bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survival in patients with unresectable melanoma: To infinity and beyond?
Authors: van Not Olivier Jules , van den Eertwegh Alfonsus Johannes Maria , Haanen John B. A. G. , Blank Christian U. , Aarts Maureen J.B. , van den Berkmortel Franchette , de Groot Jan Willem , Hospers Geke , Kapiteijn Ellen , Bloem Manja , Piersma Djura , van Rijn Rozemarijn , Stevense - den Boer Marion , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Boers-Sonderen Marye J. , Blokx Willeke , Wouters Michel , Suijkerbuijk Karijn 
Published: June 2023

e21504 Background: The introduction of checkpoint inhibitors and targeted treatment has led to significant improvements in prognosis for melanoma patients over the last years. We aimed to evaluate the survival per year of diagnosis. Methods: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the nationwide Dutch Melanoma Treatment Registry. Baseline characteristics, overall survival (OS), and melanoma-specific survival (MSS) were compared between the different years of diagnosis of unresectable melanoma. Results: In total, 6324 patients were included. Over the years, the age at start of treatment gradually increased. Patients treated in 2020 and 2021 more often had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2 and synchronous metastatic disease (table). The percentage of patients receiving systemic treatment did not change over the years. Median OS gradually increased from 11.3 months (95%CI 10.1-12.5) for patients diagnosed in 2013 to 33.3 months (95%CI 28.8-37.4) for patients diagnosed in 2019. Remarkably however, median OS was lower for patients diagnosed in 2020 and 2021 (24.8 months; 95%CI 21.1-28.2 and 18.8 months; 95%CI 17.6-NR). When excluding previously adjuvant-treated patients or looking at synchronous metastatic melanoma only, the same trends were seen. Similarly, differences in MSS mirrored our OS findings. Median OS and MSS can be found in the table. Conclusions: After a continuous survival improvement for advanced melanoma patients between 2013-2019, outcomes in 2020 and 2021 are remarkably poorer. The decreased performance status at the start of systemic treatment suggests that COVID-related delays might have played a role. [Table: see text]
Trends in overall survival in 133 cases of balloon cell melanoma: An NCDB analysis.
Authors: Wu Xinxin , Keirns Darby , Hsia Beau , Silberstein Peter T. 
Published: June 2023

e21508 Background: Balloon cell melanoma (BCM) is a rare, malignant subtype of melanoma characterized by large, foamy melanocytes lacking pigmentation with a low overall 5-year survival rate of 37.5%. The incidence of melanoma is increasing at a greater rate than other types of cancer, but the cases of this subtype remain low. Demographic factors were analyzed via the National Cancer Database (NCDB) in an attempt to mitigate the knowledge gap in BCM diagnoses. The primary site at presentation and the effects of demographic factors on overall survival are described. Methods: A retrospective cohort analysis utilizing the NCDB from 2004 to 2020 included patients diagnosed with histologically confirmed BCM (N = 133). Socio-demographic factors (sex, age at diagnosis, race, facility type, and insurance type) were analyzed for frequency. A multivariate analysis of factors was performed on overall survival via the Kaplan–Meier Method (p = 0.05). Results: Since 2004, the number of cases diagnosed with BCM has steadily decreased (R2 = 0.204). The average age at diagnosis was 58.17 years (SD = 17.3). Most patients were male (63.9%), White (94.0%), treated at a non-academic center (56.4%), and had government insurance (96.1%). On multivariate analysis, age, race, and insurance type had statically significant effects on overall survival (p < 0.001). Patients that were older at diagnosis had poorer overall survival (p < 0.001, CI = [1.022 - 1.075]). Black patients were 4.6 times more likely than White patients to have suffered death (p < 0.001, CI = [23.586 - 450.230]). Patients without insurance were more likely to die than patients with government insurance (p < 0.001, CI = [0.026 - 0.229]). The average time from diagnosis until death was 143.1 months (SD = 8.0) with a 1-year and 5-year survival rate of 92.0% and 72.2%, respectively. Conclusions: This is the first study analyzing trends and demographic features relating to BCM in the NCDB. Due to the low survival rate of this cancer, understanding the risk factors affecting overall survival serve as a valuable clinical tool for prognostic evaluation. This database analysis suggests that the survival rate of BCM might be higher than previous literature suggests. The differences in BCM treatment on overall survival were not described in this study. Future research should aim to evaluate other prognostic factors, such as treatment, on survival.
Outcomes of patients with advanced NF1-mutant melanoma treated with MEK inhibitors.
Authors: Wang Lin , Kim Kevin B. , Kashani-Sabet Mohammed , Dighe Prasad R. , Aboosaiedi Ali 
Published: June 2023

