Surveillance for pancreatic cancer in high-risk individuals.

Background: Surveillance of individuals at high risk of pancreatic ductal adenocarcinoma (PDAC) and its precursors might lead to better outcomes. The aim of this study was to determine the prevalence and outcomes of PDAC and high-risk neoplastic precursor lesions among such patients participating in surveillance programmes. Methods: A multicentre study was conducted through the International CAncer of the Pancreas Screening (CAPS) Consortium Registry to identify high-risk individuals who had undergone pancreatic resection or progressed to advanced PDAC while under surveillance. High-risk neoplastic precursor lesions were defined as: pancreatic intraepithelial neoplasia (PanIN) 3, intraductal papillary mucinous neoplasia (IPMN) with high-grade dysplasia, and pancreatic neuroendocrine tumours at least 2 cm in diameter. Results: Of 76 high-risk individuals identified in 11 surveillance programmes, 71 had undergone surgery and five had been diagnosed with inoperable PDAC. Of the 71 patients who underwent resection, 32 (45 per cent) had PDAC or a high-risk precursor (19 PDAC, 4 main-duct IPMN, 4 branch-duct IPMN, 5 PanIN-3); the other 39 patients had lesions thought to be associated with a lower risk of neoplastic progression. Age at least 65 years, female sex, carriage of a gene mutation and location of a lesion in the head/uncinate region were associated with high-risk precursor lesions or PDAC. The survival of high-risk individuals with low-risk neoplastic lesions did not differ from that in those with high-risk precursor lesions. Survival was worse among patients with PDAC. There was no surgery-related mortality. Conclusion: A high proportion of high-risk individuals who had surgical resection for screening- or surveillance-detected pancreatic lesions had a high-risk neoplastic precursor lesion or PDAC at the time of surgery. Survival was better in high-risk individuals who had either low- or high-risk neoplastic precursor lesions compared with that in patients who developed PDAC.

Antecedentes: Se podrían obtener mejores resultados con el seguimiento de individuos de alto riesgo para adenocarcinoma ductal pancreático (pancreatic ductal adenocarcinoma, PDAC) y lesiones precursoras. El objetivo de este estudio fue determinar la prevalencia y los resultados del PDAC y de las lesiones precursoras de alto riesgo neoplásico en pacientes que participaron en programas de seguimiento. Métodos: Se llevó a cabo un estudio multicéntrico a través del registro internacional del consorcio CAPS (Common Automotive Platform Standard) para identificar a las personas de alto riesgo que se habían sometido a una resección pancreática o habían progresado a PDAC avanzado mientras estaban en seguimiento. Se definieron como lesiones neoplásicas precursoras de alto riesgo la neoplasia intraepitelial pancreática de tipo 3 (PanIN­3), la neoplasia papilar mucinosa intraductal (intraductal papillary mucinous neoplasia, IPMN) con displasia de alto grado y los tumores neuroendocrinos pancreáticos (pancreatic neuroendocrine tumours, PanNET) de ≥ 2 cm de diámetro. Resultados: De 76 individuos con lesiones de alto riesgo identificados en 11 programas de seguimiento, 71 fueron tratados quirúrgicamente y 5 fueron diagnosticados de un PDAC inoperable. De las 71 resecciones, 32 (45%) tenían PDAC o una lesión precursora de alto riesgo (19 PDAC, 4 IPMN de conducto principal, 4 IPMN de rama secundaria y 5 PanIN­3). Los otros 39 pacientes tenían lesiones que se consideraron asociadas con un menor riesgo de progresión neoplásica. La edad ≥ 65 años, el sexo femenino, el ser portador de una mutación genética y la localización de la lesión en la cabeza/proceso uncinado fueron factores asociados a las lesiones precursoras de alto riesgo o al PDAC. No hubo diferencias en la supervivencia de individuos de alto riesgo con lesiones neoplásicas de bajo riesgo frente a aquellos que presentaron lesiones precursoras de alto riesgo. La supervivencia fue peor en los pacientes con PDAC. No hubo mortalidad relacionada con la cirugía. Conclusión: Un elevado porcentaje de individuos de alto riesgo que se sometieron a resección quirúrgica tras la detección de lesiones pancreáticas en el seguimiento tenían una lesión precursora neoplásica de alto riesgo o un PDAC. La supervivencia fue mejor en individuos de alto riesgo que tenían lesiones precursoras neoplásicas de bajo o alto riesgo en comparación con aquellos pacientes que habían desarrollado un PDAC.

