Dissecting the genetic heterogeneity of gastric cancer.

BACKGROUND: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. METHODS: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. FINDINGS: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. INTERPRETATION: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. FUNDING: German Research Foundation (DFG).

Patient reported exposure to smoking and alcohol abuse are associated with pain and other complications in patients with chronic pancreatitis.

BACKGROUND/OBJECTIVES: Smoking and alcohol abuse are established risk factors for chronic pancreatitis (CP). Few studies have examined how exposure to smoking and alcohol abuse act as risk factors for complications in CP. Our aim was to examine associations between patient reported exposure to smoking and alcohol abuse and complications in CP in a large cohort of patients from the Scandinavian and Baltic countries. METHODS: We retrieved data on demographics, CP related complications and patients' histories of exposure to smoking and alcohol abuse from the Scandinavian Baltic Pancreatic Club database. Associations were investigated by univariate and multivariate logistic regression analyses. Results are presented as odds ratios (OR) with 95% confidence intervals. RESULTS: A complete history of smoking and alcohol exposure was available for 932 patients. In multivariate regression analyses, the presence of pain and exocrine pancreatic insufficiency were both significantly associated with history of smoking (OR 1.94 (1.40-2.68), p < 0.001 and OR 1.89 (1.36-2.62), p < 0.001, respectively) and alcohol abuse (OR 1.66 (1.21-2.26), p = 0.001 and 1.55 (1.14-2.11), p = 0.005, respectively). Smoking was associated with calcifications (OR 2.89 (2.09-3.96), p < 0.001), moderate to severe ductal changes (OR 1.42 (1.05-1.92), p = 0.02), and underweight (OR 4.73 (2.23-10.02), p < 0.001). History of alcohol abuse was associated with pseudocysts (OR 1.38 (1.00-1.90) p = 0.05) and diabetes mellitus (OR 1.44 (1.03-2.01), p = 0.03). There were significantly increased odds-ratios for several complications with increasing exposure to smoking and alcohol abuse. CONCLUSION: Smoking and alcohol abuse are both independently associated with development of complications in patients with CP. There seems to be a dose-dependent relationship between smoking and alcohol abuse and complications in CP.

Association of multiple patient and disease characteristics with the presence and type of pain in chronic pancreatitis.

BACKGROUND AND AIM: Pain is the primary symptom of chronic pancreatitis (CP) and associates with a number of patient and disease characteristics. However, the complex interrelations of these parameters are incompletely understood, and pain treatment remains unsatisfactory in a large proportion of patients. The aim of this study is to investigate multiple pain risk factors in a large population of CP patients, with a special emphasis on patients' patterns of smoking and alcohol use. METHODS: This was a multicenter, cross-sectional study including 1384 patients with CP. Patient demographics and disease characteristics, as well as current patterns of smoking and alcohol use, were compared for patients with pain (n = 801) versus without pain (n = 583). Multivariate logistic regression models were performed to assess the variables associated with the presence and type of pain (constant vs intermittent pain). RESULTS: The mean age of participants was 52.1 ± 14.6 years, and 914 (66%) were men. Active smoking (odds ratio 1.6 [95% confidence interval 1.1-2.2], P = 0.005) and alcohol consumption (odds ratio 1.8 [95% confidence interval 1.1-3.0], P = 0.03) were independently associated with the presence of pain. In addition, patients' age at diagnosis, pancreatic duct pathology, and the presence of pseudocysts, duodenal stenosis, and exocrine pancreatic insufficiency were confirmed as pain risk factors (all P ≤ 0.01). Constant pain, as opposed to intermittent pain, was more frequently reported by smokers (P = 0.03), while alcohol consumption was associated with intermittent pain (P = 0.006). CONCLUSION: Multiple patient and disease characteristics, including patterns of smoking and alcohol consumption, associate with the presence and type of pain in patients with CP.

Pancreatic exocrine insufficiency and Crohn's disease.

