bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of metastatic acral lentiginous melanoma: Systematic review.
Authors: Ospina Serrano Aylen Vanessa , Segovia Javier , Pino Luis Eduardo , Triana Ivan Camilo , Rojas Santiago 
Published: June 2021

e21536 Background: Acral lentiginous melanoma (AML) is infrequent malignant melanoma subtype (5%) .It does not have specific treatment. The objective of this article is to summarize the best available evidence regarding the specific treatment of metastatic acral lentiginous melanoma. Methods: A systematic review of the literature was proposed. A search was carried out in the databases of Pubmed, Embase, Scopus, Lilacs in English and Spanish, during the last 20 years. The equation used was ((“acral lentiginous melanoma”) AND (“Treatment”)). For quality assessment, the JAMA guidelines for qualifying and globally through the GRADE system, the Cochrane guideline for evaluation of clinical trial bias was used. The review process involved 3 researchers and differents filters for evaluating the scientific evidence. The primary outcome was overall survival (OSm) and progression-free survival (PFS) as a secondary outcome. Results: 208 articles were found, only 3 articles were included. No phase 3 clinical trial. The summary of the data and qualification of evidence are in Table. In total there were 63 patients. It was found high heterogeneity in the 3 studies. The outcomes were those reported directly from each study, a subgroup analysis was not required. In first study, overall survival 21.1m was found with Dasatinib and PFS 2.8m. The second clinical trial, found OS with Nivolumab of 28.7% at 3 years. The last study was observational, and included three different treatment options, the outcomes were: Chemotherapy OSm 8.3m and PFS 2.1m, Immunotherapy OSm 16.6m and PFS 11.4m and Targeted therapy OSm 21.7m and PFS 11.4m. Conclusions: Worldwide, there is no good quality scientific information to define the best specific treatment for acral lentiginous melanoma. Current available evidence suggests that treatment with targeted therapies such as c-kit, V600E or immunotherapy as some useful options. Link Prospero: CRD42020171528.[Table: see text]
Machine learning imputation of metastatic status from open claims in melanoma patients.
Authors: Vaidya Vivek Prabhakar , Prajapati Rambaksh , Manirevu Sai Vinod , George Rohini , Agrawal Smita , Narayanan Babu 
Published: June 2021

e21540 Background: Metastatic status is a crucial variable in most oncology studies but is not available in claims data. The objective of this study is to develop a machine learning model for Imputation of metastatic status from claims data with ground. Truth is derived from highly curated electronic medical record data. Methods: We used a set of 11389 melanoma patients from the ConcertAI real world database of intersecting claims and EMR data that includes data from CancerLinQ Discovery. Using features from claims and our gold standard labels from EMR we built an ML model using (XGBoost) extreme gradient boosting, an algorithm that iteratively combines a set of decision trees into a single model. We used 60% of the data for training, 20% for hyper-parameter tuning, and 20% for holdout testing. The model was built using 55 features. Results: The table below summarizes results. Metrics are on the final hold out set which was unseen by the model and entirely composed of highly curated EMR data. Conclusions: We are able to build a high precision model for the imputation of metastatic melanoma status using claims data. This could enable significantly better use of claims data stemming from the ability to find a metastatic cohort with very few false positives. Providing more precise cohort identification for comparative effectiveness studies. We found features such as secondary neoplasm diagnosis, anti-neoplastic meds, and radiation ranking highly in our analysis of model feature importances. Using techniques to analyze non-linear feature interactions in our AI model we found an interaction relationship between long term anti-neoplastic therapy, reported pain and metastatic status which we plan to further study. This work is preliminary and we are working to further improve model performance.[Table: see text]
Treatment beyond progression with immune checkpoint inhibitors in advanced melanoma.
Authors: Sobczuk Pawel , Czarnecka Anna Malgorzata , Spalek Mateusz , Teterycz Pawel , Dudzisz-Śledź Monika , Switaj Tomasz , Rogala Pawel , Placzke Joanna , Kozak Katarzyna , Borkowska Aneta , Kosela-Paterczyk Hanna , Rutkowski Piotr 
Published: June 2021