Validation of histomolecular classification utilizing histological subtype, MUC1, and CDX2 for prognostication of resected ampullary adenocarcinoma.

BACKGROUND: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. METHODS: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. RESULTS: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9-109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype (P=0.0340); T1/2 vs T3/4 (P=0.001); perineural (P<0.0001) and lymphovascular (P=0.0203) invasion; and histomolecular intestinal histomolecular phenotype (INT) vs PB phenotype (106.4 vs 21.2 months, P<0.0001). Neither MUC1 nor CDX2 was statistically significant, although MUC1 positivity defined as ⩾10% staining was significant (P=0.0023). In multivariate analysis, age (HR 1.03), PB phenotype (HR 2.26) and perineural invasion (PNI; HR 2.26) were associated with poor survival. CONCLUSIONS: The prognostic ability of histomolecular phenotype has been validated in an independent cohort of ampullary adenocarcinoma patients.

Incidence of contrast-induced nephropathy in kidney transplant recipients.

UNLABELLED: Contrast-induced nephropathy (CIN) is responsible for one-third of acute kidney injuries (AKI) in the hospital setting. The incidence of CIN varies from 3% to 30%, depending on the preexisting risk factors, with higher incidence noted with diabetes mellitus, chronic kidney disease, and older age. Though CIN risk factors are common in kidney transplant recipients (KTRs), data about incidence of CIN in this population are sparse. METHODS: We retrospectively analyzed 124 consecutive patients transplanted at our center between January 2002 and December 2013 and received iodinated intravascular contrast with stable kidney function prior to contrast administration. CIN was defined as either an absolute rise in serum creatinine of ≥ 0.5 mg/dL or a ≥ 25% drop in estimated glomerular filtration rate (eGFR) after contrast administration. RESULTS: Seven of 124 (5.64%) patients developed CIN. Kidney function returned to baseline in 5 of the 7 patients within 3 weeks. In 2 patients serum creatinine remained elevated due to recurrent AKI episodes from other causes. Dialysis was not required in any patient. Calcineurin inhibitors (CNIs) were being used in 95% patients at the time of contrast administration. Diabetes mellitus, baseline serum creatinine, age, race, gender, and the use of ACE inhibitor, angiotensin receptor blocker, diuretic, or prophylaxis with intravenous hydration ± N-acetylcysteine did not affect the incidence of CIN. CONCLUSION: Incidence of CIN in KTRs was low in our study (5.6%), much less than previously reported. This low incidence may be related to the high baseline eGFR (>70 mL/min/1.73 m(2)) and use of hypo-osmolar contrast in our patients. In KTRs with baseline eGFR >70 mL/min, the incidence of CIN is low despite the concurrent use of nephrotoxic CNI.

Medical outcomes in African American live kidney donors: a matched cohort study.

It is uncertain if live kidney donation increases future risk of hypertension and kidney disease in African Americans. We conducted a cohort study across two transplant centers enrolling African Americans who donated between 1993 and 2006. A comparison group of African American nondonors were selected from healthy participants in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study. A total of 103 donors and 235 matched nondonors were assessed at mean ( ± SD) of 6.8 ± 2.3 and 6.4 ± 2.2 years after donation or cohort entry, respectively. The primary outcome was risk of hypertension in donors at follow-up. The secondary outcomes were proportion of donors with eGFR <60 mL/min/1.73 m2 and microalbuminuria. Hypertension risk was higher in donors compared to nondonors (42/103 [40.8%] vs. 42/235 [17.9%]), absolute risk difference 22.9% (95% confidence interval 12.2-33.6%) and relative risk 2.4 (95% confidence interval 1.7-3.4). Of the 42 donors with hypertension, 22 (52.4%) were untreated. Sixteen donors (15.5%) had an eGFR <60 mL/min/1.73 m(2) , 6 (5.8%) had microalbuminuria and none were on dialysis. Our retrospective study shows that live kidney donation is associated with increased risk of hypertension in African Americans and emphasizes the importance of donor follow-up.

Impact of pre-existing left ventricular dysfunction on kidney transplantation outcomes: implications for patient selection.

