Tumor Heterogeneity in Uveal Melanomas

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults with an incidence of 7-10/ million and has a predilection for hematogenous dissemination to the liver. Despite improvements in diagnosis and treatment of this intraocular tumor, there has not been a change in survival in the past decades. There is no effective treatment for liver metastases resulting in tumor-related death in about 45% of UM patients within 15 years after the initial diagnosis. Uveal melanoma usually arises ‘de novo’ from melanocytes derived from neural crest cells that have migrated to the epidermis and uveal tract during embryogenesis. Intraocular melanoma may arise in the choroid (70-80%), ciliary body (10-20%) and iris (5-10%). Iris melanomas are the least common and tend to present at a smaller size, probably because pigmented lesions of the iris are usually visible to the patient. Iris melanomas can cause drainage angle blockage and secondary elevation of the intraocular pressure.4 Melanomas located in the ciliary body are associated with a high metastatic potential. Choroidal melanomas compromise the majority and grow subretinal in a discoid, dome-shaped or mushroom-shaped pattern. The diagnosis is based on the clinical appearance of the tumor on ophthalmic examination. Ancillary tests include (Doppler-) ultrasonography, transillumination, fluorescein angiography and optical coherence tomography. For the diagnosis of melanoma, biopsy is reserved for tumors of uncertain origin. Conversely, tumor biopsy gains territory in vision-sparing therapies for cytogenetic analysis providing risk assessment of metastatic disease. Upon diagnosis of the primary tumor, patients are screened for metastases by liver enzyme tests and liver ultrasound. At time of diagnosis less than 2% of the patients have detectable metastases

Long Overall Survival After Dendritic Cell Vaccination in Metastatic Uveal Melanoma Patients

Purpose: To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma. Design: Interventional case series. Methods: We analyzed 14 patients with metastatic uveal melanoma treated with dendritic cell vaccination. Patients with metastatic uveal melanoma received at least 3 vaccinations with autologous dendritic cells, professional antigen-presenting cells loaded with melanoma antigens gp100 and tyrosinase. The main outcome measures were safety, immunologic response, and overall survival. Results: Tumor-specific immune responses were induced with dendritic cell vaccination in 4 (29%) of14 patients. Dendritic cell-vaccinated patients showed a median overall survival with metastatic disease of 19.2months, relatively long compared with that reported in the literature. No severe treatment-related toxicities (common toxicity criteria grade 3 or 4) were observed. Conclusions: Dendritic cell vaccination is feasible and safe in metastatic uveal melanoma. Dendritic cell-based immunotherapy is potent to enhance the host's antitumor immunity against uveal melanoma in approximately one third of patients. Compared with other prospective studies with similar inclusion criteria, dendritic cell vaccination may be associated with longer than average overall survival in patients with metastatic uveal melanoma

Metastatic disease in polyploid uveal melanoma patients is associated with BAP1 mutations

PURPOSE. Most of the uvea melanoma (UM) display a near-diploid (normal, ~2N) karyotype with only a few chromosomal changes. In contrast to these simple aberrations 18% of the UM samples show a polyploid character (>2N) and this was associated with an unfavorable prognosis. This study attempts to gain insight in the prognostic value of polyploidy in UM. METHODS. In 202 patients the ploidy status of the UM was determined using cytogenetic analysis, fluorescence-in-situ-hybridization (FISH), multiplex ligation dependent probe amplification (MLPA), and/or single nucleotide polymorphism (SNP) array analysis. Immunohistochemistry was used to determine the BAP1 expression and mutation analyses of BAP1 (coding regions) and the mutation hotspots for the SF3B1, EIF1AX, GNAQ, and GNA11 genes was carried out using Sanger sequencing or whole-exome sequencing. RESULTS. Twenty-three patients had a polyploid UM karyotype (11.4%). Patients with a polyploid tumor had larger tumors (15.61 vs. 13.13 mm, P = 0.004), and more often loss of heterozygosity of chromosome 3 (P ¼ 0.003). No difference in occurrence of mutations between polyploid and diploid tumors was observed for BAP1, SF3B1, EIF1AX, GNAQ, and GNA11. Polyploidy did not affect survival (P = 0.143). BAP1 deficiency was the only significant independent prognostic predictor for patients with polyploid tumors, with a 16- fold increased hazard ratio (HR 15.90, P = 0.009). CONCLUSIONS. The prevalence of mutations in the UM related genes is not different in polyploid UM compared with diploid UM. Moreover, similar to patients with diploid UM, BAP1 mutation is the most significant prognostic predictor of metastasis in patients with polyploid UM

