bluuebunny/crossref_metadata_2025_split huggingface dataset:
The management of BRAF mutant melanoma brain metastases upon tyrosine kinase failure.
Authors: Ladwa Rahul , Atkinson Victoria 
Published: September 2018

e21020 Background: Brain metastases (BM) failure on tyrosine kinase inhibitor (TKI) is a frequent complication in patients with BRAF mutant metastatic melanoma (MM) and is associated with a poor prognosis. We aimed to explore the outcome of these patients with modern therapeutic options. Methods: We retrospectively analysed 55 patients with treated BRAF mutant mm diagnosed with BM on TKI at a single site in Brisbane, QLD, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected. Results: Patient characteristics included a median age of 53 (17-82) years, presence of seizures (N = 7), LDH > 250 (N = 23) and presence of systemic disease (N = 54). BM were categorised as solitary (N = 8), 2-6 (N = 23), more than 6 (N = 13) and leptomeningeal disease (N = 11). Management of BM included surgical resection (N = 6), stereotactic radiosurgery (SRS) (N = 14), whole brain radiotherapy (N = 13) and best supportive care (N = 16). BRAF use post progression with BM was used (N = 10). Immunotherapy with Ipilimumab (N = 17) and PD1 inhibitor (N = 24) was used. With a median follow up of 5 months, 47 (85%) patients had died from MM. Death occurred due to progressive disease in the brain (N = 24), systemically (N = 5) or both (N = 18). The number of patients surviving over 6 months (N = 27) were associated with < 6 BM, use of radiotherapy, use of anti PD1 antibodies and the use of ablative therapies with immunotherapy. Statistically improved overall survival (OS) were found with < 6 BM, SRS use and PD1 inhibitor use. Ablative treatments (resection or SRS) with subsequent immunotherapy confers a median OS of 13 months in select patients. Conclusions: Despite improvements in systemic treatment for mm the outcomes of those with BRAF mutant mm on TKI who develop BM remains poor. Death is frequently due to PD within the brain. The use of ablative techniques and immunotherapy are optimal treatment options in this poor prognostic group.
CTLA4 and CD47 combinational therapy to extend survival in melanoma.
Authors: Schwartz Anthony L. , Nath Pulak , Lessey-Morillon Elizabeth , Ridnour Lisa , Allgaeuer Michael , Roberts David 
Published: September 2018

e21025 Background: Irradiation (IR) combined with chemotherapy is the post-surgical standard of care treatment for melanoma, but metastasis still results in high mortality rates. Immune checkpoint inhibitors such as cytotoxic T-lymphocyte antigen-4 (CTLA4) have proven effective for immunotherapy of melanoma. CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent rodents and humans. Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant. We are investigating CD47 blockade for the treatment of cancer. CD47 is frequently elevated in cancers and serves as an inhibitory receptor for thrombospondin-1 on immune cells in the tumor stroma. CD47 blockade on CD8 T or tumor cells significantly enhances immune-targeted tumor cell killing post-IR compared to IR alone. Here we explore the potential for antisense CD47 and anti-CTLA4 therapy alone or in combination with IR using a syngeneic mouse melanoma model. Methods: C57BL/6 mice were inoculated with 1x106B16F10 melanoma cells in the hind limb and treated with 10 Gy IR combined with CTLA4 blocking antibody, CD47 translational blocking morpholino, or the combination of CTLA4/CD47 therapies. Granzyme B along with CD4/CD8 T cell infiltration were examined in tumors. Histology was evaluated for CD3 and necrosis. Results: The combination of CD47/CTLA4 with IR significantly increased survival by 25% compared to IR/CTLA4 alone at 50 days. Granzyme B expression was significantly increased in IR mice with CTLA4/CD47 combination, which correlated with infiltration of CD8+ T cells and a concomitant decrease in Gr1+CD11b suppressor cells compared to controls. In non-IR tumors, histology revealed minimal necrosis, while all IR groups showed increased necrosis. Tumor IR in combination with CTLA4 or CD47 increased immune cell infiltration. However, the combination of IR with CTLA4/CD47 showed widespread necrosis. All groups treated with the CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA4. Conclusions: Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response.
Accelerated melanoma mortality rates among middle-aged white males with tumors of all thicknesses.
Authors: Berk-Krauss Juliana , Polsky David , Stein Jennifer , Geller Alan 
Published: September 2018