BACKGROUND: End-stage kidney disease patients with decreased left ventricular ejection fraction (EF) are often denied kidney transplantation (KT) for fear of poor graft and patient survival. METHODS: We retrospectively studied all patients who underwent KT at our center between 2001 and 2005 to determine the impact of low EF on outcomes post KT. Low EF was defined as <50% EF by noninvasive cardiac imaging. Follow-up was for 1 year post KT. Outcomes assessed included hospitalization for congestive heart failure (CHF), cardiac events, and renal allograft and patient survival. RESULTS: Among 254 patients, 37 had low EF (study group) and 217 had normal EF (≥50%; control group). Post KT, the low EF group had a significantly higher rate of hospitalization for CHF. No significant difference was noted in the rate of cardiac events, graft loss, GFR, and all cause death at 12 months post KT. CONCLUSION: Patients with low EF should not be excluded from transplantation, given favorable outcomes.

Tumour epithelial vimentin expression and outcome of pancreatic ductal adenocarcinomas.

PURPOSE: Tumour epithelial vimentin expression is a marker of mesenchymal differentiation and may be a useful marker of carcinomas with more aggressive behaviour. The aim of this study was to determine the extent and prognostic significance of vimentin expression in pancreatic ductal adenocarcinomas. METHODS: Vimentin expression was detected by immunohistochemistry on tissue microarrays of surgically resected pancreatic ductal adenocarcinomas from 387 patients. The percentage of vimentin-immunolabelled neoplastic cells was correlated with outcome and with clinico-pathological factors using the Kaplan-Meier method and Cox multivariate survival models. RESULTS: In all, 45% of primary pancreatic adenocarcinomas contained neoplastic cells that expressed vimentin, and in 27.5% of the cancers >10% of cells expressed vimentin. Vimentin expression was correlated with poor histological differentiation. By both uni- and multivariate survival analysis, neoplastic vimentin expression (P<0.01, HR 1.52, 95% confidence interval 1.14-2.04) was an indicator of a shorter postsurgical survival independent of other clinico-pathological variables. CONCLUSION: The presence of vimentin-expressing tumour epithelial cells in surgically resected pancreatic adenocarcinomas independently predicted a shorter postsurgical survival.

Seasonal variation of vitamin D in patients on hemodialysis.

BACKGROUND: Seasonal and racial differences in serum 25-hydroxyvitamin D levels have been studied extensively in the general population but not in patients with end-stage renal disease (ESRD). METHODS: Serum 25-hydroxyvitamin D levels, the best available index of vitamin D nutrition, was measured at the end of summer (September) in 142 chronic hemodialysis patients and again at the end of winter (April) in 73 of these 142 patients, to determine the prevalence and risk factors for vitamin D deficiency. RESULTS: The prevalence of vitamin D depletion, as defined by serum 25-hydroxyvitamin D level of less than 20 ng/ml (50 nmol/l), was 54% at the end of summer and further increased to 86% by the end of winter (p < 0.0001 summer vs. winter). We observed that women and African-Americans had a greater prevalence of hypovitaminosis D (p < 0.0002 and p < 0.001 for both comparisons, respectively). Surprisingly, diabetic status, age, and the duration of esrd were not associated with a significant increase in risk of vitamin d depletion. CONCLUSION: Vitamin D depletion is present in about half of ESRD patients with marked seasonal variations. Patients with ESRD should have more frequent assessments of their vitamin D nutrition by serum 25-hydroxyvitamin D levels, and vitamin D supplementation should be routinely prescribed, which may prevent many of the complications related to vitamin D deficiency and secondary hyperparathyroidism.

A novel mutation of STK11/LKB1 gene leads to the loss of cell growth inhibition in head and neck squamous cell carcinoma.

