Urvi Mujumdar

Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors.

Desmoplastic melanoma (DM) is a variant of melanoma, which may be confused with nonmelanocytic benign or malignant spindle cell proliferations. The histologic hallmark of DM is the presence of fusiform melanocytes dispersed in a prominent collagenous stroma. Phenotypic heterogeneity of DM is underrecognized. Desmoplasia may be prominent throughout the entire tumor (“pure” DM) or represent a portion of an otherwise nondesmoplastic melanoma (“combined” DM). We reviewed melanomas with desmoplasia from 92 patients seen at a single institution between 1980 and 2002. Fifty-five of the tumors were pure DM. Thirty-seven were classified as combined. Mean follow-up of patients was 46 months for those alive at the last follow-up. Univariate analysis of clinical and pathologic parameters revealed four significant variables for disease-free survival: Clark level (IV vs. V; P = 0.005), DM subtype (pure vs. combined; P = 0.01), tumor mitotic rate (<1, 1–4, >4 mitoses/mm2; P = 0.01), and tumor thickness (<1 mm, 1–4 mm, >4 mm; P = 0.02). Only histologic subtype (P = 0.02) and Clark level (P = 0.05) were independently significant by Cox regression analysis. Our results indicate that distinguishing pure from combined forms of DM is clinically relevant for prognosis (pure forms being associated with longer disease-specific survival). Failure to make this distinction may account for conflicting reports in the literature on the biologic behavior and prognosis of DM.

Ambient UV, personal sun exposure and risk of multiple primary melanomas

ObjectiveSun exposure is the main cause of melanoma in populations of European origin. No previous study has examined the effect of sun exposure on risk of multiple primary melanomas compared with people who have one melanoma.MethodsWe identified and enrolled 2,023 people with a first primary melanoma (controls) and 1,125 with multiple primary melanomas (cases) in seven centers in four countries, recorded their residential history to assign ambient UV and interviewed them about their sun exposure.ResultsRisk of multiple primary melanomas increased significantly (P < 0.05) to OR = 2.10 for the highest exposure quarter of ambient UV irradiance at birth and 10 years of age, to OR = 1.38 for lifetime recreational sun exposure, to OR = 1.85 for beach and waterside activities, to OR = 1.57 for vacations in a sunnier climate, to OR = 1.50 for sunburns. Occupational sun exposure did not increase risk (OR = 1.03 for highest exposure). Recreational exposure at any age increased risk and appeared to add to risk from ambient UV in early life.ConclusionsPeople who have had a melanoma can expect to reduce their risk of a further melanoma by reducing recreational sun exposure whatever their age. The same is probably true for a person who has never had a melanoma.

The Prevalence of CDKN2A Germ-Line Mutations and Relative Risk for Cutaneous Malignant Melanoma: An International Population-Based Study

Germ-line mutations of CDKN2A have been identified as strong risk factors for melanoma in studies of multiple-case families. However, an assessment of their relative risk for melanoma in the general population has been difficult because they occur infrequently. We addressed this issue using a novel population-based case-control study design in which “cases” have incident second- or higher-order melanomas [multiple primary melanoma (MPM)] and “controls” have incident first primary melanoma [single primary melanoma (SPM)]. Participants were ascertained from nine geographic regions in Australia, Canada, Italy, and United States. In the 1,189 MPM cases and 2,424 SPM controls who were eligible and available for analysis, the relative risk of a subsequent melanoma among patients with functional mutations who have an existing diagnosis of melanoma, after adjustments for age, sex, center, and known phenotypic risk factors, is estimated to be 4.3 (95% confidence interval, 2.3-7.7). The odds ratio varied significantly depending on the type of mutation involved. The results suggest that the relative risk of mutation carriers in the population may be lower than currently believed and that different mutations on the CDKN2A gene may confer substantially different risks of melanoma. (Cancer Epidemiol Biomarkers Prev 2006;15(8)1520–5)

Sun protection and skin self-examination in melanoma survivors

Objectives: Patients diagnosed with melanoma are at risk for developing recurrent and second primary disease. Skin self‐examination (SSE) and sun protection are standard clinical recommendations to minimize risk. In this study we examined performance of these behaviors in individuals with melanoma drawn from the general population.

