bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel drug to treat advanced melanoma.
Authors: Meng Lingbin , Xu Xiaochun , Xin Ying 
Published: May 2019

e21000 Background: Advanced melanoma is a type of malignant skin cancer without effective treatment. Ginsenoside-Rg3 (Rg3), a saponin component extracted from ginseng roots, has been revealed to have an anti-cancer effect. However, there is limited data about its involvement in advanced melanoma. In this study, we investigated the role of Rg3 in melanoma by evaluating its in-vivo efficacy to inhibit melanoma growth, lung metastasis and melanoma-induced angiogenesis. We also revealed the potential underlying mechanisms by examining ERK and Akt pathways. Methods: 6-week-old C57BL/6 mice were purchased and maintained in our animal center. A highly metastatic subline of murine B16 melanoma cells was kindly provided by Dr. Xiaochun Xu, M.D. Anderson Cancer Center. Five groups were designed for this experiment: control (PBS), 3 groups with different doses of Rg3(0.3mg/kg, 1.0mg/kg, and 3.0mg/kg), and 5-FU (20mg/kg). 7 mice per group were given subcutaneous injection of 2 x 106 melanoma cells on the right flank for xenograft assay. 5 x 105 melanoma cells wrer subcutaneously injected on the right hind footpad for metastasis assay.The formed tumor tissues and lungs were collected for tumor growth and metastasis analysis, immunohistochemical staining, and western blotting. Results: For tumor growth, all the 3 Rg3 groups had smaller size of tumor and reduced expression of PCNA, a marker for cancer cell proliferation. For lung metastasis, the 3 Rg3 groups showed a lower number of tumor colonies with a dose-dependent manner. For angiogenesis, the 3 Rg3 groups displayed suppression of tumor-induced neovascularization through inhibition of VEGF. Western results demonstrated both ERK and Akt pathways were down-regulated in the Rg3 groups. Interestingly, immunohistochemical staining showed a higher number of CD8+ T cell in Rg3 groups lungs, suggesting immune response may be activated to fight against melanoma. Conclusions: Rg3 can decrease melanoma growth and metastasis by down-regulating ERK and Akt pathways. It may also inhibit melanoma metastasis by mediating VEGF-activated angiogenesis. More importantly, Rg3 may activate immune system to fight against advanced melanoma. Our study is the first to indicate Rg3 may be a promising novel drug for advanced melanoma. Based on these results, we are performing a clinical trial to test its efficacy to treat advanced melanoma.
Inhibition of glucose metabolism through treatment of BRAF mutated metastatic melanoma with vemurafenib.
Authors: Warrier Govind , Lanceta Lilibeth , Imbert-Fernandez Yoannis , Chesney Jason Alan 
Published: May 2019

e21005 Background: Increased glucose metabolism is a hallmark of neoplastic cells that allows self-promotion of growth and survival. The enzyme 6-phosphofructo-2-kinase (PFKFB3) is an integral controller of glycolysis by promoting the synthesis of fructose 2,6-bisphosphonate (F2,6BP) which activates 6-phoshofructo-1-kinase (PFK-1), a rate-limiting enzyme and essential control point in the glycolytic pathway. Additionally, mitogen-activated protein kinase (MAPK) is a key signaling pathway in a number of cancers with mutations of the BRAF component, described most commonly in melanoma, resulting in constitutive activation of the MAPK pathway. We aim to demonstrate that vemurafenib, a BRAF inhibitor, has antiglycolytic activity in sensitive melanoma cell lines which may help guide development of future therapies with specific attention to PFKFB3 as a potential enzymatic target to decrease glycolytic flux thereby inhibiting tumor growth and survival. Methods: Vemurafenib sensitive and resistant variants of two separate human metastatic melanoma cell lines (451Lu and WM983) were treated with 3 mM Vemurafenib for 24 and 48 hours. Additionally, cells from aforementioned lines were probed for PFKFB3 after 24 hours of treatment with vemurafenib. Glycolysis was measured by incubating cells in complete media containing 1 mCi [5-3H]glucose for 60 minutes. [3H]H2O produced by glycolysis through enolase was measured. Results: A decrease in PFKFB3 protein expression was found in vemurafenib sensitive cells compared to controls but not in resistant cells after 24h treatment with 3 mM vemurafenib in both 451Lu and WM983 metastatic melanoma cell lines (n = 2). Treatment with vemurafenib led to decrease in glycolysis compared to untreated controls in both vemurafenib sensitive metastatic melanoma cell lines but not in resistant cell lines (n = 5). Additionally, there was a significant reduction in glycolysis in vemurafenib resistant WM983 at 48 hours compared to resistant untreated control. Conclusions: BRAF mutated metastatic melanoma cells showed decrease in PFKFB3 protein expression and decreased glycolysis after treatment with BRAF inhibitor vemurafenib. Future studies will focus on assessing metastatic melanoma cell viability and glycolytic activity after treatment with combination BRAF inhibition and PFKFB3 specific inhibition.
Nivolumab and Pembrolizumab in advanced cutaneous melanoma : Results from real-life data in patients from France— Evaluation of use, current practices and medico economic approach.
Authors: Grude Francoise , Travers Muriel , Moiteaux Brice , Beneton Nathalie , Jacobzone Caroline , Le Corre Yannick , Legoupil Delphine , Plantin Patrice , Porneuf Marc , Sassolas Bruno , Marhuenda Fanny , Deniel Lagadec Delphine , Pracht Marc 
Published: May 2019