BACKGROUND: According to the European evidence-based consensus, published by European Crohn's and Colitis Organization (ECCO), diseases of the pancreas are included as extra-intestinal manifestations in IBD in the forms of acute pancreatitis (AP), chronic pancreatitis (CP), autoimmune pancreatitis (AIP), pancreatic duct abnormalities and pancreatic exocrine insufficiency (PEI). Presence of pancreatic autoantibodies directed against the exocrine of the pancreas has been reported in about one-third of CD. However, association between CD and PEI is not fully elucidated. METHODS: Patients with a diagnosis of CD were recruited at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Fecal elastase-1 (FE-1) measurements were performed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: There were 20 patients included in the study, 13 (65%) males and 7 (35%) females, mean age 48.3±1.4 years (range 29-67 years). Mean duration of CD was 15.7±2.1 years (range 1-40 years). There were 11 (55%) patients without history of bowel surgery and 9 (45%) patients after ileocecal resection. FE-1 test was normal in all patients, among them 15 (75%) patients with the values of FE-1>500. CONCLUSIONS: Fecal elastase-1 level was normal in all patients with CD strongly indicated absence of PEI in this group of patients.

Pancreatic calcifications associate with diverse aetiological risk factors in patients with chronic pancreatitis: A multicentre study of 1500 cases.

BACKGROUND: Pancreatic calcifications is a common finding in patients with chronic pancreatitis (CP), but the underlying pathophysiology is incompletely understood. Past studies for risk factors of calcifications have generally been focused on single parameters or limited by small sample sizes. The aim of this study was to explore several patient and disease characteristics and their associations with pancreatic calcifications in a large cohort of CP patients with diverse aetiological risk factors. METHODS: This was a multicentre, cross-sectional study including 1509 patients with CP. Patient and disease characteristics were compared for patients with calcifications (n = 912) vs. without calcifications (n = 597). Multivariable logistic regression was performed to assess the parameters independently associated with calcifications. RESULTS: The mean age of patients was 53.9 ±â€¯14.5 years and 1006 (67%) were men. The prevalence of calcifications was 60.4% in the overall patient cohort, but highly variable between patients with different aetiological risk factors (range: 2-69%). On multivariate analysis, alcoholic aetiology (OR 1.76 [95% CI, 1.39-2.24]; p < 0.001) and smoking aetiology (OR 1.77 [95% CI, 1.39-2.26], p < 0.001) were positively associated with the presence of calcifications, while an autoimmune aetiology was negatively associated with calcifications (OR 0.15 [95% CI, 0.08-0.27], p < 0.001). Patients with pancreatic calcifications were more likely to have undergone pancreatic duct stenting (OR 1.59 [95%CI, 1.16-2.19], p = 0.004). CONCLUSION: The presence of pancreatic calcifications is associated with diverse aetiological risk factors in patients with CP. This observation attest to the understanding of CP as a complex disease and may have implications for disease classification.

Zinc deficiency in patients with chronic pancreatitis.

BACKGROUND: Zinc is a key element in numerous proteins and plays an important role in essential cell functions such as defense against free radicals and DNA damage repair. Chronic pancreatitis (CP) is a chronic inflammation with progressive fibrosis of pancreas ultimately resulting in pancreatic exocrine insufficiency (PEI), which is associated with malnutrition. Studies analyzing zinc levels in patients with CP are sparse and lead to conflicting results. AIM: To investigate serum zinc levels in patients with CP of various etiologies. METHODS: Between October 2015 and March 2018, patients with a diagnosis of CP were identified and recruited from the Pancreatic Outpatient Clinic at the Karolinska University Hospital in Stockholm, Sweden. Demographic, clinical and laboratory data were analyzed. Etiology of CP was determined according to the M-ANNHEIM classification system into the following etiological subcategories: alcohol consumption, nicotine consumption, hereditary factors, efferent pancreatic duct factors and immunological factors. Pancreatic exocrine function was defined as normal (fecal elastase 1 > 200 µg/g), mildly reduced (100-200 µg/g) and severely reduced (fecal elastase 1 < 100 µg/g). RESULTS: A total of 150 patients were included in the analysis. Zinc deficiency (< 11 µmol/L) was present in 39 (26.0%) of patients: 22 females and 17 males. In the group of patients with zinc deficiency, 76.7% of patients had an exocrine pancreatic insufficiency (FE-1 < 200 µg/g). Older age was significantly associated with low zinc levels. Following a univariate analysis, patients aged 60-69 and patients ≥ 70 years of age had a significantly higher prevalence of zinc deficiencies compared to patients < 40 years of age [OR: 3.8, 95%CI (1.08-13.4); P = 0.04]; [OR 6.26, 95%CI (1.94-20.2), P > 0.002]. Smoking and number of pack-years were additionally associated with low zinc levels. The risk of zinc deficiency in current smokers and smokers with ≥ 20 pack-years was approximately three times higher compared to those who had never smoked. Gender, body mass index, etiology of CP, presence of diabetes mellitus, levels of glycated hemoglobin (HbA1c), bone mineral density, alcohol intake and presence of PEI were not associated with low zinc levels. CONCLUSION: Zinc deficiency is common in patients with CP and is significantly associated with age ≥ 60, smoking and the number of pack-years, but not with PEI.

