bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of population-based EGFR testing in metastatic non-small cell lung cancer in Alberta.
Authors: Brenner Darren R , O'Sullivan Dylan E. , Jarada Tamer N. , Yusuf Amman , Boyne Devon J , Mather Cheryl A , Box Adrian , Morris Donald , Cheung Winson Y. , Mirza Imran 
Published: June 2022

e21139 Background: While Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors have been shown to be effective in phase III randomized trials, the value of targeted therapies have been challenging to evaluate at the population level. We examined the impact of population-level EGFR testing and treatment on survival outcomes among metastatic Non-Small Cell Lung Cancer (NSCLC) patients. Methods: Real-world, population-level data were collected from all de novo metastatic non-squamous NSCLC patients in Alberta, Canada from 2004 to 2020. EGFR testing data were collected through Alberta Precision Laboratories using various text mining approaches. Differences in survival rates and overall survival (OS) pre (2004-2012) and post-initiation (post) (2013-2019) testing periods were evaluated using interrupted time series analyses. The impact of testing and subsequent treatment weas evaluated using multivariable Cox Proportional Hazards models. Results: In total, 4,578 metastatic NSCLC patients with a confirmed non-squamous cell carcinoma histology were diagnosed pre- EGFR testing and 4,457 patients were diagnosed post- EGFR testing (2013-2019). Among patients diagnosed in the pre- EGFR testing period, the 6-month, 1-year, and 2-year survival probabilities were 0.39 (95% CI: 0.38-0.41), 0.22 (95% CI: 0.21-0.23), and 0.09 (95% CI: 0.08-0.10), while the survival probabilities for patients diagnosed in the post- EGFR testing period were 0.45 (95% CI: 0.43-0.46), 0.29 (95% CI: 0.27-0.30), and 0.16 (95% CI: 0.15-0.1 7), respectively. After adjusting for baseline patient and clinical characteristics, OS in the post- EGFR period was significantly improved compared to the pre- EGFR period (HR: 0.81; 95% CI: 0.78-0.85). In the post-EGFR period, among patients who were treated with systemic therapy, those tested for an EGFR mutation had significantly greater survival than patients who were not tested HR of 0.81 (95% CI: 0.70-0.95). Conclusions: These results show the considerable impact of population-based molecular testing and subsequent targeted therapies on survival among advanced NSCLC patients. The estimates here can be used in future studies to evaluate the population-level cost-effectiveness of testing and treatment.
Anlotinib combined with pemetrexed and carboplatin as first-line treatment in driver-gene negative advanced non-squamous non-small cell lung cancer: ALTER L012.
Authors: Wang Qiming , He Zhen , Yang Xiuli , Ma Tianjiang , Yang Qiumin , Zhang Chenghui , Chen Yunfang 
Published: June 2022

e21147 Background: Anlotinib is a novel multitarget tyrosine kinase inhibitor and can be conveniently orally administered. In the phase III trial ALTER 0303, anlotinib significantly improved overall survival (OS) and progression-free survival (PFS) in advanced NSCLC patients. The study aimed to explore the efficacy and safety of anlotinib combined with carboplatin and pemetrexed followed by anlotinib combined with pemetrexed maintenance in advanced EGFR/ALK wild-type non-squamous non-small-cell lung cancer (nsq-NSCLC). Methods: This multicenter (n = 6), single-arm clinical trial recruited patients with wild-type EGFR/ALK advanced nsq-NSCLC who received first-line therapy between March 2019 and February 2021. Patients received anlotinib (12 mg p.o., QD d1 to 14, 21 days per cycle) combined with pemetrexed (500 mg/m, iv, d1, Q3W) + carboplatin (AUC = 5, iv, d1, Q3W) for 4 cycles followed by anlotinib and pemetrexed maintenance until disease progression (PD). The primary endpoint was PFS. Secondary endpoints are OS, objective response (ORR), disease control rate (DCR) and safety. Results: Between Mar 2019 and Feb 2021, 44 patients were enrolled and 38 of them have received at least one tumor assessment. The median age was 62 (range: 33-75) years. Most of the patients were non-smoker (68.4%). The median follow-up was 13.6 (range: 12.3-14.9) months. Median PFS was 10.5 (95%CI: 4.1, 17.0) months, and median OS was 23.4 (95%CI: NE, NE) months. The DCR and ORR were 94.7% and 60.5%, respectively. Twelve participants had treatment-related adverse events (TEAEs) of grade > 3. The most common Grade 3 AEs were hypertension (23.7%), neutropenia (19.4%), and bone marrow hypocellular (10.5%). Seven patients discontinued treatment, including two during induction and five during maintenance. No grade 5 TRAE was recorded. In the non-smoker participants, the median PFS was 14.5 (95%CI: 4.0-25.0) months. Conclusions: This study finds that anlotinib plus pemetrexed and carboplatin followed by anlotinib plus pemetrexed maintenance therapy might be a promising treatment for patients with wild-type EGFR/ALK advanced nsq-NSCLC. The combination was well tolerated, and the AEs were manageable. Clinical trial information: NCT03790228.
Characterization of molecular subtypes of melanoma and development of prognostic and immunotherapy-related genetic characteristics by ferroptosis gene analysis.
Authors: Xu Libin , Mu Tianhao , Wang Weiyu , Yu Sheng Ji , Zhang Yu , Liu Ting , Luqiang Wang , Zhao Zhenguo , Xinxin Zhang , Xiaoyang Li , Wu Wence 
Published: June 2022