To investigate whether genetic alteration of the STK11 (serine/threonine kinase 11)/LKB1 tumor-suppressor gene is involved in the carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the entire encoding exons and flanking intronic sequences of the STK11/LKB1 gene were analysed with direct genomic sequencing of 15 HNSCC specimens. A novel missense mutation with presumed loss of heterozygosity (LOH) and 10 polymorphisms were identified in these samples. The novel mutation of STK11/LKB1 at nucleotide position 613 G --> A, which causes the amino-acid substitution from alanine to threonine at residue 205 within the catalytic kinase domain, was identified in cell line RPMI 2650. To further determine whether this point mutation affects the gene function, constructs of the wild type and A205T mutant of the STK11/LKB1 gene expression vectors were created and transfected into RPMI 2650 cells. Our results showed that the reintroduction of the wild-type but not the mutant STK11/LKB1 construct into RPMI 2650 cells induced suppression of the cell growth. The mutation also affected the kinase activity of the Stk11/Lkb1 protein. This led us to conclude that the A205T point mutation of the STK11/LKB1 gene produces functionally inactive proteins. This is the first described mutation of the STK11/LKB1 gene in HNSCC. While the mutation frequency of the STK11/LKB1 gene in HNSCC remains to be determined in future studies, our data strongly suggests that STK11/LKB1 is involved in the carcinogenesis of HNSCC.

Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms.

Hedgehog pathway overactivity has been implicated in the development of a variety of human cancers. The Human Hedgehog interacting protein (HHIP), a negative regulator of hedgehog signaling, has been shown to be underexpressed in pancreatic cancers. In this study we determined if the HHIP gene is a target for genetic and epigenetic alterations. While no mutations of HHIP were identified, we found complete methylation of the HHIP promoter CpG island in three pancreatic cancer cell lines, and partial hypermethylation in 13/17 (80%) pancreatic cancer cell lines, 35/75 (46%) primary pancreatic cancers and 14/18 (78%) pancreatic cancer xenografts, but no methylation in 13 normal pancreata. In pancreatic cancer cell lines, complete methylation was associated with absent or reduced HHIP expression by real-time RT-PCR. HHIP expression could be restored in methylated cell lines using epigenetic modifier drugs. Restoring the expression of HHIP in pancreatic cancer cells by 5-aza-2'-deoxycytidine led to a decrease in Gli reporter activity, consistent with downregulation of Hedgehog signaling. These results indicate in some pancreatic adenocarcinomas that HHIP is epigenetically inactivated by promoter methylation, and its silencing could contribute to the increased Hedgehog signaling observed in pancreatic neoplasms.

Comparison of long-term actual renal allograft survival in mycophenolate mofetil and azathioprine-based triple drug immunosuppression protocols.

INTRODUCTION: The use of mycophenolate mofetil (MMF) in renal transplantation results in a 50% lower incidence of acute rejection compared to azathioprine (AZA). However, the graft survival reports are conflicting: the European trial and US database analysis suggest better survival with MMF, an observation that was not seen in the US and tricontinental studies. METHODS: We retrospectively reviewed our single-center experience (60% African-Americans) comparing the serum creatinine (SCr) values and 3-year actual graft survival with MMF versus AZA-based immunosuppression. Group I included patients transplanted between January 1990 and December 1992 on cyclosporine (CSA), AZA, and steroids; group II subjects, from January 1996 to December 1998 on CSA, MMF, and steroids. We analyzed SCr and all causes of graft losses at 3, 6, 12, 18, 24, and 36 months posttransplantation. RESULTS: The patient demographics were similar in both groups as was the mean SCr values at different times. The time-group interaction for SCr, the Kruskal-Wallis test for SCr for different categories (<1.5, 1.5 to 2.0, 2.0 to 2.5, and >2.5 mg/dL) and the all-cause graft loss between the two groups were not significantly different. CONCLUSION: Our results failed to show better long-term actual graft survival despite the 6-year interval between the two groups. These findings agree with the results of the United States and the tricontinental studies. A lower incidence of acute rejection early after transplantation observed with MMF may not always translate into a long-term benefit, possibly due to the influence of nonimmunological factors, such as hypertension, calcineurin inhibitor toxicity, more frequent cytomegalovirus infections, and increased attempts to withdraw steroids using MMF-based protocols.

Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms.

The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2'-deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dose-dependent cell proliferation in a SOCS-1-methylated cell line (PL10, P=0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.

Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE).