e21541 Background: Immunotherapy (ITH) holds the possibility of tumor burden decrease after initial RECIST defined progression (PD). Clinical concept of treating of selected patients (pts) beyond PD is supported by this pseudoprogression phenomenon. The aim of this study was to evaluate real-life practice and outcomes related to treatment beyond progression (TBP) in melanoma patients. Methods: We evaluated advanced melanoma pts who started anti-PD1 treatment between 12/2015 and 12/2018 and identified pts who received TBP and had subsequent imaging to evaluate the tumor burden. Survival analyses were performed using the Kaplan-Meier method, Log-rank, chi-square and Fisher exact tests were used for comparison between groups. Data cut-off was 02/2021. Results: Of 399 subsequent melanoma pts treated, 57 (14%) patients received TBP. Anti-PD1 was 1st line treatment in 61.4% and 2nd line - in 38.6% of patients. 71.9% patients were diagnosed with skin, 7.0% - mucosal and 21.1% with FPI melanoma and 47.4% were BRAF mutated, 56.1% were male and 12.3% had 3 or more metastatic sites at treatment initiation. In this cohort median time to 1st PD (TTFP) was 4.43 months(m), while to 2nd PD (TTSP) – 8.01 m. On TBP 26.3% pts achieved objective response (OR), and next 42.1% - SD. 1st PD was reported most often as increase in 3 or more targets or one new lesion – both 22.8%; and in 24.6% cases involved central nervous system. In 56.8% second PD was observed in the same targets as 1st PD. 61.4% patients received multimodal treatment of ITH combined with radiation therapy – in 49.1%, surgery - 5.3% and both - 7.0%. There was no correlation of TTSP with gender, ECOG, initial disease stage or TNM, BRAF mutation, number of metastatic sites or pattern of progression. Multimodal treatment resulted in 13.6 m TTSP, while ITH alone - 8.0 m (p = 0.056). 1st line OR correlated with DCR on TBP while TTFP > 6 m correlated with TTSP (HR = 0.53, 95%CI 0.28-0.99). Patients with 1st line CR – had median TTSP 16.4 m, with PR – 23.5 m, while those with PD – 5.1 m. Median OS after 1st PD was 26 months and correlated with OR on TBP. Conclusions: Selected clinically fit melanoma patients despite evidence of first radiographic progression may benefit from continued treatment with PD-1 inhibitors. Multidisciplinary treatment should be offered to these patients including radiosurgery or stereotactic radiotherapy of progressing loci. Molecular biomarkers of TTSP should be analyzed in prospective studies.
Using precision microbiome profiling to develop a biomarker for immune checkpoint inhibitor response and a novel therapeutic.
Authors: Robinson Mat , Vervier Kevin , Popple Amy , Harris Simon , Hudson Robyne , Adams David , Rabbie Roy , Milne Doreen , Booth Catherine , Welsh Sarah Joanne , Bruce David , Corrie Philippa Gail , Lawley Trevor 
Published: June 2021

e21546 Background: Four independent groups have demonstrated that the pre-treatment gut microbiome of cancer patients impacts the subsequent response to Immune Checkpoint Inhibitor (ICIs) therapy [1-4]. However, the patient’s outcome was linked to different bacteria in each study, which has limited the development of drug response biomarkers and clinic-first design of novel microbiome-based therapeutics. Methods: The Cambridge (UK) MELRESIST study includes a cohort of advanced melanoma patients receiving approved ICIs. Pretreatment stool samples from MELRESIST were analysed by Microbiotica using shotgun metagenomic sequencing. Microbiotica’s platform comprises the world’s leading Reference Genome Database to give the most comprehensive and precise mapping of the gut microbiome. Results: MELRESIST samples showed an overall difference in the microbiome composition between advanced melanoma patients and healthy donors, but not between patients who did or did not respond to ICIs. However, we did identify a discrete microbiome signature that differentiated responders and non-responders with an accuracy of 93%. We extended this signature by reanalysing three published melanoma cohorts [1-3] using the Microbiotica platform, and a propriety bioinformatic model. The resultant bacterial signature was very accurate at predicting response in all 4 published studies combined (91%), and each cohort individually (82-100%). We validated the model using independent validation cohorts and the signature using lung and renal cancer studies [4]. At the core of our microbiome signature was 9 bacteria most significantly associated with ICI efficacy. All 9 were overrepresented in patients who responded to immunotherapy suggesting high abundance of these bacteria is a central driver of ICI response. A consortium comprised of all 9 strains had very potent anti-tumor efficacy in a cancer syngeneic mouse model. The bacteria also demonstrate multiple interactions with primary human immune cells in vitro leading to dendritic cells activation, Cytotoxic T lymphocyte activation and tumor cell killing. These validate the potential of this consortium as a novel therapy for use in combination with ICIs. Conclusions: We have identified a unique microbiome signature predictive of ICI response in 4 independent melanoma cancer cohorts. This removes a major challenge to the field, and could represent a new highly accurate biomarker with clinical application. Nine core bacteria appear to be driving response, and demonstrate anti-tumor activity in vivo and in vitro. This consortium holds great potential as a co-therapy with ICIs. References:1 Matson V et al, Science (2018) 359:104; 2 Gopalakrishnan V et al, Science (2018) 359:97; 3 Frankel AE et al, Neoplasia (2017) 19:848; 4 Routy B et al, Science (2018) 359:91.
Recurrent disease in patients with stage III melanoma in the era of adjuvant immune and targeted therapy.
Authors: Lo Victor , Francescutti Valerie , McWhirter Elaine , Farrokhyar Forough , Lee Linda May 
Published: June 2021