e21508 Background: The heterogeneity is a major problem in clinical treatment of skin cutaneous melanoma (SKCM). Objective and reproducible classification systems may help decode SKCM heterogeneity. Methods: Based on ferroptosis-related genes, this study used unsupervised clustering to identify two molecular subtypes of SKCM C1 and C2. A ferroptosis-related prognosis risk score (FPRS) model was constructed through analyzing the differences between C1 and C2 subtypes. Results: C1 showed a poor prognosis, with low infiltration degree of immune cells and TIED score were lower and higher homologous recombination defects, fraction altered, number of segments and copy number amplification and deletion. These characteristics of C2 were the opposite of C1. SKCM patients were divided into two risk groups based on FPRS. There were significant differences in the infiltration and proportion of immune cells, expression of immune checkpoint genes, and response to immune checkpoint therapy and sensitivity to chemotherapeutic drugs between high-risk group and low-risk group. Conclusions: In summary, we have identified two subtypes of SKCM with different molecular and immune characteristics based on ferroptosis-related genes, further developed and verified a FPRS model, which can be used as an independent prognostic indicator for SKCM. This study may provide a new insight for the development of personalized management of patients with SKCM.
Relationship between IL-1β and IL-8 serum concentrations in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Orlova Rashida , Malkova Anna , Zhukova Natalia V. , Kaledina Ekaterina , Demchenkova Alexandra , Naymushina Polina , Sharoyko Vladimir 
Published: June 2022

e21510 Background: Melanoma is a disease that is most often treated with immune checkpoint inhibitors (ICI). The principle mechanism of ICI is based on the activation of the antitumor immune response. This therapy is not effective in all patients, which may be due to the immunosuppressive effect of tumor microenvironment (TME). IL-1β is one of the most important participants in the TME, however, it is difficult to determine it in blood serum, in contrast to IL-8, the synthesis of which is induced by IL-1β. The study aims to determine the relationship between IL-1β and IL-8 in patients with metastatic (mts) melanoma and to reveal their diagnostic significance. Methods: The study involved 28 patients (pts) with mts melanoma taking ICI. The level of IL-1β and IL-8 in blood serum was determined using the ELISA method. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC, Wilcoxon matched-pairs signed rank test, Spearman statistical analysis. Results: IL-1β was detected in 35.5% (11/31) of patients before therapy, while an elevated level was recorded in only one patient. IL-8 was found in all patients, an elevated level before therapy was observed in 64.5% (20/31) of cases, after 2-3 months - in 35.5% (11/31). During ICI therapy, a statistically significant decrease in the concentration of IL-1β (p = 0.0498) and IL-8 (p = 0.0002) were observed. In the presence of IL-1β, the level of IL-8 was statistically higher (139.6±65.26 pg/ml), p = 0.024, while a mean positive correlation was found between IL-1β and IL-8 concentrations (R = 0.6469, p = 0.035). According to ROC analysis (Area = 0.76), with an increase in the concentration of IL-8 more than 42.31 pg/ml with a diagnostic sensitivity of 66.67% and a specificity of 90.00%, it can be assumed that the level of IL-1β will be detected in the patient (p = 0.025). Conclusions: According to the study, with an IL-8 concentration of more than 42.31 pg/ml in patients with mts melanoma, the presence of IL-1β in the blood serum can be expected. At the same time, the level of IL-8 correlated with the level of IL-1β. It can be assumed that high level of IL-8 may indicate the overexpression IL-1β in TME and it`s high activity, which may be associated with the possible risk of low ICI efficacy.
Two checkpoint inhibitor combinations in patients with cutaneous melanoma: A systematic review of clinical trials.
Authors: Aiman Wajeeha , Dad Ullah Mati Ullah , Ali Mukarram Jamat Jamat , Khan Iman Waheed , Choudhry Mina , Chaudry Hafsa , Anwar Aqsa , Avula Sreekant , Anwer Faiz , Ali Muhammad Ashar 
Published: June 2022