Aberrant microRNA expression and its implications for uveal melanoma metastasis

Uveal melanoma (UM) is the most frequently found primary intra-ocular tumor in adults. It is a highly aggressive cancer that causes metastasis-related mortality in up to half of the patients. Many independent studies have reported somatic genetic changes associated with high metastatic risk, such as monosomy of chromosome 3 and mutations in BAP1. Still, the mechanisms that drive metastatic spread are largely unknown

Genetics of ocular melanoma: Insights into genetics, inheritance and testing

Ocular melanoma consists of posterior uveal melanoma, iris melanoma and conjunctival melanoma. T

Multi-Modality Analysis Improves Survival Prediction in Enucleated Uveal Melanoma Patients

PURPOSE. Uveal melanoma (UM) is characterized by multiple chromosomal rearrangements and recurrent mutated genes. The aim of this study was to investigate if copy number variations (CNV) alone and in combination with other genetic and clinico-histopathological variables can be used to stratify for disease-free survival (DFS) in enucleated patients with UM. METHODS. We analyzed single nucleotide polymorphisms (SNP) array data of primary tumors and other clinical variables of 214 UM patients from the Rotterdam Ocular Melanoma Study (ROMS) cohort. Nonweighted hierarchical clustering of SNP array data was used to identify molecular subclasses with distinct CNV patterns. The subclasses associate with mutational status of BAP1, SF3B1, or EIF1AX. Cox proportional hazard models were then used to study the predictive performance of SNP array cluster-, mutation-, and clinico-histopathological data, and their combination for study endpoint risk. RESULTS. Five clusters with distinct CNV patterns and concomitant mutations in BAP1, SF3B1, or EIF1AX were identified. The sample’s cluster allocation contributed significantly to mutational status of samples in predicting the incidence of metastasis during a median of 45.6 (interquartile range [IQR]: 24.7–81.8) months of follow-up (P < 0.05) and vice versa. Furthermore, incorporating all data sources in one model yielded a 0.797 C-score during 100 months of follow-up. CONCLUSIONS. UM has distinct CNV patterns that correspond to different mutated driver genes. Incorporating clinico-histopathological, cluster and mutation data in the analysis results in good performance for UM-related DFS prediction

Adolescents' responses to a school-based prevention program promoting healthy eating at school

Contains fulltext : 178856.pdf (publisher's version ) (Open Access)Background: To improve the effectiveness of school-based obesity prevention programs, it is essential to understand the views and behaviors of the target group. The present study aimed to get a better understanding of adolescents' food and health perceptions and their willingness to be involved in a specific school-based prevention program, i.e., the Dutch 'Healthy School Canteen Program'. Methods: The present study used a mixed methods research design. First, seven semi-structured focus groups were conducted using a selective sample of 42 Dutch adolescents (24 girls, 18 boys, aged 13-16 years). Second, an online survey among 133 adolescent respondents (72 girls, 61 boys, aged 12-19 years) using snowball sampling was conducted. Content analysis was performed to make inferences about the focus group discussions, whereas statistical analyses were conducted to analyze the survey data. Results: Findings from the group discussions indicated that healthy eating was only an issue of importance when adolescents perceived negative physical changes (e.g., with regards to looks or physical performance). Adolescents also indicated that they clearly wanted to make their own food and drink choices at school. The quantitative data indicated that taste, price and variety were seen as the most important aspects of a healthy food assortment (mean scores 8.1, 7.8 and 7.7 on a 10-point scale respectively). In general, most adolescents (64%) expressed that students should be involved in the organization of a healthy food environment in schools. At the same time, however, adolescents were not willing to participate themselves. This was mostly because they were skeptical about their ideas being heard and put into action by their schools. Conclusions: School-based prevention programs, such as the Healthy School Canteen, should take into account that adolescents have a low risk perception of unhealthy eating and are seeking food choice autonomy. In addition, schools should not lose sight of product price, taste, and variety to make their food assortment attractive to students. If schools aim to involve adolescents in universal prevention programs that promote healthy eating, it is essential that they have a formal student involvement process that ensures that adolescents' suggestions are valued.11 p

