endoscopic ultrasonography (EUS), computed tomography, magnetic resonance imaging and EUS-guided fine needle aspiration. The patient underwent surgery and radiological findings are correlated with histopathology. The preoperative diagnosis of solid pseudopapillary tumor of the pancreas is challenging, frequently leading to imaging by multiple different modalities.

Adjuvant chemotherapy for colon cancer: evidence on improvement in survival.

Clear progress has been made in the adjuvant treatment of colon cancer. Until very recently, the absolute benefit for survival obtained with the administration of 6 months' FU/LV compared with control was about 6%. Fluoropyrimidines have been shown to be at least as active and can replace intravenous FU/LV in stage III colon cancer. Based on the results of the MOSAIC and NSABP C-07 trials, the addition of oxaliplatin to FU/LV improves disease-free survival and FOLFOX for 6 months can be recommended as adjuvant treatment for patients with stage III colon cancer. The benefit of adjuvant chemotherapy in stage II disease is limited and it should be proposed in patients with high-risk features. Adjuvant treatment of colon cancer improving and the use of genetic/molecular markers with the new targeted therapies may further improve survival.

Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer.

The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(stratified) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup.

Influence of surgical resection and post-operative complications on survival following adjuvant treatment for pancreatic cancer in the ESPAC-1 randomized controlled trial.

BACKGROUND/AIMS: The influence of type of surgery and occurrence of post-operative complications on survival following adjuvant therapy for pancreatic cancer are uncertain. METHODS: Cox proportional hazard modelling was used to investigate the influence of type of surgery and the presence of complications on survival in conjunction with clinico-pathological variables in the 550 patients of the ESPAC-1 adjuvant randomized controlled trial. RESULTS: Standard Kausch-Whipple (KW) was performed in 282 (54%) patients, 186 (35%) had a pylorus-preserving (PP) KW, 39 (7%) had a distal pancreatectomy and 21 (4%) had a total pancreatectomy. Post-operative complications were reported in 140 (27%) patients. PP-KW patients survived longer with a median (95% CI) survival of 19.9 (17.3, 23.1) months compared to 14.8 (13.0, 16.7) for KW patients (chi(2)(LR) = 15.1, p < 0.001). KW patients were more likely however to have R1 margins (67 (24%) vs. 29 (16%), chi(2) = 4.59, p = 0.032), poorly differentiated tumours (70 (26%) vs. 19 (10%), chi(2) = 18.65, p < 0.001) and positive lymph nodes (165 (60%) vs. 81 (44%), chi(2) = 11.32, p < 0.001). Post-operative complications did not significantly affect survival. Independent prognostic factors were tumour grade, nodal status and tumour size but not type of surgery or post-operative complications. There was a survival benefit for chemotherapy irrespective of the type of surgery or post-operative complications. CONCLUSIONS: The KW and PP-KW procedures did not significantly influence the hazard of death in the presence of tumour staging, demonstrating that ESPAC-1 surgeons showed good judgement in their choice of operation. Post-operative complications did not adversely affect the survival benefit from adjuvant chemotherapy.

Staging acute pancreatitis: where are we now?

Acute pancreatitis is a potentially lethal disease in about 20% of all the cases. Early identification of those patients with the severe type of the disease is of a great importance as intensive care treatment and other therapeutic manipulations can apply to alter the clinical course, and finally the outcome. Therefore, there is a need for precise criteria for severity prediction--that can be easily applied with high accuracy and sensitivity--very early after the onset of acute pancreatitis. Although no 'ideal' predictor exists so far, APACHE II score, C-reactive protein and the trypsinogen activation peptide, could be used in clinical practice. Other prognostic markers such as interleukin-6 and interleukin-8 could be useful in the near future, as soon as proper assays will be available. Furthermore, the development of logistic models, based on different parameters concerning the severity of the individual patient, is another option for the future.

Etiologic links between chronic pancreatitis and pancreatic cancer.

In all forms of pancreatitis there appears to be a cellular dysfunction, glandular destruction, and, presumably, increased cell turnover. Increased cell division has been suggested as a potential precursor of cancer in many organs. The excess risk of pancreatic cancer that has been documented in epidemiologic studies in patients with various types of pancreatitis is consistent with this hypothesis. The uncertainties in epidemiologic studies notwithstanding, the existence of a clear association between pancreatitis and the subsequent risk of pancreatic cancer is found too often to be only randomized. The clinical relevance of a causal relationship between chronic pancreatitis and pancreatic cancer is, however, limited, since the prognosis of chronic pancreatitis cannot be separated from that of chronic alcoholism.