e21009 Background: In 2016, Nivolumab (N) and Pembrolizumab (P) have been registred for first line ECOG PS 0-1 adult patients with non-resecable or metastatic melanoma. The Brittany and Pays de la Loire Cancer Observatory has collected data on their real-life indications, current management, safety, efficacy and medico-economics Methods: All non opposing adult patients (pts) with advanced cutaneous melanoma who initiated a treatment with N (3 mg/kg q2w) or P (2 mg/kg q3w) in 2016 and 2017 were included. Minimum follow-up for survival was 12 months. Sex, age, mutation profile, lines of treatment, toxicities, response rate, survival and treatment cost have been collected. Results: 149 pts were treated by N and 201 pts by P with a median age of respectively 68 [21-88] and 69 years [28-96]. Of the 350 patients, 34% were at least 75 years and around 30% presented a BRAF mutation. The median duration of treatment was 4.9 months [0-34.6] for N and 4.2 [0-35.8] for P (Not Significant NS). 65% of pts were treated in 1st line for N and 69% for P. 24% of the pts were treated in 2nd line for both treatments. 81% of the pts had a baseline PS of 0 or 1. All lines combined (first line for wt BRAF and first or second line for m BRAF melanoma), clinical benefit was 53% for N and 47% for P. Median OS was respectively 21.7 m for N and 22.8 m for P (NS). mPFS were respectively 6.4 m and 4.6 m (NS). 18% of pts presented grade III/IV toxicities with N and 17% with P. wt BRAF pts showed more grade III/IV toxicities than m BRAF pts (p = 0.046). For N, pts with grade III/IV toxicities showed better PFS (p = 0.051) and OS (p = 0.064). For both cohorts, PS ≥2, BRAF status and treatment line identified subgroup of pts with worsened PFS and OS 55% (24/44) of pts who stopped N or P because of death had a baseline PS of 0-1 showing PS alone is not sufficient to predict survival. Aggressive diseases (high metastasis rate, cerebro-meningeal metastasis, high tumor growth rate with any previous treatment) appear to be the worse candidates for immunotherapy. N and P courses during the 2 years costed 6.6 and 9.7 millions of euros respectively with approximatively 84% or 79% of this cost for N and P clinically benefitting pts. Conclusions: Immunotherapy in real-life setting in cutaneous advanced melanomas confirms literature’s data regarding clinical benefit, survival rate and safety profile and suggests to think about a composite predictive biomarker including BRAF status, ECOG PS, toxicity and treatment line.
Expression of tryptophan metabolizing enzymes (TMEs) and its transporter, LAT1, in metastatic melanoma (MM): Prognostic and therapeutic implications.
Authors: Trembath Dimitri G. , Googe Paul B. , Frank Jill S. , Kowalski Madeline H , Spearman Marcus , Lagler Taylor Marie , Ezzell Jennifer Ashley , Thomas Nancy E. , Ollila David W. , Moschos Stergios J. 
Published: May 2019