e21530 Background: Melanoma is a cancer of melanocytes and has the potential to metastasize to distant organs. Immune checkpoint inhibitors (ICI) enhance the immune response against cancer cells. Programmed cell death protein-1 (PD-1), PD-ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene (LAG-3) are the common targets of ICI. Blocking two pathways can have an additive/synergistic effect. This systematic review will assess the efficacy of two ICI combinations in cutaneous melanoma. Methods: A search was performed on PubMed, Embase, and clinicaltrials.gov. We used the following mesh and Emtree terms, “Melanoma” AND “Immune checkpoint inhibitors,” from the inception of literature till 01/15/2022. We screened 11,287 articles and included 4 randomized clinical trials (N = 1,948) and 6 single-arm clinical trials (N = 438) in this review. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and irrelevant clinical trials. Results: In 10 clinical studies (N = 2,386), two ICI combinations were assessed in adult patients with melanoma. Nivolumab (nivo) + ipilimumab (ipi), relatlimab (rela) + nivo, pembrolizumab (pemb) + ipi, lag525 + spartalizumab (spa), fianlimab (fian) + cemiplimab (cem) and single drug/placebo were used to treat 560, 365, 223, 42, 48, and 1,148 patients, respectively. 2,119, 70, and 197 patients had advanced untreated, PD-1/L1 refractory, and resectable stage III/IV melanoma. The response rates (RR) and survival rates are given in table. Conclusions: Two ICI combinations of nivo, ipi, and rela were more effective than monotherapy in patients with untreated advanced melanoma. In early phase trials, combinations of ipi, nivo, pemb, lag525, spa, fian, and cem were effective in advanced melanoma. Nivo, ipi, and rela were effective in patients with resectable melanoma. Pemb+ipi was effective in patients with PD-1/L1 refractory melanoma. More randomized double-blinded clinical trials are needed to confirm these results.[Table: see text]
Outcomes in patients with resected stage IIIA melanoma treated with adjuvant nivolumab or monitored with observation: A real-world study.
Authors: Pavlick Anna C. , Amin Asim , Moser Justin C , Poretta Tayla , Sakkal Leon Alan , Moshyk Andriy , Klink Andrew J. , Schuler Tammy , Feinberg Bruce A. 
Published: June 2022