Chronic Pancreatitis Is Characterized by Distinct Complication Clusters That Associate With Etiological Risk Factors.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by several disease-related complications and multiple etiological risk factors. Past studies of associations between complications and risk factors have mostly been limited to single complications or highly focused on single etiologies. Using an objective data-driven approach (cluster analysis), we characterized complication clusters and their associations with etiological risk factors in a large cohort of patients with CP. METHODS: This was a multicenter, cross-sectional study including 1,071 patients with CP from the Scandinavian and Baltic countries. Complications to CP were classified according to the M-ANNHEIM system, and treelet transform was used to derive complication clusters. Cluster complication frequencies were analyzed for their association with main etiological risk factors (smoking and alcohol). RESULTS: The mean age of participants was 57 years and 66% were men. Alcohol (55%) and smoking (53%) were the most common etiological risk factors and seen in combination in 36% of patients. Cluster analysis identified 3 distinct complication clusters characterized by inflammation, fibrosis, and pancreatic insufficiencies. An independent association between inflammatory complications and alcoholic etiology was seen (odds ratio [OR] 2.00 [95% CI [confidence interval], 1.38-2.90], P < 0.001), whereas smoking was associated with fibrosis-related complications (OR 2.23 [95% CI, 1.56-2.3.20], P < 0.001) and pancreatic insufficiencies (OR 1.42 [95% CI, 1.00-2.01], P = 0.046). DISCUSSION: Three distinctive clusters of complications to CP were identified. Their differing associations with alcoholic and smoking etiology indicate distinct underlying disease mechanisms.

Diagnosis, treatment and long-term outcome of autoimmune pancreatitis in Sweden.

INTRODUCTION: Autoimmune pancreatitis (AIP) is a pancreatic inflammatory process characterized by a strong inflammatory cell infiltration and two histopathologically distinct subtypes: type 1 and type 2. Diagnosis is often challenging and requires a combination of clinical, laboratory and imaging data. AIP can mimic pancreatic tumours leading to unnecessary resections if not correctly diagnosed. Short- and long-term outcomes of AIP have been poorly investigated so far and no large series have been previously reported from Sweden. METHODS: A single-centre, retrospective, cohort study of patients with histologically confirmed or highly probable diagnosis of AIP according to ICDC criteria. Demographic, clinical and radiological characteristics, type of treatment and its outcomes were collected and analysed. RESULTS: Seventy-one patients with AIP (87% with type 1), were evaluated at Karolinska University Hospital between 2004 and 2018; 49% males, mean age 49 years (range 44-53). Among them, 28% were histologically confirmed, 35% presented with jaundice, 22% with acute pancreatitis, 39% had non-specific symptoms such as weight loss or abdominal pain, 84% showed other organ involvement (OOI). Radiologically, 76% showed a focal pancreatic enlargement, 27% diffuse enlargement, 27% signs of acute pancreatitis and 10% of chronic pancreatitis. Overall, 58 patients (81%) underwent treatment with different medications: 46 (79%) cortisone, 7 (12%) azathioprine, 5 (8%) other immunosuppressive drugs. Twenty-six (36%) underwent biliary stenting and 12 (16%) were given surgery. In total, 47% of patients developed pancreatic exocrine insufficiency (PEI), of whom 76% had a severe form (faecal elastase-1 < 100 µg/g) and 21% of patients developed diabetes mellitus (pancreatic endocrine insufficiency), of whom 73% required insulin. CONCLUSIONS: AIP is a challenging disease for diagnosis and treatment. Cortisone treatment is generally successful and provides clinical remission in the large majority of patients (>90%). In the further course of the disease, a considerable number of patients develop PEI and diabetes. Only one-quarter of patients exhibit on imaging the characteristic "sausage-like" pancreas (diffuse enlargement), approximately three-quarters had a focal mass that could be misdiagnosed as pancreatic malignancy.