e21029 Background: Effective early detection of melanoma remains one of the most crucial strategies in improving patient prognosis, due to the inverse relationship between primary tumor thickness and survival time. However, recent studies have demonstrated the mortality burden of thin melanomas is at least as severe as that of thicker melanomas. Recognizing specific mortality trends among men and women by age and thickness is essential for establishing targeted melanoma screening efforts. Methods: We evaluated Surveillance, Epidemiology and End Results (SEER) data from 2009-2013. Melanoma thickness was divided into four standard categories: 0.01-1.00mm, 1.01-2.00mm, 2.01-4.00mm and > 4.01 mm. Melanoma mortalities were calculated among white men and women by age and thickness. We used a Bayesian analysis to calculate the probability of an individual dying from a melanoma of a given gender, age, and thickness. We then compared these probabilities between men and women. Results: Among white men, the largest increases in mortality rates occurred in the jump from the 45-49 to 50-54 age group at an increase of 68% for 0.01-1.00mm tumors, and from the 50-54 to 55-59 age group at an increase of 91% for 1.01-2.00mm tumors, 71% 2.01-4.00mm tumors and 80% for > 4.01mm tumors. In white women, mortality rates regardless of thickness increased at a slow incremental pace, across all age groups at an average overall rate of 36%. Mortality rates for white men with < 1mm and 1.01-2mm melanomas were comparable within the age groups less than 64 years, as was the case for white women with tumors of these thicknesses. The probability of a man dying was greater than of a woman for any age or thickness category. Conclusions: Melanoma mortality rate trends are nuanced and can vary significantly by age, thickness, and gender. In white men, mortality rates begin to accelerate sharply around the mid-50s age group. Screening efforts should therefore target detecting melanoma in middle-aged males in the in situ or earliest stage.
Immune cell profiling of melanoma metastases from patients treated with TriMixDC-MEL dendritic cell therapy in combination with ipilimumab.
Authors: Schats Kelly , Van Vre Emily A. , Debyser Isolde , Vandenbroeck Arno , Jansen Yanina , Seremet Teofila , Marien Koen , Fransen Erik , Schrijvers Dorien , Van Criekinge Wim , Thielemans Kris , Neyns Bart , De Meester Ingrid , Kockx Mark 
Published: September 2018

e21030 Background: Ipilimumab has proven clinical benefit in a subset of melanoma patients. Previously a high rate of durable complete response was shown with the combination of ipilumumab and TriMixDC-MEL therapy (Wilgenhof et al. JCO 2016). Methods: Melanoma metastases were collected from patients, before initiation of combined ipilimumab and dendritic cell (TrimixDC-MEL) therapy [NCT01302496]. Formalin-fixed, paraffin-embedded samples were available from 24 patients of which 6 had durable benefit (DB) and 18 had no clinical benefit (NB). Serial 4µm slides were stained with immunohistochemistry (IHC) for immune response markers. Semi-automated analysis (Definiens software) was applied to estimate the tumor area stained for CD8, CD20, CD163, OX40, ICOS and LAG3, % of FOXP3 positive T-cells and IRF1-positive tumor nuclei. H-scores were calculated for IDO, STING and MHC-I on tumor cells (TC). A qualified pathologist scored the % PD-L1 on TC and immune cells (IC). In addition, RNA was extracted (n = 19) and analyzed using the NanoString nCounter Pan Cancer immune profiling panel. Results: The IHC and NanoString variables were tested for predictive response, as single marker using logistic regression and the area under the curve (AUC) values. The top 15 biomarkers for either IHC or NanoString are listed in the table below (AUC in descending order). Gene Ontology analysis (GOstat) of Nanostring markers revealed over-representation of genes involved in the response to other organisms (GO: 0051707) and viruses (GO: 0009615) in DB patients. Conclusions: This study identified a set of potentially new predictive biomarkers, including virus response related genes, for DB following ipilimumab plus TriMixDC-MEL therapy. Further prospective validation is warranted. [Table: see text]
Coupling a phenotypic assay-based platform, multi-plex IHC and quantitative pathology to predict anti-tumor efficacy to immune checkpoint blockade in melanoma.
Authors: Radhakrishnan Padhma , Biswas Manjusha , Smalley Munisha , Majumder Biswanath , Berger Raanan , Goldman Aaron 
Published: September 2018