Serum Markers and Intestinal Mucosal Injury in Chronic Gastrointestinal Ischemia

Diagnosing chronic gastrointestinal ischemia (CGI) is a challenging problem in clinical practice. Serum markers for CGI would be of great diagnostic value as a non-invasive test method. This study investigated serum markers in patients with well-defined ischemia. Furthermore, intestinal mucosal injury was also evaluated in CGI patients. Consecutive patients suspected of CGI were prospectively enrolled and underwent a diagnostic work-up consisting of gastrointestinal tonometry and either CT or MR angiography. Blood samples for analysis of intestinal fatty acid-binding protein (I-FABP), D-dimer, lactate dehydrogenase (LDH), leucocyte counts, C-reactive protein (CRP), and L-lactate were drawn before and after a standard meal. Intestinal mucosal injury was assessed with glutamine, citrulline and arginine in blood samples and compared to a sugar absorption test (SAT). Test reproducibility was validated in healthy subjects. Forty patients and nine healthy subjects were included. Ischemia was diagnosed in 32 patients (80%). I-FABP, leucocyte counts, LDH, CRP, glutamine, citrulline, arginine and SAT levels did not differ between patients with and without ischemia. L-lactate concentration showed a significant elevation in ischemia patients as compared to non-ischemia patients. In ischemia patients, D-dimer levels showed a significant elevation postprandially as compared to D-dimer levels at baseline. However, these ischemia patients did not show intestinal mucosal injury. I-FABP, leucocyte counts, LDH and CRP levels are not clinically useful for the diagnosis of CGI. However, postprandial rises in L-lactate and D-dimer serum levels can serve as non-invasive indicators of CGI

Transient postprandial ischemia is associated with increased intestinal fatty acid binding protein in patients with chronic gastrointestinal ischemia

Background Chronic gastrointestinal ischemia (CGI) is still a difficult diagnosis to make. Currently, the only diagnostic with an acceptable sensitivity for actual mucosal ischemia is gastrointestinal tonometry. However, tonometry is a cumbersome and invasive diagnostic test. We are in need of a more simple, noninvasive test for diagnosing mucosal ischemia. A sensitive and early serum marker could be of great use in this setting. The aim of this study was to evaluate the use of promising serum markers for mucosal ischemia [intestinal fatty acid binding protein (I-FABP), D-lactate, and lipopolysaccharide] and compared findings with corresponding gastrointestinal tonometry measurements. Methods Patients referred for evaluation of CGI were included. All patients had visualization of abdominal arteries and gastrointestinal tonometry. Before, during, and after tonometry blood samples were drawn for measurements of serum markers. Results Forty-nine patients were eligible for evaluation. CGI was diagnosed in 24 (49%) patients. The baseline measurements showed a significant increase in I-FABP before exercise tonometry in the abnormal-response groups compared with the normal-response group, respectively, 0.45 and 1.3 mu g/l (P=0.04). An abnormal response on meal tonometry was associated with increased I-FABP levels, 1, 2, and 4 h after tonometry, compared with the patients with a normal response, respectively, 1.26, 1.11, and 0.58 mu g/l (P=0.048, 0.01, and 0.03). The measurements of D-lactate and lipopolysaccharide were undetectable, or low, at all different points of time. Conclusion Transient postprandial mucosal ischemia, as detected with gastrointestinal tonometry, is associated with increased I-FABP levels, indicating epithelial damage. Late markers for mucosal ischemia remained negative. Eur J Gastroenterol Hepatol 21:278-282 (c) 2009 Wolters Kluwer Health vertical bar Lippincott Williams &amp; Wilkins