e21570 Background: Advancements in systemic therapy have reduced recurrence, and the adoption of nodal surveillance in place of dissection has reduced morbidity for patients with Stage III melanoma. The objective of this study was to describe the timing and pattern of recurrence in stage III melanoma patients and evaluate the impact of adjuvant treatment and nodal surveillance. Methods: A multicenter retrospective chart review of patients with pathologically confirmed Stage III cutaneous melanoma seen at either the Juravinski Cancer Centre or Walker Family Cancer Centre in Ontario, Canada from January 1, 2017 to December 31, 2019. Results: There were 137 patients with Stage III melanoma: 18% IIIA, 22% IIIB, 52% IIIC, and 8% Stage IIID as per the 8th American Joint Committee on Cancer (AJCC) 2018 staging system. 103 (75%) patients had sentinel lymph node biopsy (SLNB) only as part of initial surgical therapy, 6 (4%) had SLNB with completion dissection, and 25 (18%) had upfront radical nodal dissection. 67 (49%) patients received adjuvant therapy, of which 50 (74%) had immunotherapy, 17 (25%) received BRAF-targeted therapy, and 1 (1%) had interferon. 54 (39%) patients developed recurrent disease, with a median time to recurrence of 8.5 months (IQR: 4.3-14.9). The recurrence rates were 63% in patients who did not have adjuvant treatment and 37% in those who had adjuvant therapy, with a median time-to-recurrence of 7.5 and 9.0 months respectively. There were 30 (56%) loco-regional recurrences and 24 (44%) distant recurrences. Of the patients with loco-regional recurrence, 26 (87%) had SLNB only compared to 4 (13%) who had upfront or completion dissection. 12 (24%) patients recurred while on adjuvant treatment (7 distant recurrences and 5 loco-regional recurrences), and 8 (13%) patients recurred following completion of adjuvant treatment (5 distant recurrences and 3 loco-regional recurrences). Recurrences were detected by patients, clinicians, CT and nodal US surveillance in 43%, 20%, 28% and 9% of cases, respectively. The majority of loco-regional recurrence was detected clinically (67%) rather than by radiologic surveillance (33%). Of the 30 loco-regional recurrences, 24 underwent surgical resection of the recurrence, 4 had subsequent systemic therapy without surgery, 1 had intra-tumoral injections and 1 had no treatment. Conclusions: Recurrences in Stage III melanoma occur early, often within a year, with higher rates of loco-regional rather than distant disease. Recurrence rates were lower in those who received adjuvant therapy, but the majority of recurrences were detected by patients or clinicians, including loco-regional recurrences in patients who had SLNB only despite surveillance nodal US.
BRAF testing timelines and impact on the starting of systemic treatment.
Authors: Arteaga Diana Paola , Saeed Kamil Zaid , Pimentel Muniz Thiago , Liu Diane , King Ian , Stockley Tracy , Gray Diana , Saibil Samuel , Hogg David , Spreafico Anna , Butler Marcus O. 
Published: June 2021