e21041 Background: Emerging clinical evidence using immunotherapy suggests there is extraordinary antitumor potential by releasing the brakes on the immune system. However, clinical responses vary widely among patients, and a majority do not experience positive response. There is a huge unmet need to understand these disparities at the individual patient level. Methods: Here, we describe a quantitative approach to predict the antitumor effect of immune checkpoint blockade using a live-tissue ex-vivoplatform technology, CANscript™, which captures the native 3D tumor microenvironment. Utilizing fresh melanoma resections we interrogated phenotypic changes to the tumor-immune contexture in response to PD-1 and PD-L1 inhibitors in combination and as single agents. To do this, we used a multi-plexed immunohistochemistry (primarily CD8, CD45, FOXP3, CXCR4, CD68, PDL1, PD1, ERK-phosphorylation), and quantification of immune cell migratory potential, which were correlated to antitumor indications such as tumor cell proliferation, and cell death. Results: The data confirmed that CANScript™ preserves the tumor-immune contexture and native heterogeneity across different patients. Importantly, we observed that PD-1 and PD-L1 blockade resulted in patient-specific therapeutic response, which was characterized by differential, quantitatively distinct distribution and infiltration of immune cells, distinct patterning of cytokines linked to functional dysregulation, and changes in tumor proliferation and apoptosis. Interestingly, the data demonstrated unique immune signatures associated with single agent vs. combination therapy, inducing functionally distinct mechanisms in the tumor immune compartment, and disparate antitumor effects within an individual patient tumor. Conclusions: Together, these findings demonstrate that quantitative pathology can help predict therapeutic response of immune checkpoint inhibitors at the individual patient level. Such information can re-shape our understanding of patient selection and rational combinations for novel immune checkpoint inhibitors.
Mutation analysis of mucosal and cutaneous melanomas during progression.
Authors: Palmieri Giuseppe , Colombino Maria , Casula Milena , Lissia Amelia , Botti Gerardo , Scognamiglio Giosuè , Caraco Corrado , Ascierto Paolo Antonio , Fraggetta Filippo , Paliogiannis Panagiotis , Manca Antonella , Sini MariaCristina , Doneddu Valentina , Cossu Antonio 
Published: September 2018

e21047 Background: The prevalence of mutations in driver genes during progression in cutaneous and mucosal melanomas remains inconclusive. We investigated the prevalence and distribution of mutations in main candidate genes involved in melanomagenesis among different melanoma tissues using a next-generation sequencing (NGS) approach. Methods: Forty-eight tumor samples from 36 patients with mucosal melanoma (MM) and fifty-two tumor samples from 34 patients with cutaneous melanoma (CM) were collected, after obtaining patients’ written informed consent for tissue sampling. Genomic DNA was isolated from macrodissected tumor tissues containing at least 80% neoplastic cells and analyzed for mutations in 25 most common melanoma-associated oncogenes and tumor suppressor genes, using the IMI Diagnostic Melanoma Panel on the Ion Torrent platform (Life Technologies, USA). Results: A total of 100 tumor tissues from 70 melanoma patients were analyzed. BRAF mutations were detected in 21/34 (62%) CM patients and 13/36 (36%) mm patients. The second most prevalent mutations were found in K-/N-RAS (6/34; 18%) and cKIT (6/36; 17%) genes among CM and mm patients, respectively. No concomitant mutations of BRAF, RAS, and cKIT genes were detected. Among others, mutations were more frequently found in CCND1 (20%), ARID2 (16%), and NF1(12%) genes, considering the entire series of patients. Vast majority of patients who had paired samples of primary and secondary melanomas showed consistent mutation patterns between primary tumors and metastatic lesions. Similar frequencies of mutations in driver genes were seen across metastatic sites. Conclusions: In the era of targeted therapies, assessment of the spectrum and distribution of mutations in main molecular targets among patients with melanoma is needed. Our findings about the prevalence of mutations in driver genes in paired tumor lesions from patients with cutaneous and mucosal melanoma may be useful in the management of such diseases. The Italian Melanoma Intergroup (IMI) includes the following additional members who participated as investigators in this study: Mario Mandalà, Paola Queirolo, Ignazio Stanganelli, Vanna Chiarion Sileni, Pietro Quaglino, Anna Maria Di Giacomo.
Influence of job assignment on melanoma (MEL) incidence in commercial aircrew.
Authors: Cranmer Lee D. 
Published: September 2018