e21513 Background: Mutations in neurofibromin 1 ( NF1) constitute the third most frequent driver mutation in melanoma, occurring in approximately 15% of patients. NF1 is a tumor suppressor gene that negatively regulates the MAPK pathway by inactivating RAS through the hydrolysis of RAS-GTP to the inactive form, RAS-GDP. Preclinical studies have demonstrated that NF1 mutations induce the activation of the MAPK pathway through constitutively maintaining the active form of RAS protein, and that MEK inhibitors cause growth arrest of NF1-mutant melanoma in vitro and tumor regressions in vivo. Methods: We conducted a retrospective analysis to evaluate the outcomes of patients with NF1-mutant melanoma who were treated with MEK inhibitors using our institutional melanoma database. We searched for all melanoma patients whose melanoma was analyzed with next generation sequencing (NGS), and their clinical, pathological and molecular characteristics were examined along with the details of MEK inhibitor treatment and clinical outcomes. Results: Among 229 patients whose melanoma was analyzed with the NGS, we identified 32 patients whose melanoma harbored a pathogenic or likely pathogenic NF1 mutation, of which four were treated with trametinib. The clinical, molecular characteristics and the outcomes of the 4 patients are summarized in the table. All had previously experienced disease progression following anti-PD1 antibody therapy. One patient with metastatic mucosal melanoma had a confirmed partial response to trametinib treatment with time to progression of 18 months. Two patients had regression of the metastatic lesions at the initial tumor response evaluation, but due to significant toxicity, treatment was discontinued. Their disease progressed within 3 months after treatment discontinuation. Two patients with initial tumor regression had a mucosal primary melanoma. Interestingly, the patient with a prolonged response had the highest variant allele frequency (VAF) of NF1 whereas the early progressor had the lowest VAF (Table). All responders (including the unconfirmed responders) had a VAF of >35%. Conclusions: Despite the small sample size, our findings suggest a potential promising efficacy of trametinib in the setting of NF1-mutant melanoma, particularly those with high allelic frequency, thereby providing a strong rationale for a prospective study to evaluate the clinical efficacy of MEK inhibitors in this molecular subtype of melanoma. [Table: see text]
A dual institution real-world study of avelumab for advanced Merkel cell carcinoma.
Authors: Miller David Michael , Wright Kayla , Silk Ann W. , Thakuria Manisha , Shalhout Sophia 
Published: June 2023

e21514 Background: Merkel cell carcinoma (MCC) is a rare, aggressive, cutaneous neoplasm with an increasing incidence rate and poor prognosis. The treatment landscape has changed dramatically over the last half decade, beginning with the 2017 approval of the anti-programmed death-ligand 1 (PD-L1) monoclonal antibody avelumab. Accelerated approval for avelumab was based on data from the JAVELIN Merkel 200 study, which demonstrated an objective response rate (ORR) of 33% in previously treated subjects (≥2L). In the first-line (1L) clinical-trial setting, avelumab was associated with an ORR of 40% and a durable response rate (DRR) of 30%. There are limited data regarding the efficacy of avelumab in the real-world setting. Methods: We performed a Mass General Brigham (MGB) Institutional Review Board-approved retrospective study of patients with advanced MCC. Clinical data regarding the disease course, including diagnosis and treatment, were collected from the Electronic Health Record and stored in a REDCap database. Response category was assigned based on the text of the radiology reports and clinician notes. Analysis was performed in R. Results: 1249 patients with MCC were identified; 260 received systemic therapy; 54 were treated with avelumab (our primary analysis cohort, PAC). Median age of the PAC was 74 years. 80% were male. 83% had an initial ECOG of 0 or 1. 20% were immunosuppressed at the time of MCC diagnosis. The real-world response rate (rwORR) for all patients treated with avelumab was 45.83%. rwORR in the 1L was 53.57% and 35% in the second line and beyond. The median duration of treatment response in the 1L was 518 days and 144 days for ≥2L. Median progression-free survival was 158 days and 95 days, and median overall survival was 553 days and 323 days for 1L and > 2L, respectively. Conclusions: Our study provides important data about the real-world treatment of patients with advanced MCC. The response rate and progression-free survival were consistent with those observed in other real-world studies as well as the clinical trials. While the subjects studied in previously published studies differ from that in MGB cohort, the overall body of literature continues to demonstrate positive outcomes attributable to avelumab monotherapy in both the 1L as well as second-line or beyond and in patients with competent, as well as compromised, immune systems. Limitations of this study include its retrospective nature. Furthermore, given the small sample size, we are limited in making statistical inferences from the current data set and specific results may not be generalizable to all patients with MCC.
Multi-modal and longitudinal characterization of the tumor and immune microenvironment from primary to in-transit and distant metastasis in acral melanoma.
Authors: Tarantino Giuseppe , Zaremba Anne , Vallius Tuulia , Rambow Florian , Pelletier Roxanne , Makhzami Samira , Zimmer Lisa , Sucker Antje , Livingstone Elisabeth , Hadaschik Eva , Lian Christine , Murphy George , Sorger Peter , Liu David , Schadendorf Dirk 
Published: June 2023