DNA Damage and Repair Capacity in Patients With Lung Cancer: Prediction of Multiple Primary Tumors

PURPOSE Patients who survive one occurrence of non-small-cell lung cancer (NSCLC) are at higher risk of a second malignancy. Capacity to repair damaged DNA may modulate individual susceptibility to develop lung cancer. Therefore, we evaluated constitutive and induced DNA damage, and repair capacity, in patients with multiple NSCLCs (cases) and compared the results to those obtained in patients with a single NSCLC (controls). PATIENTS AND METHODS One hundred eight cases and 99 controls matched by age, sex, and time since diagnosis were studied. DNA damage was assessed on peripheral blood lymphocytes by the comet assay before and after exposing cells to a tobacco-derived carcinogen, using the tail moment and the tail intensity as measures to assess baseline damage, induced damage and repair capacity. RESULTS Constitutive DNA damage, benzo(a)pyrene diol epoxide-induced damage, and repair after BPDE-induced damage were all significantly higher in cases than in controls. These results were confirmed in regression analyses adjusted for potential confounders. CONCLUSION DNA damage as measured by the comet assay is associated with the development of multiple primary tumors in individuals with NSCLC.

Familial aggregation of melanoma risks in a large population-based sample of melanoma cases.

ObjectiveMelanoma has been shown in numerous studies to be associated with sun exposure, and with host phenotypic factors of genetic origin. In this study we use information from a large series of incident cases of melanoma from an international population-based study to examine the patterns of incidence of melanoma in the first-degree relatives of these cases. Methods: A total of 2508 incident cases of melanoma provided information on basic demographic data and pigmentary characteristics, in addition to detailed information on family history of melanoma. These data were used to examine the incidence rates ratios of melanoma in the relatives of cases in relation to population rates, and also with respect to phenotypic characteristics of the probands that have been shown to be associated with melanoma: mole counts, hair color, eye color, and skin sensitivity to the sun. Results: The incidence rates reflect the underlying patterns of incidence in the source populations, with generally higher rates in the Australian sample, low rates in Italy, and intermediate rates in the USA and Canada. Also, rates are higher in men than in women, except at very young ages. Phenotypic characteristics of the probands were only weakly associated with the observed rates in the relatives although there is a strong inverse association with age at diagnosis. Cumulative risk of melanoma rises to 6.9 (6.1) at age 80 in male (female) first-degree relatives of cases, and to 10.8 (9.5) in relatives of cases diagnosed before age 50. Conclusions: Relatives of cases diagnosed with melanoma are at considerable lifetime risk of the disease, especially if the case is diagnosed at a young age.

Vitamin D Receptor Gene Haplotypes and Polymorphisms and Risk of Breast Cancer: A Nested Case–Control Study

Background: Observational and experimental studies suggest that vitamin D may influence breast cancer etiology. Most known effects of vitamin D are mediated via the vitamin D receptor (VDR). Few polymorphisms in the VDR gene have been well studied in relation to breast cancer risk and results have been inconsistent. Methods: We investigated VDR polymorphisms and haplotypes in relation to breast cancer risk by genotyping 26 single nucleotide polymorphisms (SNP) that (i) had known/suspected impact on VDR function, (ii) were tagging SNPs for the three VDR haplotype blocks among whites, or (iii) were previously associated with breast cancer risk. We estimated odds ratios (OR) and 95% confidence intervals (CI) in relation to breast cancer risk among 270 incident cases and 554 matched controls within the Agricultural Health Study cohort. Results: In individual SNP analyses, homozygous carriers of the minor allele for rs2544038 had significantly increased breast cancer risk (OR = 1.5; 95% CI: 1.0–2.5) and homozygous carriers of the minor allele for rs11168287 had significantly decreased risk (OR = 0.6; 95% CI: 0.4–1.0). Carriers of the minor allele for rs2239181 exhibited marginally significant association with risk (OR = 1.4; 95% CI: 0.9–2.0). Haplotype analyses revealed three haplotype groups (blocks “A,” “B,” and “C”). Haplotype GTCATTTCCTA in block B was significantly associated with reduced risk (OR = 0.5; 95% CI: 0.3–0.9). Conclusions: These results suggest that variation in VDR may be associated with breast cancer risk. Impact: Our findings may help guide future research needed to define the role of vitamin D in breast cancer prevention. Cancer Epidemiol Biomarkers Prev; 21(10); 1856–67. ©2012 AACR.