e21014 Background: The ECHO-301/KEYNOTE-252 trial failed to show clinical benefit of adding epacadostat to pembrolizumab in PD-1 inhibitor-naïve MM. We reasoned that the expression of other TMEs and/or LAT1 by melanoma cells plays a more important role. Methods: Melanoma tissues from stage III/IV pts were stained for the 4 TMEs (TPH1, TPH2, TDO2, IDO1) and LAT1 by single-color immunohistochemistry. Tissues were scored for the status of tumor-infiltrating lymphocytes (TILs) and the expression of 5 proteins separately in melanoma cells and TILs (if present). Association between protein expression, TIL status, and melanoma-specific overall survival was performed. Results: Tissues from 87 pts (stage IV, n = 25) were available. Expression of all 4 TMEs and LAT1 was significantly higher in melanoma cells compared to TILs ( p< 0.001); TPH1, TPH2, and TDO2 expression in melanoma cells was significantly higher than IDO1 (p < 0.001). Lower TPH1 expression in melanoma cells was associated with presence of TILs. Multivariate analysis using a Cox proportional hazards model that included expression of the 5 proteins in melanoma cells showed that high IDO1 was a favorable and high LAT1 expression was an adverse prognostic factor. Conclusions: Expression of TMEs and LAT1 by melanoma cells may have more important role in metastatic melanoma by depleting an essential amino acid from the tumor microenvironment. Pharmacologic targeting of TPH1/TPH2 (e.g. telotristat) may be more clinically relevant in MM as opposed to IDO1 inhibition.
Adrenal metastases in malignant melanoma, is it a privileged site?
Authors: Mushtaq Rao Rashid , Gao Dexiang , Raeburn Christopher , Tobin Richard P. , Robinson William 
Published: May 2019

e21016 Background: Currently there is a very limited data reporting response of adrenal metastases to immunotherapy in patients with metastatic malignant melanoma. Certain sites in the body may serve as sanctuary sites due to tumor microenvironment. Lower response rates and shorter PFS are reported in malignant melanoma with liver metastases while higher objective response rates are seen with lung metastases. We hypothesized that adrenal glands are sanctuary sites for melanoma metastases and thus would have poor response to immunotherapy due to steroid production in the adrenals making microenvironment less optimum for the anti-tumor effects of immunotherapy. Methods: A retrospective single-institution chart review of all malignant melanoma with metastasis to adrenal gland treated at University Colorado Hospital from 2008 till 2018, with age ≥ 18 yrs of age who received at least one dose of immunotherapy. Immune-related response criteria (irRC) was used to assess the response to immunotherapy on the imaging. Kaplan Meier estimate, and Chi square test were used for statistical analysis. Results: Sixty-five patients met the inclusion criteria. Mean age of 61 yrs. with range from 25 to 90 yrs. 71% were males and 95% were Caucasians. Median duration of follow up was 51.3 months with range of 1.5-212 months. Forty-three percent were cutaneous, 35% unknown primary, 11% each with mucosal and ocular melanoma. Based on the category of malignant melanoma, 60% were metastatic, 12% nodular, 8% choroidal, 8% superficial spreading, 6% acral lentiginous and 6% other. BRAF mutations were present in 38%, wild type in 54% and unknown in 8%. NRAS was mutated in 18% and wild type in 17% and unknown in 65% of the patients. Comparison of response between adrenal metastasis and non-adrenal metastasis, showed that 71% adrenal metastases had progressive disease compared to 54% of non-adrenal metastases. The overall response rate (ORR) to immunotherapy was 15% in adrenal metastases compared to 20% of non-adrenal metastases. Disease control rate (DCR) was 29% in adrenal metastases compared to 46% non-adrenal metastases with p value = 0.015. Conclusions: The adrenal glands appear to be a sanctuary site for metastases in patients with malignant melanoma receiving immunotherapy. The reasons behind this are unclear but may be related to the microenvironment and local corticosteroid production suppressing the immune response. Preliminary data examining cellular responses in nine surgically removed adrenal metastases support this hypothesis and will be presented.
Progression and hyperprogression after anti-PD1 therapy for unresectable stage III or IV melanoma patients.
Authors: Colle Elise , Dalle Stéphane , Mortier Laurent , Guillot Bernard , Dutriaux Caroline , Leccia Marie Thérèse , Dalac Sophie , Legoupil Delphine , De Quatrebarbes Julie , Montaudié Henri , Arnault Jean-Philippe , Brunet-Possenti Florence , Saiag Philippe , Momenzadeh Mathieu , Dreno Brigitte , Porcher Raphael , Oriano Bastien , Lebbe Celeste 
Published: May 2019