e21534 Background: Nivolumab is approved in the United States and other countries as an adjuvant treatment for patients with completely resected stage III–IV melanoma based on results of the phase 3 CheckMate 238 trial, though the trial enrolled a limited number of patients with stage IIIA disease (AJCC-8). The objective of this real-world study is to describe characteristics, treatment patterns, and outcomes of patients with resected stage IIIA melanoma (AJCC-8) treated with adjuvant nivolumab or monitored with observation. Methods: In this retrospective, chart-review study, physicians from Cardinal Health’s proprietary Oncology Provider Extended Network (OPEN) extracted data from electronic health records of patients who had undergone complete surgical resection of stage IIIA melanoma between Jan. 1, 2018, and Dec. 31, 2019. Recurrence-free survival (RFS) and overall survival (OS) were evaluated from the date of resection and compared between the adjuvant nivolumab and observation cohorts using log-rank tests and adjusted Cox proportional hazards models (covariates included age, sex, race, region, payer type, ECOG PS, and Charlson Comorbidity Index). Discontinuations and deaths due to adjuvant nivolumab toxicity were assessed. Results: This study included 171 patients treated with adjuvant nivolumab and 38 patients monitored with observation. In the adjuvant nivolumab and observation cohorts, respectively, mean age was 57.4 and 68.1 years; most patients were male (59% and 68%) and white (90% and 87%); and median follow-up from resection was 20.7 and 25.0 months. Sentinel lymph node tumor burden of < 1 mm was reported in 12% (n = 20) and 16% (n = 6) of patients in the adjuvant nivolumab and observation cohorts, respectively. The scheduled treatment course with adjuvant nivolumab was completed by 91% of patients (n = 155). RFS and OS rates were numerically higher with adjuvant nivolumab than with observation (Table). There was a trend toward RFS and OS benefit with adjuvant nivolumab versus observation (unadjusted RFS HR 0.53, 95% CI 0.26–1.09; adjusted RFS HR 0.62, 95% CI 0.28–1.40; unadjusted OS HR 0.55, 95% CI 0.19–1.57; adjusted OS HR 0.81, 95% CI 0.25–2.61). Discontinuation of adjuvant nivolumab due to toxicity occurred in 2% of patients (n = 4); no treatment-related deaths were reported. Conclusions: These real-world results confirm that patients with resected stage IIIA melanoma (AJCC-8) have a good prognosis. Treatment with adjuvant nivolumab may provide modest survival benefit over observation in this population, though increased sample size and additional follow-up are warranted.[Table: see text]
Is the BRAF mutation still an unfavorable risk factor in patients with metastatic melanoma in the era of modern therapies?
Authors: Cybulska-Stopa Bozena , Czarnecka Anna Malgorzata , Ostaszewski Krzysztof , Piejko Karolina , Zietek Marcin , Dziura Robert , Rutkowska Ewa , Galus Łukasz , Calik Jacek , Sałek-Zań Agata , Zemelka Tomasz , Kamycka Agnieszka , Bal Wieslaw , Kubiatowski Tomasz , Rogala Pawel , Switaj Tomasz , Kaminska-Winciorek Grazyna , Suwiński Rafał , Mackiewicz Jacek , Rutkowski Piotr 
Published: June 2022

e21544 Background: BRAF-mutated (MUT) melanoma is characterized by specific clinical features including more aggressive biological behavior than BRAF wild-type (WT) melanoma. BRAF mutations are historically known as negative prognostic factor for to shorter overall survival (OS) in patients with stage IV disease with melanoma. Methods: Consecutive patients with unresectable or metastatic melanoma started treatment with BRAF inhibitors (BRAFi), BRAFi and MEK inhibitors (MEKi) or IT (anti-PD-1 antibody) between 1/Jan/2013 and 31/Dec/2020. Clinical factors including age, gender, primary location of melanoma, ECOG performance status, baseline LDH level, and location of metastases, response to treatment were analyzed. Survival analyses were performed using the Kaplan-Meier method, Log-rank and chi-square tests were used for comparison between groups. Data cut-off was 31/Dec/2021. Results: In total 1456 patients were enrolled. BRAF mutation was found in 723 (49.7%) patients and 733 (50.3%) patients were BRAF WT. All BRAF WT patients received first-line IT, while BRAF MUT patient received first-line treatment with BRAFi (n = 134/723, 18%), BRAFi and MEKi (n = 426, 58%) or anty-PD-1 (n = 173, 24%). BRAF MUT patients were significantly younger (median 60 vs 69; p < 0.0001), had worse ECOG (p = 0.0008), elevated LDH (p < 0.0001), had higher number of metastatic sites (p < 0.0001) and brain metastases (p < 0.0001). The estimated median OS (mOS) in BRAF WT group was 17.3 month while in BRAF MUT - 14.8 months (p = 0.33; HR = 0.94, Cl 95% 0.8-1.1). mOS in BRAF MUT group treated with BRAFi was - 10.0, while with BRAFi and MEKi combination - 14.9. BRAF WT and BRAF MUT groups treated with IT did not differ significantly in baseline characteristics. BRAF MUT group treated with IT achieved mOS of 26.2 months, while in BRAF WT 17.3 months. Conclusions: The analysis showed no differences in the median OS between BRAF MUT and BRAF WT patients with unresectable or metastatic melanoma treated with novel therapies (BRAFi-MEKi combination or IT), despite unfavorable prognostic factors in the BRAF MUT group. Moreover mOS was significantly prolonged in the BRAF MUT patients treated with IT.
Assessment of tissue and blood tumor mutational burden in patients with melanoma using a 523-gene clinical assay.
Authors: Giardina Tindaro , Humphries Timothy , Reid Anna , MesbahArdakani Nima , Robinson Cleo , Millward Michael , Gray Elin , Amanuel Benhur 
Published: June 2022