Pancreatic Exocrine Insufficiency after Bariatric Surgery.

Morbid obesity is a lifelong disease, and all patients require complementary follow-up including nutritional surveillance by a multidisciplinary team after bariatric procedures. Pancreatic exocrine insufficiency (PEI) refers to an insufficient secretion of pancreatic enzymes and/or sodium bicarbonate. PEI is a known multifactorial complication after upper gastrointestinal surgery, and might constitute an important clinical problem due to the large number of bariatric surgical procedures in the world. Symptoms of PEI often overlap with sequelae of gastric bypass, making the diagnosis difficult. Steatorrhea, weight loss, maldigestion and malabsorption are pathognomonic for both clinical conditions. Altered anatomy after bypass surgery can make the diagnostic process even more difficult. Fecal elastase-1 (FE1) is a useful diagnostic test. PEI should be considered in all patients after bariatric surgery with prolonged gastrointestinal complaints that are suggestive of maldigestion and/or malabsorption. Appropriate pancreatic enzyme replacement therapy should be part of the treatment algorithm in patients with confirmed PEI or symptoms suggestive of this complication.

Bioinformatory-assisted analysis of next-generation sequencing data for precision medicine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence-based software that analyzes next-generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence-based software, could be conducted within a 2-week period, thus being feasible for clinical routine. Therapy recommendations were principally off-label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome-associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software-analysis of NGS data provides evidence-based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.

Diagnosing autoimmune pancreatitis with the Unifying-Autoimmune-Pancreatitis-Criteria.

BACKGROUND/OBJECTIVES: We had developed the Unifying-Autoimmune-Pancreatitis-Criteria (U-AIP) to diagnose autoimmune pancreatitis (AiP) within the M-ANNHEIM classification of chronic pancreatitis. In 2011, International-Consensus-Diagnostic-Criteria (ICDC) to diagnose AiP have been published. We had applied the U-AIP long before the ICDC were available. The aims of the study were, first, to describe patients with AiP diagnosed by the U-AIP; second, to compare diagnostic accuracies of the U-AIP and other diagnostic systems; third, to evaluate the clinical applicability of the U-AIP. METHODS: From 1998 until 2008, we identified patients with AiP using U-AIP, Japanese-, Korean-, Asian-, Mayo-HISORt-, Revised-Mayo-HISORt- and Italian-criteria. We retrospectively verified the diagnosis by ICDC and Revised-Japanese-2011-criteria, compared diagnostic accuracies of all systems and evaluated all criteria in consecutive patients with pancreatitis (2009 until 2010, Pancreas-Outpatient-Clinic-Cohort, n = 84). We retrospectively validated our diagnostic approach in consecutive patients with a pancreatic lesion requiring surgery (Surgical-Cohort, n = 98). RESULTS: Overall, we identified 21 patients with AiP. Unifying-Autoimmune-Pancreatitis-Criteria and ICDC presented the highest diagnostic accuracies (each 98.8%), highest Youden indices (each 0.95238), and highest proportions of diagnosed patients (each n = 20/21, U-AIP/ICDC vs. other diagnostic systems, p < 0.05, McNemar test). In the Pancreas-Outpatient-Clinic-Cohort, seven patients were diagnosed with AiP (n = 6 by U-AIP, n = 1 by Asian-criteria). International-Consensus-Diagnostic-Criteria confirmed the diagnosis in these individuals. Based on partial fulfillment of U-AIP, AiP was initially suspected in 13% (n = 10/77) of remaining patients from the Pancreas-Outpatient-Clinic-Cohort. In the Surgical-cohort, we identified one patient with AiP by U-AIP and ICDC. CONCLUSIONS: Unifying-Autoimmune-Pancreatitis-Criteria revealed a satisfactory clinical applicability and offered an additional approach to diagnose AiP.