PURPOSE: Effective new markers of pancreatic carcinoma are urgently needed. In a previous analysis of gene expression in pancreatic adenocarcinoma using serial analysis of gene expression (SAGE), we found that the tag for the mesothelin mRNA transcript was present in seven of eight SAGE libraries derived from pancreatic carcinomas but not in the two SAGE libraries derived from normal pancreatic duct epithelial cells. In this study, we evaluate the potential utility of mesothelin as a tumor marker for pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Mesothelin mRNA expression was evaluated in pancreatic adenocarcinomas using reverse-transcription PCR (RT-PCR) and in situ hybridization, whereas mesothelin protein expression was evaluated by immunohistochemistry. RESULTS: Using an online SAGE database (http://www.ncbi.nlm.gov/SAGE), we found the tag for mesothelin to be consistently present in the mesothelioma, ovarian cancer, and pancreatic cancer libraries but not in normal pancreas libraries. Mesothelin mRNA expression was confirmed by in situ hybridization in 4 of 4 resected primary pancreatic adenocarcinomas and by RT-PCR in 18 of 20 pancreatic cancer cell lines, whereas mesothelin protein expression was confirmed by immunohistochemistry in all 60 resected primary pancreatic adenocarcinomas studied. The adjacent normal pancreas in these 60 cases did not label, or at most only rare benign pancreatic ducts showed weak labeling for mesothelin. CONCLUSIONS: Mesothelin is a new marker for pancreatic adenocarcinoma identified by gene expression analysis. Mesothelin overexpression in pancreatic adenocarcinoma has potential diagnostic, imaging, and therapeutic implications.

The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma.

PURPOSE: SMAD4 (also called Dpc4) is a tumor suppressor in the TGF-beta signaling pathway that is genetically inactivated in approximately 55% of all pancreatic adenocarcinomas. We investigated whether prognosis after surgical resection for invasive pancreatic adenocarcinoma is influenced by SMAD4 status. EXPERIMENTAL DESIGN: Using immunohistochemistry, we characterized the SMAD4 protein status of 249 pancreatic adenocarcinomas resected from patients who underwent pancreaticoduodenectomy (Whipple resection) at The Johns Hopkins Hospital, Baltimore, MD, between 1990 and 1997. The SMAD4 gene status of 56 of 249 (22%) pancreatic carcinomas was also determined. A multivariate Cox proportional hazards model assessed the relative risk of mortality associated with SMAD4 status, adjusting for known prognostic variables. RESULTS: Patients with pancreatic adenocarcinomas with SMAD4 protein expression had significantly longer survival (unadjusted median survival was 19.2 months as compared with 14.7 months in patients with pancreatic cancers lacking SMAD4 protein expression; P = 0.03). This SMAD4 survival benefit persisted after adjustment for prognostic factors including tumor size, margins, lymph node status, pathological stage, blood loss, and use of adjuvant chemoradiotherapy. The relative hazard of mortality for cancers lacking SMAD4 after adjusting for other prognostic factors was 1.36 (95% confidence interval, 1.01-1.83; P = 0.04). CONCLUSION: Patients undergoing Whipple resection for pancreatic adenocarcinoma survive longer if their cancers express SMAD4.

STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas.

Despite the growing awareness of intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas among clinicians, the molecular features of IPMNs have not been well characterized. Previous reports suggest that inactivation of the STK11/LKB1, a tumor-suppressor gene responsible for Peutz-Jeghers syndrome (PJS), plays a role in the pathogenesis of gastrointestinal hamartomas as well as several cancers, including pancreatic adenocarcinoma. Using polymerase chain reaction amplification of five microsatellite markers from the 19p13.3 region harboring the STK11/LKB1 gene, we analyzed DNA from 22 IPMNs for loss of heterozygosity (LOH). LOH at 19p13.3 was identified in 2 of 2 (100%) IPMNs from patients with PJS and 5 of 20 (25%) from patients lacking features of PJS (7 of 22, 32% overall). Sequencing analysis of the STK11/LKB1 gene in these IPMNs with LOH revealed a germline mutation in one IPMN that arose in a patient with PJS and a somatic mutation in 1 of the 20 sporadic IPMNs. None of the 22 IPMNs showed hypermethylation of the STK11/LKB1 gene. These results suggest that the STK11/LKB1 gene is involved in the pathogenesis of some IPMNs.

Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma.