e21058 Background: Commercial cabin and cockpit aircrews are at increased cutaneous MEL risk. Occupational and social factors have been invoked to explain this. However, the two groups work in on-board environments with different types/levels of potential exposures. Meta-analysis is conducted to address the hypothesis that differences exist in aircrew MEL risk based on location of in-aircraft job assignment, reflecting differential etiologic occupational exposures. Methods: Medline was searched with the keywords “Cancer,” “Aviation,” and “Melanoma.” Included studies: (1) primarily focused on cutaneous MEL; (2) were in commercial aircrew; (3) measured risk vs a general population; (4) measured risk by Standardized Incidence Ratio (SIR) with 95% confidence intervals (CI); (5) defined the gender distribution; and (7) defined cabin vs cockpit job assignment. Summary SIRs and CIs were calculated using maximum-likelihood, random effects meta-analysis. Values obtained were compared to one another using a z-test, with p < 0.05 pre-specified for null hypothesis rejection. Results: 6 primary studies were identified in the initial search. These were screened for other pertinent references. The secondary search yielded an additional 9 primary studies. For cabin crew, 10 study groups from 6 studies were included. 411,561 person-years of follow-up among 28,093 subjects (86% female) were included (SIR 2.18, 95% CI 1.83-2.60). For cockpit crew, data from 9 studies representing 830,670 person-years of follow-up among 45,986 subjects (1% female) were included (SIR 2.44, 95% CI 1.94-3.08). z-test for the difference indicated that the two SIR values were not statistically different ( z= 0.77, p = 0.441). Conclusions: Though cockpit crew demonstrate an increased SIR vs cabin crew, this is not statistically significant. These results suggest that occupational exposures in different locations within commercial aircraft does not influence MEL risk. Other factors, such as cosmic radiation, non-aircraft occupational exposures and avocational exposures, should be the targets of further assessment.
Effect of very small tumor size on cancer-specific mortality in node-positive melanoma.
Authors: Liu Xinyang , Wang Zhichao , Li Qingfeng 
Published: September 2018

e21059 Background: Traditionally, larger tumor size and lymph node (LN) involvement have been considered independent predictors of mortality in melanoma. We aimed to characterize the interaction between tumor size and LN involvement in melanoma specific mortality. In particular, we evaluated whether very small tumor size represented a particularly aggressive disease variant compared with larger LN-positive melanoma. Methods: Using Surveillance, Epidemiology and End Results registry data, we identified 57,223 patients (aged 18-85 years) diagnosed between 1998 and 2012 with histologically confirmed nonmetastatic melanoma treated with surgery. Primary study variables were tumor size, LN involvement, and their corresponding interaction term. Kaplan-Meier methods, adjusted Cox proportional hazards models with interaction terms were performed. Potential confounders included age, sex, year of diagnosis, marital status and number of LN dissected. Results: Median follow-up was 48 months. In multivariable analysis, there was significant interaction between tumor size and LN involvement ( P < 0.0001) using the likelihood ratio test and Wald test. In the absence of LN involvement (n = 54,922), the hazard ratio (HR) increased monotonically with increasing tumor size. Among patients with LN involvement (n = 2,301), using the smallest tumors as the reference group, hazard ratio of cancer specific mortality decreased unexpectedly in 0.01-1.00mm tumors (HR 0.61, p = 0.022) and 1.01-2.00mm tumors (HR 0.58, p = 0.007), and reached to a similar level in tumors sized 2.01-4.00mm (HR 0.81, p = 0.280), and subsequently increased in tumors sized larger than 4.00mm (HR 1.57, p = 0.016). Conclusions: In LN positive melanoma, very small tumors may predict for higher mortality compared with larger tumors. These results should be validated in future database studies. Table. Effect of tumor size in LN positive and LN negative melanoma. [Table: see text]
Non-classical BRAF melanoma: A retrospective review of disease characteristics and prognostic implications.
Authors: Parmar Ambika , Feilotter Harriet , Baetz Tara D. 
Published: September 2018

