Patient Perspective on the Value of Genetic Counselling for Familial Pancreas Cancer

<p>Abstract</p> <p>Purpose</p> <p>To assess patient views regarding the value of genetic counselling for familial pancreas cancer in the absence of predictive genetic testing.</p> <p>Patients and methods</p> <p>At-risk adults with three or more relatives with pancreas cancer received genetic counselling prior to research screening via endoscopic ultrasound. Questionnaires were mailed after the visit to assess perceived value of the counselling session.</p> <p>Results</p> <p>Ninety-three percent of respondents felt genetic counselling for pancreas cancer was helpful despite the lack of a causative gene, while only 7% felt that it should not be offered until such a gene is discovered. Over half of respondents believed the pancreas cancer in their family was caused by a gene mutation, and 42% thought they had inherited the mutation. The average perceived lifetime risk of developing pancreas cancer was 51%, and 87% of respondents would ultimately seek predictive genetic testing. When more information is gained, 89% would be interested in another genetic counselling session, and 82% would recommend current genetic counselling for pancreas cancer to a friend or relative with a family history of the disease.</p> <p>Conclusion</p> <p>Despite the lack of an identified major causative gene for pancreas cancer, respondents found genetic counselling for this malignancy to be helpful. These patients perceive their personal cancer risk to be high, and would seek predictive genetic testing if it were available. Referral for genetic counselling should be offered to appropriate individuals.</p

HIV Impairs Lung Epithelial Integrity and Enters the Epithelium to Promote Chronic Lung Inflammation.

Several clinical studies show that individuals with HIV are at an increased risk for worsened lung function and for the development of COPD, although the mechanism underlying this increased susceptibility is poorly understood. The airway epithelium, situated at the interface between the external environment and the lung parenchyma, acts as a physical and immunological barrier that secretes mucins and cytokines in response to noxious stimuli which can contribute to the pathobiology of chronic obstructive pulmonary disease (COPD). We sought to determine the effects of HIV on the lung epithelium. We grew primary normal human bronchial epithelial (NHBE) cells and primary lung epithelial cells isolated from bronchial brushings of patients to confluence and allowed them to differentiate at an air- liquid interface (ALI) to assess the effects of HIV on the lung epithelium. We assessed changes in monolayer permeability as well as the expression of E-cadherin and inflammatory modulators to determine the effect of HIV on the lung epithelium. We measured E-cadherin protein abundance in patients with HIV compared to normal controls. Cell associated HIV RNA and DNA were quantified and the p24 viral antigen was measured in culture supernatant. Surprisingly, X4, not R5, tropic virus decreased expression of E-cadherin and increased monolayer permeability. While there was some transcriptional regulation of E-cadherin, there was significant increase in lysosome-mediated protein degradation in cells exposed to X4 tropic HIV. Interaction with CXCR4 and viral fusion with the epithelial cell were required to induce the epithelial changes. X4 tropic virus was able to enter the airway epithelial cells but not replicate in these cells, while R5 tropic viruses did not enter the epithelial cells. Significantly, X4 tropic HIV induced the expression of intercellular adhesion molecule-1 (ICAM-1) and activated extracellular signal-regulated kinase (ERK). We demonstrate that HIV can enter airway epithelial cells and alter their function by impairing cell-cell adhesion and increasing the expression of inflammatory mediators. These observed changes may contribute local inflammation, which can lead to lung function decline and increased susceptibility to COPD in HIV patients

Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds

Individuals with a family history of pancreatic cancer have an increased risk of developing pancreatic cancer. Quantification of this risk provides a rational basis for cancer risk counseling and for screening for early pancreatic cancer. In a prospective registry-based study, we estimated the risk of pancreatic cancer in individuals with a family history of pancreatic cancer. Standardized incidence ratios were calculated by comparing the number of incident pancreatic cancers observed with those expected using Surveillance, Epidemiology and End Results (SEER) rates. Familial pancreatic cancer (FPC) kindreds were defined as kindreds having at least one pair of first-degree relatives with pancreatic cancer, and sporadic pancreatic cancer (SPC) kindreds as families without such an affected pair. Nineteen incident pancreatic cancers developed among 5,179 individuals from 838 kindreds (at baseline, 370 FPC kindreds and 468 SPC kindreds). Of these 5,179 individuals, 3,957 had at least one first-degree relative with pancreatic cancer and contributed 10,538 person-years of follow-up. In this group, the observed-to-expected rate of pancreatic cancer was significantly elevated in members of FPC kindreds [9.0; 95% confidence interval (CI), 4.5-16.1], but not in the SPC kindreds (1.8; 95% CI., 0.22-6.4). This risk in FPC kindreds was elevated in individuals with three (32.0; 95% CI, 10.2-74.7), two (6.4; CI, 1.8-16.4), or one (4.6; CI, 0.5-16.4) first-degree relative(s) with pancreatic cancer. Risk was not increased among 369 spouses and other genetically unrelated relatives. Risk was higher in smokers than in nonsmokers. Individuals with a strong family history of pancreatic cancer have a significantly increased risk of developing pancreatic cance

X4 tropic virus and dual tropic virus increase airway epithelial permeability.

<p><b>A.</b> NHBE cells were exposed in the basolateral compartment to either an X4 tropic virus or an R5 tropic virus and after a four hour exposure to an X4 tropic virus, IIIB, there was a statistically significant increase in barrier permeability as measured by FITC Dextran that was not seen after four hours of exposure to an R5 tropic virus, BAL. At lower virus titers (0.05ng/ml or 0.5ng/ml), IIIB caused an increase in epithelial permeability although these changes were not statistically significant. (n = 22, *p<0.05, Anova with Bonferroni correction) <b>B.</b> Lower titers of IIIB virus (0.5ng/ml) were able to cause statistically significant increases in epithelial permeability with a 24 hour exposure. (n = 14, *p<0.05, Anova with Bonferroni correction) <b>C.</b> Both X4 tropic virus, MN and HXB2, and dual tropic virus, RF, (all at concentrations of 5ng/ml) caused similar changes in barrier permeability after four hours of exposure (n = 10, *p<0.05, Anova with Bonferroni correction).</p

HIV reduces the abundance of E-Cadherin.

<p><b>A.</b> Immunofluorescence shows a reduction in E-Cadherin along the basolateral membrane (white arrow) after exposure to X4 tropic virus IIIB at a concentration of p24 (5ng/ml) which was not seen after exposure to R5 tropic virus BaL at the same concentration. <b>B.</b> Western blot probing for E-Cadherin at a dilution of 1:1000 shows marked reduction in abundance of E-Cadherin following four hour basolateral exposure to X4 tropic virus but not R5 tropic virus. (n = 6 BaL and 10 IIIB samples, *p<0.05, Mann-Whitney rank sum test) <b>C.</b> By Western analysis, there is a marked reduction in E-cadherin in an epithelial cell whole cell lysate from a patient with HIV and COPD when compared to that obtained from an HIV negative COPD negative individual and an HIV positive COPD negative individual. <b>D.</b> While in the control patients, there is a normal distribution of E-cadherin level, there is a suggestion of two subpopulations of E-cadherin abundance in HIV patients. One with higher E-Cadherin levels and one with lower E-Cadherin levels. While study patients did not have viral tropism studies performed, the dots circled in red represents patients on the CCR5 inhibitor miraviroc suggesting R5 tropic disease. (Data compared using Kruskal-Wallis assessment).</p