e21518 Background: Patients with in-transit metastases (ITM) in melanoma are a heterogeneous subset of patients where melanoma recurrence is anatomically detected between the site of the primary tumor and the draining lymph node. Notably, a significant subset of those patients has locoregional recurrences with long-term survival without progression to distant sites. The underlying mechanisms responsible for these distinct phenotypes are unknown. Methods: To understand the evolution from primary melanoma to in-transit and distant metastasis, we characterized the tumor and immune microenvironment among 9 patients with acral lentiginous melanoma using whole exome sequencing (WES), bulk RNAseq, snRNAseq and high-plex Cyclic Immunofluorescence (CyCIF) imaging. We further profiled the dynamics and the evolution of the tumor and immune compartments using 28 tumor samples obtained longitudinally over 9 years from a single patient (pt222) with recurrent in-transit and distant metastases undergoing CDK4/6, MEK inhibition and immune checkpoint blockade. Results: Our cohort included 5 patients that progressed from ITM to distant disease and 4 patients with only local recurrence and without distant progression (Table). WES profiling identified enriched RAS mutations (5 out of 9), independent of progression and treatment response. Pt222 showed multiple morphological features related to aggressive tumor growth and high risk of recurrence such as clefting, ulceration detected within the primary tumor by the histopathological assessment of the H&E section. Phylogenetic analysis revealed co-evolution of 7 genetic lineages that shared 35 clonal mutations, including NRAS p.Q61H, with independent resistance-associated alterations. The metastases at distant sites emerged from a lineage featured with high aneuploidy and tumor mutational burden (TMB). The brain metastasis showed the highest TMB and aneuploidy. Bulk RNAseq deconvolution, snRNAseq, CyCIF and H&E revealed low and heterogeneous immune composition among different samples and lineages with macrophages and DCs as dominant populations. Interestingly, we did not observe the lineage characterized by the highest absolute immune infiltrates after ICB treatment. Another specific lineage that disappeared after the treatment with ICB showed angiotropic growth and the over-expression of a WNT-betacatenin transcriptional signature linked with T cell exclusion. An orthogonal validation using bulk RNAseq, snRNAseq and CyCIF confirmed these findings. Conclusions: This study helps define a high-resolution map of the evolutionary dynamics from primary to in-transit and distant metastasis. [Table: see text]
Immune checkpoint inhibitors in advanced cutaneous squamous cell carcinoma: Real-world evidence.
Authors: Koch Hein Erica C. , Vilbert Maysa , Hirsch Ian , Ribeiro Mauricio Fernando , Mantle Luke , Fournier Cynthia , Butler Marcus O. , Spreafico Anna , Saibil Samuel 
Published: June 2023