e21021 Background: Primary progression (PP) and secondary progression (SP) to anti-PD1 therapy (APD) are poorly described in advanced melanoma in real life practice. Hyperprogression with a deleterious effect is reported in many cancers but is poorly assessed in advanced melanoma. Methods: Characteristics of 793 patients treated by APD (nivolumab or pembrolizumab) between July 2014 and May 2018 were collected from MelBase, a prospective French biobank (NCT02828202).We considered: group A (progressive disease as best response), group AHP (hyperprogression) within group A patients (progression/death within 3 months with normal initial LDH and ECOG at baseline, and either ECOG increased from 0 to 3-4, either LDH increased from normal to elevated or both), group B SP (response or stable disease then progression). Characteristics for all and survival for patients alive at progression (AAP) were also described. Results: Median follow-up was 11.3 months (Q1-Q3 4.8–23.6). Characteristics at baseline are in the table. In group A, 14% patients died at progression; within 262 patients AAP, 17% continue APD (the same or switch), 15.1% (CI95 11.1-20.6) were alive 1-year after progression (1YAP); 20.5% for patients in first line and 11.5% for pretreated. In group AHP, 41% patients died at progression; within 48 patients AAP, 12% continue APD, 11.1% (CI95 7.8-13.6) were alive 1YAP. In group B, 11% patients died at progression; within 88 patients AAP, 36% continue APD, 10.3% (CI95 5.2-20.1) were alive 1YAP, 15.9% for patients in first line and 7.0% for pre-treated. Conclusions: Our study shows that PP and SP to APD differ at baseline, but have similar survival rates at progression, while mechanisms involved might be different, providing important landmarks to build second line trials. This study thus highlights the existence of hyperprogressors among which 41% patients died within 3 months, as well as describes their associated characteristics. [Table: see text]
Clinical heterogeneity of elderly melanoma patients in the real-world setting: Potential implications for treatment outcomes following immune based therapy.
Authors: Hegde Upendra P. , Parmar Harsh V , Stevenson Christina Elizabeth 
Published: May 2019

e21026 Background: Recent studies have indicated that immune checkpoint inhibitor treatment of metastatic melanoma is effective irrespective of older age. However, in the real world setting, not all older patients (pts.) diagnosed with high-risk cutaneous melanoma have same levels of immune function due to wide variation of older age and aging associated diseases that adversely influence it. Frailty associated with co-morbidities, autoimmunity, cancer, and their treatments are three such conditions that influence treatment outcomes following immune based treatment of melanoma in older subjects. To better understand this interaction between melanoma, aging-associated diseases and potential outcomes following immune checkpoint inhibitor treatment in the real world, we reviewed clinical data of elderly melanoma pts. from the University of Connecticut's Neag Cancer Center following an IRB approval. Methods: We retrospectively reviewed clinical characteristics of elderly pts. diagnosed with high-risk cutaneous melanoma (Stage IIC, III, IV) at the University of Connecticut from 2012-2019. Pts. over the age of 60 years were divided into two main groups: Group I ("Fit elderly") and Group II ("Elderly with immune suppressive conditions"). Group II pts. were further divided into three subgroups: A ("Co-morbidities and frailty"), B ("Autoimmunity and its treatment") and C ("Cancer and its treatment"). Results: From 2012-2019, a total of 56 elderly pts. diagnosed with high-risk cutaneous melanoma were stratified as the following: Group I - 31 pts. (55%) and Group II - 25 pts. (45%); among the Group II pts., Group A contained 14 pts. (56%), Group B 5 pts. (20%), and Group C 6 pts. (24%). The median age for all 56 elderly pts. was 77 yrs. (range 61 to 99). In Group I, the median age was 73 yrs. (range 61-91). In Group II, the median age was 82 years (range 66-99); A median age 85 yrs (range 66-99), B median age 78 yrs (range 66-86), and C 80.5 yrs. (range 66-86). 9 out of 56 pts. (16%) did not receive immune checkpoint inhibitor treatment, of which 7 pts. (56%) were frail and 2 pts. (22%) were non-frail. Conclusions: Our data indicate that the existence of significant clinical heterogeneity among high-risk elderly melanoma pts. encountered in the community setting reflects a wide spectrum of immune function. Larger studies stratifying elderly subjects by co-morbidities and immune suppressive conditions will help shed accurate light on clinical relevance of immune based treatment of melanoma in older subjects.
Combined BRAF and MEK Inhibition in Patients with unresectable or metastatic cutaneous melanoma: A meta-analysis of randomized controlled trials.
Authors: Biedny Adam , Chahine Adam , Abdalla Ahmed , Sidahmed Shima , Kheiri Babikir , Kafri Zyad , Hadid Tarik H. 
Published: May 2019