Transplantation of tissue-engineered cell sheets for stricture prevention after endoscopic submucosal dissection of the oesophagus.

BACKGROUND AND OBJECTIVE: Endoscopic mucosal dissection (ESD) is a treatment option for oesophagus tumours localized to the mucosa enabling en bloc removal of large lesions. The resulting larger mucosal defects have resulted in an increase in the occurrence of post-treatment strictures. Transplantation of autologous cell sheets, cultured from oral mucosa, has been shown to prevent post-ESD strictures. The aim of the study was to assess the efficacy and safety of cell sheet transplantation after oesophageal ESD in a Western patient population where reflux-associated pre-malignant and malignant conditions predominate. METHODS: Patients with Barrett's oesophagus associated high-grade dysplasia or early adenocarcinoma where ESD entailed a resection >3 cm in length and ≥75% of the circumference were eligible for treatment under hospital exemption. Cell sheets were cultured from buccal mucosa according to Good Manufacturing Practice and were endoscopically applied to the post-ESD defect directly after resection. Patients were followed with weekly endoscopy examinations, including confocal laser microscopy, for a total of four weeks. RESULTS: Five patients were treated. ESD was extensive with resections being circumferential in three patients and 9-10 cm in length in two. The number of transplanted cell sheets ranged from two to six. Three patients developed strictures requiring two to five dilatation sessions. CONCLUSIONS: Cell sheet transplantation shows to be safe and feasible in a Western population. Results suggest that transplantation has a protective effect on the mucosal defect after ESD, decreasing both the risk for and extent of stricture formation.

Outcome of probe-based confocal laser endomicroscopy (pCLE) during endoscopic retrograde cholangiopancreatography: A single-center prospective study in 45 patients.

BACKGROUND: Diagnosis of pre-malignant and malignant lesions in the bile duct and the pancreas is sometimes cumbersome. This applies in particular to intraductal papillary mucinous neoplasia (IPMN) and bile duct strictures in primary sclerosing cholangitis (PSC). AIMS: To evaluate in a prospective cohort study the sensitivity and specificity of probe-based confocal laser microscopy (pCLE) during endoscopic retrograde cholangiopancreatography (ERCP). METHODS: We performed pCLE together with mother-baby endoscopy (SpyGlass) during 50 ERCP sessions in 45 patients. The Miami and Paris criteria were applied. Clinical diagnosis via imaging was compared to pCLE and the final pathological diagnosis from surgically-resected, biopsy, or cytology specimens. Patients were followed up for at least 1 year. RESULTS: We were able to perform pCLE in all patients. Prior to endoscopy, the diagnosis was benign in 23 patients and undetermined (suspicious) in 16 patients, while six patients had an unequivocal diagnosis of malignancy. Sensitivity was 91% and specificity 52%. The positive (PPV) and negative predictive value (NPV) was 82% and 100%, respectively. Apart from mild post-ERCP pancreatitis in two patients, no complications occurred. CONCLUSIONS: Our study showed that pCLE is a safe, expert endoscopic method with high technical feasibility, high sensitivity and high NPV. It provided diagnostic information that can be helpful for decisions on patient management, especially in the case of IPMN and unclear pancreatic lesions, in individuals whom are at increased risk for pancreatic cancer.

Short-term Results of a Magnetic Resonance Imaging-Based Swedish Screening Program for Individuals at Risk for Pancreatic Cancer.