e21575 Background: Targeted therapy with BRAF and MEK inhibitors constitute part of the standard treatment for BRAF V600 mutated melanoma. Timely detection of BRAF mutation is necessary for clinicians and patients to make treatment decisions. We aimed to map the BRAF testing timelines from the time of request until the reported result in order to assess obstacles to timely BRAF reporting in our community, and its impact on the initiation of systemic therapy. Methods: In this single-center retrospective study, we included adult patients referred to the Medical Oncology Department at the Princess Margaret Cancer Centre (PM) from January 2019 to August 2019 with histologically confirmed cutaneous or mucosal melanoma and BRAF molecular testing performed in 2019. The Log-Rank method was applied to detect differences in BRAF turnaround time and time to treatment initiation in specified subgroups. A p value < 0.05 was considered statistically significant. Results: Sixty-six cases were identified. The median age was 64 (24-88), and 42 (64%) were male. At the time of BRAF request, 10 (15%) patients had stage II, 33 (50%) had stage III, and 23 (35%) had stage IV disease. Twenty-eight (43%) were positive for the BRAF V600E/K mutation by ARMS assay and 4 (6%) for other variants by NGS test. Thirty-three (50%) patients had the BRAF test available at their first PM Medical Oncology visit. Median time between BRAF request and result was 17 days; when a reflex BRAF test was ordered by the Pathology Department, the median turnaround time was 12 days (95% CI 8-15), compared to 20 days (95% CI 16-23) if the order was requested by another specialist ( p < 0.001). Median time to transfer samples between institutions was 6 days. If the BRAF test was processed within the institution where the biopsy was performed, the BRAF median turnaround time was 13 days (95% CI 6-19) compared to 19 days (95% CI 16-21) if a sample was transferred to another institution ( p = 0.02). In total, 49 patients had systemic therapy. Median time between the first visit with Medical Oncology and treatment initiation was 29 days and was not statistically different if the BRAF result was available or not (28 vs. 34 days; p = 0.09). In the subgroup with stage IV disease (Table), 20 patients received systemic therapy; the median time to treatment initiation was 24 days and differed with BRAF result availability (20 vs. 31 days, p = 0.03). Conclusions: The current BRAF testing timeline at the PM varies from days to weeks. A major factor impacting this timeline is transfer time, which can be streamlined by pathology reflex testing. Delays in turnaround time appears to impact subsequent timing and type of therapeutic interventions, especially in patients with stage IV disease.[Table: see text]
Somatic mutations predict immune-related adverse events (irAEs) and survival following CTLA4 blockade in melanoma patients.
Authors: Shah Savan , Yu Xiaoqing , Teer Jamie K. , Conejo-Garcia Jose , Lyons Maureen , LaFramboise William , Tarhini Ahmad A. 
Published: June 2021

e21584 Background: Predicting immune-related adverse events (irAEs) resulting from immune checkpoint inhibitors (ICIs) as well as the likelihood of clinical benefit is an area of great interest. irAEs have been associated with clinical outcome measures and we were interested in examining somatic mutations that may correlate with irAEs and subsequently with relapse free survival (RFS) and overall survival (OS). Methods: Our irAEs of interest for this analysis were rash and colitis based on prior data and these were tested for association with RFS and overall OS. Nonsynonymous somatic mutations were identified utilizing tumor and matched blood samples from 22 metastatic melanoma patients treated with neoadjuvant ipilimumab. Whole exome sequencing was performed using the SOLiD 5500 Next-Generation Sequencing platform. Somatic mutations were identified by subtraction of germline variants. Total mutational burden was assessed, and individual mutations were correlated with irAEs and with clinical outcome. Results: MUC16 was the most commonly mutated gene (82%). Of notable known oncogenic mutations, BRAF was the most common (50%) followed by NRAS (23%). Among known oncogenic signaling pathways, enrichment was most common in RTK-RAS (58%), followed by NOTCH and WNT. Development of colitis showed a strong trend in association with RFS. Development of rash indicated a similar trend. 20 different statistically significant mutations (p < 0.05) were identified among patients with colitis and these were also associated with OS and RFS. Notably, PTPRO mutation status (known to antagonize PDL1 expression) appeared protective against colitis and associated with worse RFS and OS. Similarly, ADGB mutation was significantly associated with developing rash and also associated with improved RFS and OS. Correcting for TMB in a multivariate model confirmed the associations. Conclusions: Somatic mutations were found to be associated with the irAEs of rash and colitis and with clinical outcome following ipilimumab treatment of melanoma. Our findings warrant further investigation and validation in independent cohorts.
High expression of ferroptosis-sensitizer ACSL4 as an indicator of good response to immune checkpoint inhibitors and preferable survival with increased TIICs in skin cutaneous melanoma.
Authors: Wu Jinchun , He Zhengxi , Liu Xianyu , Mou Yanhua , Lu Jingchen , Duan Chaojun , Li Bin 
Published: June 2021