e21030 Background: Malignant melanoma is a dangerous disease with increasing incidence. Over the past several years, medical advancements have allowed for markedly improved therapeutic options. In patients with BRAF V600E or V600K mutations, the use of various BRAF inhibitors in combination with MEK inhibitors have been approved for stage III unresectable and metastatic disease. Therefore, we aimed to evaluate the efficacy and safety of this combination in comparison to a single agent BRAF inhibitor. Methods: A comprehensive electronic database search was conducted for all randomized controlled trials (RCTs) comparing the clinical outcomes of combination BRAF inhibitor and MEK inhibitor versus BRAF inhibitor alone in patients with unresectable stage III or stage IV BRAF-mutated malignant melanoma. The primary outcome was progression-free survival (PFS). Secondary outcomes included overall survival (OS), overall response, and various selected adverse events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included five RCTs with 2,113 total patients, with a mean age of 55.5 years and 56.1% male. The combination therapy of BRAF and MEK inhibitors showed superior results with regard to PFS (HR 0.57; 95% CI: 0.50-0.67; p < 0.001), OS (HR 0.69; 95% CI: 0.61-0.78; p < 0.001), and overall response (HR 1.32; 95% CI: 1.23-1.43; p < 0.001) when compared to BRAF inhibitor alone. Additionally, patients treated with combination therapy had a lower incidence of cutaneous squamous cell carcinoma (Risk Ratio: 0.22; 95% CI: 0.10-0.47; p < 0.001) and arthralgia (Risk Ratio 0.34; 95% CI: 0.15-0.74; p < 0.001). Patients who received combination therapy, however, had a higher incidence of diarrhea (risk ratio 2.53; 95% CI: 1.05-6.09; p = 0.04) and pyrexia (risk ratio 4.98; 95% CI: 2.27-10.92; p < 0.001). Conclusions: For patients with unresectable stage III malignant melanoma or metastatic malignant melanoma, combination therapy with BRAF inhibitor and MEK inhibitor was associated with superior PFS, OS, overall response, and lower incidence of cutaneous squamous cell carcinoma and arthralgia compared with BRAF inhibitor alone. The combination therapy, however, was associated with a higher incidence of diarrhea and pyrexia.
​obesity and metastatic melanoma: A national perspective from the pre-immune checkpoint inhibitor era.
Authors: Desai Aakash , Parmar Harsh V , Hegde Upendra P. 
Published: May 2019

e21032 Background: There is an ongoing debate about correlation of obesity with favorable outcomes in patients with metastatic melanoma receiving treatment. Our study measured the differences in in-hospital outcome parameters such as length of stay (LOS), cost and mortality in patients with metastatic melanoma with respect to obesity. Methods: We used National Inpatient Sample (NIS) dataset from 2008 to 2014 to identify the diagnosis of Metastatic melanoma (ICD-9 code:172.9) among hospitalized patients. Data was matched and weighted to obtain a nationally representative sample for analysis. The AHRQ comorbidity measure of obesity was utilized to identify obesity as a coexisting medical condition that is not directly related to the principal diagnosis. Categorical and continuous variables were tested using Chi-square test and Student t-test respectively. Multivariate hierarchical regression was used for the analysis of primary outcomes of interest. Results: We identified a total of 1,809 cases of metastatic melanoma from 2008 to 2014. Among them, 908 (50.19%) were obese and 901 (49.80%) non-obese. 195 out of the 1,809 (10.77%) patients were treated with high dose infusion of IL-2. Overall, the mean LOS (≈6.03 days [non-obese] vs ≈5.72 days [obese], p = 0.949) and mean cost of hospitalization (16720.28$ vs 17639.95$, p = 0.428; mean difference of 919.67$) was not significantly different based on obesity as a comorbid condition. The mortality rate was found to be significantly lower in obese patients (41% vs. 59%, p = 0.017), but did not reach statistical significance on logistic regression analysis (OR:0.95, p = 0.130). Further subgroup analysis of patients with metastatic melanoma who received high dose IL-2, we found no significant differences in mean LOS (5.03 vs 7.03, p = 0.14) as well as mean cost of hospitalization (27432.72$ vs 41881.13$, p = 0.485) between non-obese and obese patients. However, the in-hospital mortality for patients undergoing high dose IL-2 therapy could not be studied given no cases of in-hospital mortality occurred in this subgroup. Conclusions: Our study demonstrates that there are no significant differences in in-hospital outcomes for patients with metastatic melanoma with respect to obesity, even in the subgroup of patients treated with IL-2 immunotherapy. Thus, there is a need for further studies to adequately understand the exact biological mechanism of obesity in metastatic melanoma, the influence of obesity on immunotherapy outcomes and its translation into patient care outcomes.