e21570 Background: High tumor mutation burden (TMB) predicts improved efficacy of immune checkpoint inhibitors (ICIs) across a range of malignancies, including melanoma. Circulating tumor DNA (ctDNA) has emerged as a powerful complement to tumor biopsies for the diagnosis and clinical management of cancer patients. The TruSight Oncology 500 (TSO500) clinical assay interrogates 523 cancer-related genes and has shown good concordance between tissue and ctDNA using a high throughput sequencer such as NovaSeq. There are no studies looking at concordance and utility of this assay using more affordable mid throughput platforms. Here we present a pilot study comparing TSO500 sequencing results from matched tumor and plasma specimens and concordance of selected actionable gene variants investigated by ctDNA digital PCR. Methods: Samples from 18 metastatic cutaneous melanoma patients with matched formalin-fixed, paraffin-embedded (FFPE) tumor tissue and plasma collected in Streck tubes had DNA extracted for library preparation using the Illumina TSO500 NGS assay with inputs of ≥40ng of FFPE DNA and ≥10ng of ctDNA. Libraries were sequenced on a NextSeq2000 P3 flow cell to achieve recommended sequencing depth of 800 million reads per sample. A TMB cut off ≥10 mut/Mb was used as high TMB. Droplet digital PCR (ddPCR) was performed for orthogonal validation of selected clinically significant somatic mutations. Results: Sequencing on the NextSeq2000 achieved an average of 797 million pass filter reads per sample and somatic variant allele frequency (VAF) sensitivity down to 0.12%, which exceeded vendor recommendations. There was 75% concordance on the TMB classification (low and high values, Cohen’s k = 0.714) based on tumor and plasma (r = 0.86, p < 0.01) on 8 paired samples (extended analysis will be presented). Some high TMB cases carried POLE or POLD1 variants. Actionable variants identified by ctTSO500 in 15 cases were confirmed by ddPCR, with an outstanding concordance of their VAF (R2= 0.99, p < 0.0001). Diagnosis of tier I/II actionable variants (21 variants; 81% accuracy) was achieved in 7 matched tumor tissue and blood samples. Some variants found in tumor tissue were not detected in the blood. Conclusions: This pilot study demonstrates the clinical utility of the TSO500 ctDNA panel using an affordable mid throughput sequencing platform to identify actionable variants and TMB from blood specimens with high sensitivity and specificity. Testing of a larger cohort of matched tumor and plasma samples will serve to evaluate the clinical utility of the TSO500 ctDNA panel as a complement or alternative strategy to tissue biopsy for the genomic profiling of melanoma patients.
Clinical and biologic predictors of response to MIBG therapy: A report from the new approaches to neuroblastoma therapy (NANT) consortium.
Authors: Vo Kieuhoa Tran , Matthay Katherine K. , Groshen Susan G. , Chi Yueh-Yun , Granger Meaghan , Park Julie R. , Marachelian Araz , DuBois Steven G. 
Published: June 2022

e22003 Background: 131I-metaiodobenzylguanidine (MIBG) remains one of the most active agents for neuroblastoma. The clinical and biologic predictors of response to MIBG therapy have not been systematically characterized in a recent era trial. Methods: Patients 1-30 years were enrolled on the randomized phase 2 trial of MIBG vs. MIBG/vincristine/irinotecan vs. MIBG/vorinostat for relapsed/refractory neuroblastoma (NANT2011-01, NCT02035137) between 2014-2019. Data were compared between those who had an objective response (partial response or better using NANT response criteria) to MIBG after the first cycle and those who did not according to clinical features (age at study enrollment; sex; response to prior therapy; prior receipt of MIBG therapy; bone marrow involvement at study enrollment; and measurable disease status at study enrollment) and MYCN status. Univariate analyses were performed using odds ratio and Fisher exact tests. Multivariate logistic regression analysis was used to identify predictors of response to MIBG therapy while controlling for key confounders. Results: 105 response-evaluable patients were included in the analytic cohort. Across the 3 study arms, 20% (21/105) had an objective response to the treatment. Only measurable disease status was statistically significantly associated with response to therapy, with higher rates of response among patients without measurable disease at study enrollment (30% vs. 13%, p = 0.049). Response to prior therapy, sex, MYCN status, and measurable disease status showed univariate odds ratios of 2 or greater (Table). Only measurable disease status remained statistically significant in the multivariate analysis (p = 0.043, Table). Conclusions: Patients without measurable disease have a higher rate of objective responses to MIBG therapy. Understanding these differences based upon predictors of response may help to inform stratification methods for future MIBG clinical trials.[Table: see text]