e21519 Background: Immune checkpoint inhibitors (ICI) Cemiplimab and Pembrolizumab have revolutionized the treatment of advanced cutaneous squamous cell carcinoma (cSCC). We aimed to evaluate efficacy and safety of ICI in a real-world cSCC population, including patients with conditions which would exclude trial participation. Methods: In this single-center retrospective cohort study, we included all non-trial patients with advanced cSCC treated with ICI between 2017 and 2022. We aimed to assess efficacy outcomes according to age, comorbidities, and immune-related adverse events (irAE). Best overall response (BOR) was investigator-assessed. X2, Fisher’s exact, and Mann-Whitney U tests were used to compare subgroups of interest, and Cox proportional hazards models were fitted. The log-rank test was used to assess progression free survival (PFS) and overall survival (OS). Results: We identified 35 patients. Characteristics are displayed in the table. Median follow-up was 21.8 months (95% CI 19.3-24.4). BOR to ICI was partial response (PR) in 42.9%, complete response (CR) in 28.6%, and stable disease in (SD) 14.3% of patients. Main reasons for discontinuation of treatment were progression of disease (PD) in 20%, achievement of maximum benefit in 17.1%, and toxicities in 14.3%. Treatment beyond progression was given to 22.9% patients. The PFS rate at 1 year was 62%; median PFS was not reached (NR). PFS and OS were similar between patients with or without comorbidities, ECOG performance status 0-1 versus 2-3, or between age groups ≥75 years versus <75. IrAE grade 1-2 and 3-4 were seen in 80% and 14.3% of patients, respectively. Patients with grade 1-2 irAE had greater PFS than those without toxicities (HR 0.16; 95%CI 0.045-0.567, p=0.005). The OS rate at 1 year was 76%, with a median OS of 38.57 months (95% CI 19.4-57.7). Responders (CR+PR) had a prolonged median OS compared to non-responders (SD+PD): 38.57 months versus 9 months (HR 0.083; 95%CI 0.17-0.406, p=0.002). Conclusions: ICI were effective and safe among real-world cSCC patients, independent of age, comorbidities or ECOG. Our BOR was higher than in the published clinical trials, which might reflect the subjective nature of investigator-assessed response or the small sample size assessed. [Table: see text]
Meta-analysis of efficacy outcome measures across immune checkpoint inhibitors (ICIs) and targeted therapies (TTs) in melanoma to guide future clinical trial design.
Authors: Ousey James , Ahadieh Sima , Di Pietro Alessandra , Sturtz Keren , Williams Jason H. , Fetterly Gerald 
Published: June 2023

e21520 Background: Systemic treatments (Tx) for unresectable or metastatic melanoma include TTs and ICIs, with TT+ICI combinations under exploration. Heterogeneity in clinical trial sample size and subject characteristics pose obstacles for treatment class comparisons. We applied meta-analysis to elucidate Tx and covariate effects on efficacy outcomes in melanoma. Methods: A PICOS-guided literature search was conducted from 2000-2022 for TT or ICI given as monotherapy or in combination for unresectable or metastatic melanoma. Median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR) were recorded. Random-effects models were fit to endpoints with study arms weighted by variance. Covariate inclusion was based on likelihood-ratio tests (P < 0.05). For simulation, parameter distributions from weighted linear regression (wi ~ nstudy) of mPFS to ORR were sampled (N = 5000) with residual error scaled by mean Phase 3 arm size. ORR uncertainty was modeled by normal approximation. Results: From 134 publications, 100 (mPFS), 73 (mOS), and 111 (ORR) outcomes were retained, from 53, 44, and 63 studies, respectively, and classified by treatment. For all endpoints, Tx classification was an outcome predictor (P< 0.001). BRAFi+MEKi+PD-1 combination therapy had the greatest predicted duration of mPFS (16.7 months [11.8, 23.6]) and ORR (62.8% [53.7%, 71.1%]). mPFS and mOS outcomes were reduced by prior Tx failure and evidence of brain metastases, with mOS also impacted by elevated lactate dehydrogenase. I2 statistics for the final models were 89.0% (mPFS), 73.9% (mOS), and 51.8% (ORR). A robust correlation between ORR and mPFS (R2= 0.77, P < 0.001) was observed across all treatment classes. The predictive power of this relationship was demonstrated by simulating the probability of achieving target Phase 3 mPFS outcomes from ORR derived from as few as 20 patients. Conclusions: This meta-analysis characterizes the shifting space of Tx in unresectable or metastatic melanoma and provides a model-based framework for simulation of efficacy endpoints and trial designs for TT+ICI combinations. ORR-based predictions of trial success illustrate the value of utilizing early endpoints to inform decisions in drug development, across all Tx options in melanoma. Further investigation will include longitudinal PFS and OS modeling and refinement of PFS predictions from tumor growth metrics and clinical benefit rate.
Trends, predictors and impact of atrial fibrillation on inpatient outcomes among malignant melanoma patients: A 5-year National Inpatient Sample (NIS) study.
Authors: Olafimihan Ayobami Gbenga , Kanemo Philip Onyekaoso , Jackson Inimfon , Litvin Rafaella , Turk Ekrem , Vakil Jay , Cuartas Mesa Maria Cristina , Ibrahim Muhammad Bilal , Batra Kunnal 
Published: June 2023