IMPORTANCE: Pancreatic cancer is the fourth leading cause of cancer-related death in Western countries. In approximately 10% of all patients with pancreatic cancer, it is possible to define a positive family history for pancreatic cancer or for one of the other related genetic syndromes. A screening program for individuals at risk is recommended; however, surveillance modalities have not been defined yet. OBJECTIVE: To analyze the short-term results of a prospective clinical surveillance program for individuals at risk for pancreatic cancer using a noninvasive magnetic resonance imaging (MRI)-based screening protocol. DESIGN, SETTING AND PARTICIPANTS: A prospective observational study of all patients with a genetic risk for developing pancreatic cancer who were referred to Karolinska University Hospital between January 1, 2010, and January 31, 2013, using an MRI-based surveillance program. All patients were investigated for the most common genetic mutations associated with pancreatic cancer. EXPOSURE: A noninvasive MRI-based screening protocol. MAIN OUTCOMES AND MEASURES: The ability of MRI to identify potential precancerous or early cancers in individuals at risk for pancreatic cancer. RESULTS: Forty patients (24 women and 16 men) were enrolled. The mean age was 49.9 years. The mean length of follow-up was 12.9 months. The numbers of relatives affected by pancreatic cancer were 5 in 2 patients (5%), 4 in 5 patients (12.5%), 3 in 17 patients (42.5%), 2 in 14 patients (35%), and 1 in 2 patients (5%). In 4 patients (10%), a p16 mutation was found; in 3, a BRCA2 mutation (7.5%); and in 1, a BRCA1 mutation (2.5%). In 16 patients (40%), MRI revealed a pancreatic lesion: intraductal papillary mucinous neoplasia (14 patients, 35%) and pancreatic ductal adenocarcinoma (2 patients, 5%). One patient had a synchronous intraductal papillary mucinous neoplasia and pancreatic ductal adenocarcinoma. Five patients (12.5%) required surgery (3 for pancreatic ductal adenocarcinoma and 2 for intraductal papillary mucinous neoplasia), while the remaining 35 are under continued surveillance. CONCLUSIONS AND RELEVANCE: During a median follow-up of approximately 1 year, pancreatic lesions were detected in 40% of the patients, of whom 5 underwent surgery. Although the study time was relatively short, the surveillance program in individuals at risk seems to be effective.

Desmoplasia and chemoresistance in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) occurs mainly in people older than 50 years of age. Although great strides have been taken in treating PDAC over the past decades its incidence nearly equals its mortality rate and it was quoted as the 4th leading cause of cancer deaths in the U.S. in 2012. This review aims to focus on research models and scientific developments that help to explain the extraordinary resistance of PDAC towards current therapeutic regimens. Furthermore, it highlights the main features of drug resistance including mechanisms promoted by cancer cells or cancer stem cells (CSCs), as well as stromal cells, and the acellular components surrounding the tumor cells-known as peritumoral desmoplasia-that affects intra-tumoral drug delivery. Finally, therapeutic concepts and avenues for future research are suggested, based on the topics discussed.

Encapsulated cells expressing a chemotherapeutic activating enzyme allow the targeting of subtoxic chemotherapy and are safe and efficacious: data from two clinical trials in pancreatic cancer.

Despite progress in the treatment of pancreatic cancer, there is still a need for improved therapies. In this manuscript, we report clinical experience with a new therapy for the treatment of pancreatic cancer involving the implantation of encapsulated cells over-expressing a cytochrome P450 enzyme followed by subsequent low-dose ifosfamide administrations as a means to target activated ifosfamide to the tumor. The safety and efficacy of the angiographic instillation of encapsulated allogeneic cells overexpressing cytochrome P450 in combination with low-dose systemic ifosfamide administration has now been evaluated in 27 patients in total. These patients were successfully treated in four centers by three different interventional radiologists, arguing strongly that the treatment can be successfully used in different centers. The safety of the intra-arterial delivery of the capsules and the lack of evidence that the patients developed an inflammatory or immune response to the encapsulated cells or encapsulation material was shown in all 27 patients. The ifosfamide dose of 1 g/m2/day used in the first trial was well tolerated by all patients. In contrast, the ifosfamide dose of 2 g/m2/day used in the second trial was poorly tolerated in most patients. Since the median survival in the first trial was 40 weeks and only 33 weeks in the second trial, this strongly suggests that there is no survival benefit to increasing the dose of ifosfamide, and indeed, a lower dose is beneficial for quality of life and the lack of side effects. This is supported by the one-year survival rate in the first trial being 38%, whilst that in the second trial was only 23%. However, taking the data from both trials together, a total of nine of the 27 patients were alive after one year, and two of these nine patients were alive for two years or more.