Evaluation of the Clonal Origin of Multiple Primary Melanomas Using Molecular Profiling

Numerous investigations have been conducted using molecular profiling to evaluate the possible clonal origin of second malignancies in various cancer types. However, to date no study assessing clonality of multiple primaries has been conducted in melanoma. In this investigation using patients treated at a specialist melanoma treatment center, we compared the somatic mutational profiles of pairs of melanomas designated as independent on the basis of thorough assessment of their clinical and pathologic characteristics. We used a set of highly polymorphic genetic markers selected on the basis of their chromosomal positions and the frequencies of reported allelic losses at these genetic loci. Our statistical testing strategy showed no significant evidence of clonal origin of the two primaries in 17 of the 19 patients examined. The results suggest that most second melanomas designated as independent primary tumors on the basis of their clinicopathologic features are indeed independent occurrences of the disease, supporting the validity of the criteria used by experienced pathologists in distinguishing new primaries from metastases.

Sun Exposure, Vitamin D Receptor Genetic Variants, and Risk of Breast Cancer in the Agricultural Health Study

Background: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D. Objectives: Our goal was to examine sun exposure and its interaction with vitamin D receptor (VDR) gene variants on breast cancer risk. Methods: We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators’ wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated interactions between sun exposure, VDR variants, and breast cancer in a nested case–control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case–control data. Results: We observed a small decrease in breast cancer risk in association with usual sun exposure of ≥ 1 hr/day (versus < 1 hr/day) 10 years before the start of follow-up among all participants [hazard ratio (HR) = 0.8; 95% CI: 0.6, 1.0]. The association appeared to be slightly stronger in relation to estrogen receptor–positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor–negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure ≥ 1 hr/day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (interaction p-value = 0.07). Conclusion: Our results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in whom low levels of usual sun exposure can be more precisely characterized. Citation: Engel LS, Satagopan J, Sima CS, Orlow I, Mujumdar U, Coble J, Roy P, Yoo S, Sandler DP, Alavanja MC. 2014. Sun exposure, vitamin D receptor genetic variants, and risk of breast cancer in the Agricultural Health Study. Environ Health Perspect 122:165–171; http://dx.doi.org/10.1289/ehp.1206274

Real-world evidence (RWE) to show improved time to progression among resected pancreatic cancer (RPC) patients receiving adjuvant chemotherapy (adjch).

242Background: Two recent clinical trials (IMPRESS and APACT) suggest the overall survival (OS) of patients with resected pancreatic cancer (RPC) is far longer than previously believed. Improvements in patient selection, intra/post-operative surgical care adjch are suggested as explanations for the improved OS. RWE of time to progression (TTP) from surgery were calculated to assess if the results of these trials are generalizable. Methods: RPC patients (ICD-9=157.x, excluding 157.4; CPT=48140, 48146, 48150, 48152-5) diagnosed between 03/2012-06/2015 were selected from the Inovalon More2 administrative claims database. Adjch was defined as initiating chemotherapy within 90 days of surgery. TTP was the time from surgery until the first claim for metastatic disease (ICD-9 =196.0-.3, .5-.6, 197.0-.8, 198.0-.8) using the Kaplan-Meier method. Patients without a metastatic diagnosis during their follow-up were censored at 12 months to adjust for underreporting of metastatic disease codes in claims. Results: 1,01...