e21525 Background: Malignant melanoma (MM), a very aggressive cancer, is associated with the highest mortality rate among dermatologic malignancies. Atrial fibrillation (AF) is the most common cardiac arrhythmia. Very little is reported in the literature on the association between both diseases, and there is marked paucity of studies comparing outcomes in patients with concomitant MM and AF. Methods: Retrospective cohort analyses were performed using the National Inpatient Sample (NIS) data collected between 2016 and 2020. Multivariable logistic and linear regression models were used to examine the predictors of AF and inpatient outcomes among MM patients. Results: Out of 9,760 hospitalizations with a diagnosis of MM, the overall prevalence of AF was 13.3% with an increasing trend from 10.1% in 2016 to 16.4% in 2020. MM patients with AF had similar odds (adjusted odds ratio (AOR) = 0.9; 95% confidence interval (CI) = 0.451.61) of inpatient all-cause mortality when compared to those without atrial fibrillation. However, they were more likely to have longer hospital stays (beta coefficient (β) = 1.27; 95% CI = 0.392.0) and total hospital charges (β = $12,830; 95% CI: $7041.4$25426.4) when compared to their counterparts without atrial fibrillation. Furthermore, patients with AF had a double likelihood (AOR: 1.90; 95% CI: 1.252.90) of developing an acute kidney injury (AKI). We also found that female MM patients were 50% (AOR: 0.50; 95% CI: 0.360.68) less likely to have a diagnosis of AF relative to their male counterparts. Similarly, Hispanic MM patients were significantly less likely (AOR: 0.06; 95% CI: 0.0080.459) to have AF in comparison to Non-Hispanic White patients. Conclusions: There is an increasing trend of comorbid atrial fibrillation in patients hospitalized for malignant melanoma, and this is associated with longer hospital stays and higher total hospital charges. These findings highlight the need for surveillance to enable early detection of atrial fibrillation in this population.
Trends, sociodemographic and hospital-level factors associated with inpatient palliative care utilization among malignant melanoma patients: A 5-year National Inpatient Sample (NIS) study.
Authors: Olafimihan Ayobami Gbenga , Jackson Inimfon , Vakil Jay , Kanemo Philip Onyekaoso , Litvin Rafaella , Obeidat Khaldun , Turk Ekrem , Ibrahim Muhammad Bilal , Gajjar Rohan , Batra Kunnal 
Published: June 2023

e21526 Background: Palliative care improves the quality of life in cancer patients; however, there is no literature on specific factors that predict its use in patients with malignant melanoma. We explored the prevalence trends, and predictors of palliative care utilization among hospitalized patients with malignant melanoma. Methods: Retrospective analyses were conducted using the National Inpatient Sample (NIS) data collected between 2016 and 2020. Descriptive analyses and multivariable regression models were used to investigate the prevalence trends, and sociodemographic and hospital-level factors associated with palliative care utilization in hospitalized malignant melanoma patients. Results: Of the 9,760 hospitalizations with a diagnosis of malignant melanoma over the study duration, 14% utilized palliative care during their hospital stay. Overall, 9.2% of malignant melanoma patients used palliative care and were discharged alive. There was a stable trend of palliative care use over the 5-year period (14%). Compared to patients on Medicare, those on Medicaid were twice (adjusted odds ratio (AOR): 2.12; 95% confidence interval (CI): 1.263.64) more likely to utilize palliative care. Relative to other regions in the US, patients hospitalized in the West were 40% less likely to receive the service of the palliative team (AOR: 0.61; 95% CI: 0.38-0.96). Those admitted to teaching hospitals (AOR: 0.55; 95% CI: 0.40-0.77) had lower odds of having palliative care consultations when compared to non-teaching hospitals. Patients admitted to urban hospitals had 50% (AOR: 0.51; 95% CI: 0.270.98) lesser odds of getting palliative care when compared to their counterparts in rural hospitals. Individuals who were either discharged to a facility/with home health (AOR: 8.81; 95% CI: 5.8813.23) or died during hospitalization (AOR: 128.42; 95% CI: 72.10228.77) had higher odds of utilizing palliative care when compared to those with a routine discharge. Conclusions: The prevalence of palliative care utilization was low, and factors associated with utilization in our population were identified. Our findings emphasize the necessity to improve awareness among medical oncologists and primary inpatient teams on the importance of involving the palliative care service early in the management of hospitalized patients with malignant melanoma.