Alcohol consumption and digestive tract cancer.

PURPOSE OF REVIEW: The data indicating that alcohol is an important factor increasing the risk to develop gastrointestinal cancer are consolidating. The purpose of this review is to summarize current evidence. RECENT FINDINGS: Acetaldehyde is the first metabolite of ethanol metabolism and has direct carcinogenic and mutagenic effects by modifying DNA via generation of DNA adducts. Oxidative stress has a prominent role in triggering chronic inflammation and carcinogenesis through formation of reactive oxygen species. Recently published large prospective cohort studies with sufficient statistical power and meta-analyses could refine the knowledge regarding the impact of alcohol on gastrointestinal cancer. Functional genetic variants of alcohol-metabolizing enzymes proved to be associated with increased risk for esophageal and gastric cancer.The highest risk increase for malignancy was observed in the upper aerodigestive tract (oral cavity, pharynx, larynx) and esophagus (squamous cell carcinoma), weaker correlations were established regarding gastric, pancreatic, and colorectal neoplasias. SUMMARY: Alcohol overconsumption is a serious avoidable risk factor for the development of gastrointestinal tract cancer, both alone but even more in combination with other risk factors such as tobacco and obesity.

Transforming growth factor-beta induces nerve growth factor expression in pancreatic stellate cells by activation of the ALK-5 pathway.

Nerve growth factor (NGF), a survival factor for neurons enforces pain by sensitizing nociceptors. Also in the pancreas, NGF was associated with pain and it can stimulate the proliferation of pancreatic cancer cells. Hepatic stellate cells (HSC) respond to NGF with apoptosis. Transforming growth factor (TGF)-beta, one of the strongest pro-fibrogenic activators of pancreatic stellate cells (PSC) induced NGF and its two receptors in an immortalized human cell line (ihPSC) and primary rat PSC (prPSC) as determined by RT-PCR, western blot, and immunofluorescence. In contrast to HSC, PSC expressed both NGF receptors, although p75(NTR) expression was weak in prPSC. In contrast to ihPSC TGF-beta activated both Smad signaling cascades in prPSC. NGF secretion was diminished by the activin-like kinase (ALK)-5 inhibitor SB431542, indicating the predominant role of ALK5 in activating the NGF system in PSC. While NGF did not affect proliferation or survival of PSC it induced expression of Inhibitor of Differentiation-1. We conclude that under conditions of upregulated TGF-beta, like fibrosis, NGF levels will also increase in PSC which might contribute to pancreatic wound healing responses.

Expression of tissue factor in pancreatic adenocarcinoma is associated with activation of coagulation.

AIM: To study expression of tissue factor (TF) in pancreatic cancer and its role in the development of thromboembolism. METHODS: TF expression was studied in eight human pancreatic carcinoma cell lines by Northern blot and indirect immunofluorescence. Expression of alternatively spliced TF (asTF) was assessed by RT-PCR. In addition, TF expression was determined by immunofluorescence in pancreatic tissues of 19 patients with pancreatic adenocarcinoma (PCa), 9 patients with chronic pancreatitis (CP) and 20 normal controls. Plasma samples (30 PCa-patients, 13 CP-patients and 20 controls) were investigated for soluble TF levels and coagulation activation markers [thrombin-antithrombin III complex (TAT), prothrombin fragment 1 + 2 (F1 + 2)]. RESULTS: All pancreatic carcinoma cell lines expressed TF (8/8) and most of them expressed asTF (6/8). TF expression at the protein level did not correlate with the differentiation of the carcinoma cell line. All but two pancreatic cancer tissue samples stained positive for TF (17/19). In all samples of CP weak staining was restricted to pancreatic duct cells, whereas only a few subendothelial cells were positive in 9/20 of normal controls. TF and TAT levels in PCa patients were significantly elevated compared to controls whereas elevated F1 + 2 levels did not reach statistical significance compared to controls. In CP patients TAT and F1 + 2 levels proved to be significantly elevated compared to controls, although TAT elevation was less pronounced than in PCa patients. CONCLUSION: We conclude that in addition to the upregulated expression of TF on the cell membrane, soluble TF might contribute to activation of the coagulation system in pancreatic cancer.