e21594 Background: Skin cutaneous melanoma (SKCM) has a high incidence and mortality. Immune checkpoint inhibitors (ICIs) are promising but show heterogeneous efficacy in the SKCM treatment. T cell-promoted tumor ferroptosis is a vital anti-tumor mechanism of ICIs. Acyl-CoA synthetase long chain family member 4 (ACSL4) can sensitize ferroptosis by facilitating lipid peroxidation. So we proposed that ACSL4 is a positive predictor for ICIs efficacy and correlated with tumor-infiltrating immune cells (TIICs) in SKCM. Methods: The responses of SKCM patients to ICIs were evaluated from Tumor Immune Dysfunction and Exclusion (TIDE) using the gene expression data of The Cancer Genome Atlas (TCGA)-SKCM downloaded from UCSC Xena browser and datasets within TIDE. The correlation between ACLS4 expression and survival was obtained from the Online consensus Survival webserver for Skin Cutaneous Melanoma (OSskcm) and TIDE databases. The relationships between ACSL4 and TIICs were evaluated using the database of Tumor Immune Estimation Resource 2.0 (TIMER2.0). Results: ACSL4 expression was positively correlated with the predicted responder of ICIs in TCGA dataset (R = 0.12, p = 0.0093) and therapy outcomes of ICIs in Gide2019_PD1+CTLA4 (Progression-free survival(PFS), contimuous z = -2.39, p = 0.0169) and Lauss2017_ACT (PFS, contimuous z = -2.08, p = 0.0371; overall survival(OS), contimuous z = -2.96, p = 0.00309). Favorable OS was observed in the patients with high ACSL4 expression in the TCGA (HR = 0.6567, 95% CI = 0.5015̃0.8599, p = 0.0022) and GSE19234 (HR = 0.4135, 95% CI = 0.1748̃0.9784, p = 0.0445) from OSskcm and the GSE8401 (contimuous z = -2,24, p = 0.025) and GSE54467 (contimuous z = -2.26, p = 0.0239) from TIDE database. TIICs including CD8+ T cells, CD4+ T cells (memory, Th2), B cells, neutrophils, monocytes, M1 macrophages, and cancer-associated fibroblasts (CAFs) were positively associated with the expression level of ACSL4. Conclusions: High ACSL4 expression maybe indicates a good response to ICIs and long survival in SKCM. The increased T cells within the tumor microenvironment correlated with high ACSL4 expression possibly implied the synergism effects of ferroptosis and ICIs, deserving further investigation. Keywords: ACSL4, ICIs, TIICs, SKCM.
CD8+ T-cell lymphocyte infiltration predict clinical outcomes Wilms’ tumor.
Authors: Rahbar Mahtab , Mardanpour Keykhosro , Mardanpour Sourena 
Published: June 2021

e22001 Background: The abundance and location of CD8+ tumor-infiltrating lymphocytes demonstrate important facets of the anticancer immune response. CD8-expressing lymphocytes have been used in immunotherapy for multiple cancers. This study aims to determine the association between the abundance and localization of CD8+ tumor-infiltrating lymphocytes and clinical outcomes Wilms’ tumor. Methods: This retrospective study employed 42 pediatric patients diagnosed with Wilms’ tumor. CD8+ tumor-infiltrating lymphocyte counts were calculated based on the mean percentage of stroma occupied by CD8+ lymphocytes at the center and the invasive border of the tumor using immunohistochemistry. Results: CD8+ tumor-infiltrating lymphocyte counts were significantly higher in the center and the invasive border of the early-stage tumor samples. CD8+ tumor-infiltrating lymphocytes in the invasive border and tumor center positively correlated with tumor invasion, regional lymph node invasion, histological type, metastasis, and stage of the tumor. A high CD8+ tumor-infiltrating lymphocyte scores at the invasive margin of the tumor correlated with low tumor recurrence. Low CD8+ tumor-infiltrating lymphocyte scores in the two tumor regions correlated with poor prognosis and shorter disease-free survival. Conclusions: Overall, these findings show that patients with high CD8+ tumor-infiltrating lymphocytes are associated with better clinical outcomes. Therefore, measuring the abundance of CD8+ tumor-infiltrating lymphocytes may be useful in predicting response to cancer immunotherapies.