Mechanisms of local immunosuppression in cutaneous melanoma

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFβ1 and TGFβ2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT–PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor β receptor 1 (TGFβR1), and are therefore susceptible to TGFβ1 and TGFβ2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFβ2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFβ1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic

Identification of Lynch syndrome risk variants in the Romanian population.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadTwo familial forms of colorectal cancer (CRC), Lynch syndrome (LS) and familial adenomatous polyposis (FAP), are caused by rare mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) and the genes APC and MUTYH, respectively. No information is available on the presence of high-risk CRC mutations in the Romanian population. We performed whole-genome sequencing of 61 Romanian CRC cases with a family history of cancer and/or early onset of disease, focusing the analysis on candidate variants in the LS and FAP genes. The frequencies of all candidate variants were assessed in a cohort of 688 CRC cases and 4567 controls. Immunohistochemical (IHC) staining for MLH1, MSH2, MSH6, and PMS2 was performed on tumour tissue. We identified 11 candidate variants in 11 cases; six variants in MLH1, one in MSH6, one in PMS2, and three in APC. Combining information on the predicted impact of the variants on the proteins, IHC results and previous reports, we found three novel pathogenic variants (MLH1:p.Lys84ThrfsTer4, MLH1:p.Ala586CysfsTer7, PMS2:p.Arg211ThrfsTer38), and two novel variants that are unlikely to be pathogenic. Also, we confirmed three previously published pathogenic LS variants and suggest to reclassify a previously reported variant of uncertain significance to pathogenic (MLH1:c.1559-1G>C).European Union EE

New Methodology for Nonparametric Survival Comparison Applied to Kaplan-Meier and Life-tables Methods

Objectives. 1. Identify the most appropriate test to be used when the equality of survival curves is hypothesized, and use the new taxonomy through the guidelines. 2. Define appropriate alternative hypotheses for the given data based survival curves and assess their specific characteristics. 3. Develop a reliable nonparametric survival curves comparison based on the use of the critical margins and the guidelines. Background. Hypothesis tests of the equality of Kaplan- Meier and life-table survival curves is typically accomplished using one of the available methods designed for this purpose but, without doubt, the logrank test is the one most commonly used. Perhaps the reason for the popularity of the logrank test rests in its ready availability in almost all statistical software packages. However, what many users do not appreciate is that the logrank test has very low power for some alternative hypothesis. Methods. This research used statistical power simulations for nonparametric tests under various alternatives and a meta-analysis of 172 published papers in the New England Journal of Medicine. Results. This study presents a new taxonomy for the test of the equality of survival curves that includes critical margins that are used to enhance the new created methodology. A specific guideline was created to ease the researcher tasks. The simulations led to tables of statistical comparison, specifically built for the purpose of the research. Conclusion. There is no general test that fits all comparisons, therefore the testing should be performed according to the alternative hypothesis of interest and the relationship of the hazard functions. Acknowledgement. SAS, STATA, and S-plus statistical packages where used to accomplish this research

Frequencies of Negative Cultures in Clients Treated with Antibiotics for Suspected Chlamydia or Gonorrhea

Objective. This descriptive study was designed to determine the percentages of negative cultures among all clients age 18 years and older presumptively treated with antibiotics for suspected chlamydia and/or gonorrhea infections according to the guidelines of the US Centers for Disease Control (CDC) and Prevention in the Sexually Transmitted Disease (STD) Clinic of the Palm Beach County Health Department (PBCHD). Background. At present it remains unclear what proportion of patients treated for chlamydial and/or gonococcal infections with antibiotics presumptive treatment in the PBCHDSTD clinic have negative cultures. By determining the extent of negative cultures in people treated by antibiotics for those diseases, we can recommend directions of further search for possible better testing and treatment strategies. Methods. Clinic logs were reviewed for a case series of all 1209 clients treated from November 1, 2007 to October 31, 2008. Culture results were retrieved from Department of Health’s Health Management System. Results. Of the 1209, 556 (46%) were treated for chlamydia, 30 (2.6%) for gonorrhea, and 623 (51.5%) for both. The frequencies of negative cultures were 68% overall, 70.9% for chlamydia, 86.6% for gonorrhea, and 65.2% for both. Conclusions. These descriptive data indicate that implementation of the CDC guidelines by the PBCHDSTD Clinic results in treatment of a large majority of clients with negative cultures for chlamydia, gonorrhea, or both. They also suggest the possible need to develop treatment algorithms to maximize treatment of clients with positive cultures and minimize treatment of clients with negative cultures. Grants. PBCHD supported

Physician Views on Physical Activity and its Impacts on their Patients’ Physical Fitness Level