e21060 Background: Activating mutations in the BRAF gene occur in 40-60% of melanomas with the majority of mutations resulting in V600E/K. Previous cohort studies have identified rates of non-V600E/K BRAF mutations to occur in 5-12% of patients. Despite this, there remains limited evidence characterizing the disease characteristics and outcomes of patients who harbor the non-classical BRAF mutation. Methods: Retrospective review of all melanoma patients treated at a tertiary cancer center that had BRAF mutation testing through targeted sequencing. Three groups of patients were identified and compared with respect to patient and disease characteristics: a) BRAF negative; b) BRAF V600E/K positive; c) BRAF non-V600E/K positive. Results: BRAF testing was performed in 168 melanoma patients of which 101 (60%) were BRAF negative; 55 (33%) were BRAF V600E/K positive; 12 (7%) were BRAF non-V600E/K positive (2 G466E, 1 of each G469E, K601N, K601E, L597Q, L597S, V741I, N594G, D594N, V600R and 1 with both K601N & V600E). Of these, 147 patients had baseline demographic and treatment data available for analysis. BRAF mutations were more common among males (45.6% of men vs. 22.7% of women, p = 0.03). No significant differences between other baseline patient demographics noted. Pathological characteristics revealed a non-significant trend toward poorer prognostic factors with BRAF non-V600E/K patients having increased Breslow depth (7.0 mm vs. 5.0 mm BRAF negative, 4.3 mm BRAF V600E/K) and higher rates of ulceration (71% vs. 44% BRAF negative, 30% BRAF V600E/K). BRAF non-V600E/K patients displayed a non-significant trend toward poorer overall survival (71 months vs. 215 months BRAF negative, 125 months BRAF V600E/K). Conclusions: Non-V600E/K BRAF positive patients appear to display less favorable disease characteristics and outcomes as compared to BRAF negative and BRAF V600E/K positive patients. Non-V600E/K melanoma show limited response to BRAF targeted therapy; however, evidence suggests the presence of non-classical mutations may confer susceptibility to MEK inhibition. Further characterization of non-V600E/K BRAF melanoma may allow for more refined prognostication and treatment decisions.
Role of testosterone synthesized by skin melanocytes in preventing malignant transformation of nevi.
Authors: Frantsiyants Elena Mikhaylovna , Bandovkina Valeria , Pogorelova Yulia A. , Kaplieva Irina V. , Cheryarina Natalia D. , Maksimova Natalia A. , Maksimova Maria I. , Neskubina Irina Valerevna , Trepitaki Lidia K. , Kit Oleg I. 
Published: September 2018

e21066 Background: Melanocytes are involved into the synthesis and metabolism of steroid hormones in the skin. Cutaneous melanoma in 75% of cases occurs in congenital or acquired pigmented nevi. There are no studies comparing local hormonogenesis in nevi and melanomas. The purpose of the study was a comparative analysis of hormone levels in tissues of dysplastic nevi and cutaneous melanoma (pТ1-2N0M0). Methods: Levels of prolactin (PRL), progesterone (P4), total and free testosterone (T and fT), estrone (E1) and estriol (E3) and sex steroid-binding globulin (SSBG) were studied by ELISA in 17 samples of рТ1-2N0M0 melanoma and in 23 samples of dysplastic nevi. Intact tissues (n = 15) obtained from non-cancer patients during surgical treatment was used as the control. Results: Levels of T in nevi, compared to intact tissues, were 1.4 times higher, fT – 8.7 times higher, while SSBG content was 1.9 times lower; E3 was 1.6 times higher, PRL – 1.4 times lower, and levels of E1 in nevi were similar to the values in intact tissues. рТ1-2N0M0 melanomas, compared to intact tissues, demonstrated local androgen imbalance: T levels were decreased by 1.8 times, while fT exceeded the norm by 1.8 times, and SSBG – by 6 times. E1 content increased by 1.6 times, E3 decreased by 2.8 times. The E1/E3 ratio in nevi was reduced by 1.6 times, while in melanoma it was increased by 4.4 times. The T/E1 ratio in nevi was increased by 1.4 times, and in melanoma it was decreased by 2.8 times. Levels of PRL and P4 in melanomas, nevi and in intact tissues did not differ significantly. Conclusions: Melanoma was characterized by hyperestrogenia due to increased levels of E1 and low E3 concentrations which caused malignant transformation of melanocytes. Most likely, in melanoma spent SVT estrone synthesis, as evidenced by increase in the E1 / E3 and decrease T / E1.Apparently, fT in melanoma is used for estrogen synthesis, as indicated by the E1/E3 increase and decrease in the T/E1 ratio. Increased E1 synthesis can contribute to the realization of estrogen genotoxic effects. These mechanisms are absent in tissues of nevi. Hyperandrogenism in nevi probably prevents malignant transformation due to low aromatase activity.