To identify CpG islands differentially methylated in pancreatic adenocarcinoma, we used methylated CpG island amplification (MCA) coupled with representational difference analysis. Of 42 CpG islands identified by MCA/representational difference analysis, 7 CpG islands [methylated in carcinoma of the pancreas (MICP)] were differentially methylated in a panel of eight pancreatic cancer cell lines compared with normal pancreas. In a larger panel of 75 pancreatic adenocarcinomas, these 7 MICPs (ppENK, Cyclin G, ZBP, MICP25, 27, 36, and 38) were methylated in 93, 3, 9, 15, 48, 19, and 41% of cancers, respectively, by methylation-specific PCR but not in any of 15 normal pancreata. In pancreatic cancer cell lines, methylation of ppENK, a gene with known growth suppressive properties, was associated with transcriptional silencing that was reversible with 5-aza-2'-deoxycytidine treatment. Relationships between the methylation patterns of pancreatic adenocarcinomas and their clinicopathological features were also determined. Larger pancreatic cancers and those from older patients (P = 0.017) harbored more methylated loci than smaller tumors and those from younger patients (P = 0.017). ppENK, MICP25, and 27 were variably methylated in normal gastric, duodenal, and colonic mucosae. These data indicate that aberrant methylation of ppENK and its transcriptional repression is a common event in pancreatic carcinogenesis.

Familial pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States and will be responsible for an estimated 28,900 deaths in 2001. Relatively little is known of its etiology, and the only well-established risk factor is cigarette smoking. Studies over the past 3 decades have shown that 4%-16% of patients with pancreatic cancer have a family history of the disease. A small fraction of this aggregation can be accounted for in inherited cancer syndromes, including familial atypical multiple-mole melanoma, Peutz-Jeghers syndrome, hereditary breast-ovarian cancer, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer. These syndromes arise as a result of germline mutations in the BRCA2, pl6 (familial atypical multiple-mole melanoma), mismatch repair (hereditary nonpolyposis colorectal cancer), and STK11 (Peutz-Jeghers syndrome) genes. In addition, hereditary plays a role in predisposing certain patients with apparently sporadic pancreatic cancer. Many patients with pancreatic cancers caused by a germline mutation in a cancer-causing gene do not have a pedigree that is suggestive of a familial cancer syndrome. A recent prospective analysis of the pedigrees in the National Familial Pancreatic Tumor Registry found that individuals with a family history of pancreatic cancer in multiple first-degree relatives have a high risk of pancreatic cancer themselves. The identification of such high-risk individuals will help clinicians target screening programs and develop preventive interventions with the hope of reducing the mortality of pancreatic cancer in these families.

Molecular pathology of pancreatic cancer.

Until recently, pancreatic cancer was a poorly understood disease. Research in the past decade has shown conclusively, however, that pancreatic cancer is primarily genetic in nature. Inactivation with a variety of tumor-suppressor genes such as p16, DPC4, and p53, coupled with activation of oncogenes such as K-ras, are a few of the mutations that trigger the growth of cancerous cells. Understanding these mutations is critical to a better understanding of familial pancreatic cancer and to the development of gene-based screening tests and therapies. In this article, we review the genetic alterations identified in pancreatic cancer and provide examples of how this information can be applied to patient care.

Soluble adhesion molecules in inflammatory bowel disease.

BACKGROUND: Soluble adhesion molecules are elevated in a number of inflammatory conditions. AIMS: To investigate the correlation of soluble intercellular adhesion molecule-1 (sICAM-1) and sE-selectin with the activity of inflammatory bowel disease (IBD). METHODS: sICAM-1 and sE-selectin were measured by an enzyme-linked immunosorbent assay (ELISA) in 53 patients with ulcerative colitis (UC) and 38 patients with Crohn's disease (CD). RESULTS: Patients with active UC and CD had significantly higher sICAM-1 than patients with inactive disease and controls. Patients with pancolitis had significantly higher levels than patients with distal colitis. There was a significant difference in sE-selectin levels between patients with active CD and control sICAM-1. sE-selectin did not correlate with the Harvey Bradshaw index (HBI). C-reactive protein (CRP) and microalbuminuria were better markers than sICAM-1 or sE-selectin which correlated with serum tumour necrosis factor (TNF)-alpha. CONCLUSION: sICAM-1 and sE-selectin are elevated in the serum of patients with IBD but CRP and microalbuminuria reflect clinical disease activity more accurately. This study does not support the routine use of soluble adhesion molecules as disease activity markers in IBD.