Objective. This study was conducted to determine if physicians appreciate the importance of physical activity and if so encourage their patients to lead physically active lives. Background. Physical exercise in combination with routine medical exams is important 30 in maintaining a healthy living. Most Americans get regularly visits to their physicians but few however participate in physical exercises hence increasing their risk factors for cardiovascular diseases. The U.S Preventive Services Task Force has recommended that primary care physicians counsel their patients about the benefits of physical activity. Methods. For this study an anonymous survey was distributed to and completed by private practice physicians in selected area of Metro Atlanta and within the State of Georgia. Results. Pending. Conclusion. Our hypothesis is that physicians who appreciate the importance of physical activity are more likely to encourage their patients to incorporate physical activity into their daily lives as part of a healthy regimen. Grants. Not funded

Testing if Parents are Making Healthy Nutritional Choices for Their Infants and Toddlers

Objective. This study was conducted to determine if parents of infants and toddlers were making healthy nutritional choices and if they are aware of the unhealthy ones. Background. Although levels of overweight and obesity among adults in the United States have reached epidemic proportions, concerns about overweight among children have only recently garnered the attention of public health researchers. The purpose of this study is to test parent’s awareness of what a nutritional healthy choice is. Methods. For this study an anonymous questionnaire was given out to mothers of infants and/or toddlers. The questionnaire was testing the mother’s knowledge about certain nutritional terms that are used to market “healthy” choices for children such as “Organic” and “sugar free”. Results. This study showed that mothers who chose to exclusively breastfeed and use homemade of the first introduction to solid food for their toddlers, make healthier nutritional choices then the mothers who don’t breastfeed. Yet, this study also showed that many mothers thought that “organic” and “sugar free” automatically means “Healthy” which is not true. Conclusion. There are many choices that are marketed for infants and toddlers as healthy food yet they are usually very high in sugar, sodium, and artificial ingredients. Parents should not fall into the marketing trap and should work on educating themselves on what healthy nutrition really means. Grants. None

Impact of Training on Administration and Interpretation of PPD Testing

Background. Several studies have determined the importance of training on the skills shown to apply and interpret the Tuberculin test. Objective. To determine the impact of the Palm Beach County Health Department educational strategy, on the administration and interpretation of the Tuberculin test. Methods. In this descriptive study our health care providers were surveyed through an anonymous questionnaire to measure their competency on both areas. Their score was then correlated to the type of Tuberculin testing training they had. The data results were analyzed using a regression analysis. Results. Competency score was significantly different between Train the Trainer and the Health Department Training (P=0.15). Train the Trainer vs. Other was not statistically significant (P= 0.27). Health Department Training vs. Other was not statistically significant( P=0.18) as well as other paired comparisons. Conclusions. Type of training alone does not influence competency score, it only does it after adjusting for other covariates. Most of the participants in this study have completed the Train the Trainer or the Health Department Tuberculin testing course. When measuring one type of training against the other there’s significant influence over score mostly for the train the trainer course. The other variables found to influence score where year since training, department and center where the employee is working at, years working at the health department and number of tuberculin tests administered per month. This study is measuring scores obtained in a validated questionnaire which does not necessary corresponds to the skills of that particular practitioner. Grants. Funded by PBCHD

Childhood Brain Tumors in The Acreage: A Potential Cancer Cluster in Palm Beach County, Florida

Objective. This study will be conducted to describe and analyze the demographics and potential environmental risk factors of 6 confirmed cases of Pediatric Malignant Brain Tumors in an area being studied for a possible Brain Cancer Cluster. Background. In August 2009 the Division of Environmental Health from the Florida Department of Health (FDOH) released the report of a Preliminary Cancer Cluster Investigation in the area of Palm Beach County. Standardized Incidence Ratios (SIR) were used to analyze observed cases confirmed with the Florida Cancer Data System and the expected number of cases in the area; increased rates of malignant brain tumors for children in the period 2000-2007 were found, and consequently the Palm Beach County Health Department (PBCHD) will conduct a second phase of the investigation. Methods. A case series design will be used. An extensive structured questionnaire addressing exposures during pregnancy and after birth of the index case to possible environmental carcinogens that have been postulated as being associated with the development of Childhood Brain Tumors (CBT) will be administered to the parents of the total 14 cases (1996-2009) during the face-to-face interviews. Results. Frequencies of exposures to different potential carcinogens including but not limited to chemicals like N-nitroso compounds that could be found in water, type of diet during pregnancy, maternal and child farming activities, head trauma, radium in the soil and ionizing radiation will be analyzed and reported related to time and duration. Conclusion. The description of the environmental exposures of each case, when compared to the others, could provide early evidence of association between one or many environmental factors in the development of CBT and generate a hypothesis that would grant the need for further research using an analytical approach. Grants. PBCHD supported