bluuebunny/crossref_metadata_2025_split huggingface dataset:
Four-year survival follow-up of toripalimab (JS001) as salvage therapy in Chinese melanoma patients.
Authors: Tang Bixia , Chi Zhihong , Chen Yingbo , Liu Xiufeng , Wu Di , Chen Jing , Song Xin , Wang Weifeng , Dong Lihou , Song Haifeng , Wu Hai , Qin Shukui , Guo Jun , Zhang Xiaoshi , Yao Sheng , Feng Hui 
Published: June 2021

e21522 Background: Toripalimab, a PD-1 monoclonal antibody received conditionally approval in China as a salvage therapy for metastatic melanoma in 2018 based on a phase II trial with confirmed objective response rate of 17.3%. With four-year survival follow-up, here we report long-term survival results and related predictive biomarkers (NCT03013101). Methods: Patients with advanced melanoma who had failed prior systemic treatments were given toripalimab at 3 mg/kg i.v. Q2W until disease progression, intolerable toxicity or 2-year of treatment. Pts were followed for survival every 3 mo after discontinuation of treatment. Pts were transferred to an extension study after 2-year treatment. The Primary endpoint for the extension study was overall survival (OS). Results: 127 pts were enrolled, including50 (39.4%) acral, 22 (17.3%) mucosal, 29 (22.9%) nonacral cutaneous, and 26 (20.5%) unknown primary subtypes. After a median follow-up of 16.5 mo (range, 0.9-48.8), 74 (58%) pts had died. Median duration of response was 25.6 mo (95%CI:12.8-NE). Median OS was 22.0 mo (95%CI: 15.3-32.5). The OS rates for year 1 to 4 were 67.1%, 48.2%, 38.0% and 31.7% respectively. The median OS of complete response (CR)/ partial response (PR) (n = 22), stable disease (SD) (n = 51), progression disease (PD) (n = 54) were not reached, 34.0 mo and 9.7 mo, respectively. The median OS of non-acral cutaneous, unknown primary, acral and mucosal melanoma subtypes were 46.1, 37.3, 16.9 and 10.3 mo, respectively. The median OS of PD-L1+ (n = 26) and PD-L1- (n = 84) patients were 46.1 and 14.4 mo (P = 0.026, HR = 0.45, 95%CI 0.26-0.76). The median OS of TMB high (n = 20), TMB low (n = 78) was 16.0 and 22.3 mo with no statistically significance (P = 0.49, HR = 1.28, 95%CI 0.63-2.58). Conclusions: Salvage treatment with toripalimab leads to long-term survival benefit in advanced melanoma patients, especially for those with non-acral cutaneous and unknown primary subtypes, CR/PR/SD as best response or PD-L1+.
PALB2 mutation as a predictive biomarker for immunotherapy in patients with advanced melanoma: Results from (a pooled analysis of) five multicenter, randomized clinical trials.
Authors: You Changxuan , Zheng Yating , Huang Mengli 
Published: June 2021

e21537 Background: PALB2, a gene in the homologous recombination repair (HRR) pathway, has been shown to be associated with the efficacy of platinum based chemotherapy, and PARP inhibitor therapy in breast, prostate, ovarian, and pancreatic cancers. However, their predictive value of PALB2 remained unknown in patients with advanced melanoma. Methods: Five independent cohorts (Miao2018, Samstein2018, Allen 2015, Hugo2016, and Synder2014. study cohort) with data from 672 patients with advanced melanoma were used to analyze the correlation with immunogenic marker, and the prognostic effect of PALB2 on immunotherapy. Results: A pooled analysis of five independent cohorts of 672 advanced patients melanoma show that 31 (4.6%) harbored PALB2 mutation ( PALB2mut). PALB2mut (72.63Muts/Mb) was associated with higher tumor mutation burden (TMB) (P < 0.001) than PALB wild-type ( PALB2wt) (19.71Muts/Mb). The same phenomenon has also been observed in TNB, PALB2mut (1983 counts) was associated with higher tumor neoantigen burden (TNB) than PALB2wt (603.5 counts) (P = 0.0147). The objective response rate (ORR) of immunotherapy was 53.33% for the patients with PALB2mut and 24% for the PALB2wt subgroup (P = 0.027). The PALB2mut patients had significantly improved median overall survival (mOS) than the PALB2wt group (Not reach versus 29 months, hazard ratio (HR) = 0.38, 95%CI 0.19−0.73, P = 0.003). A subgroup analysis of CTLA4 inhibitor treatment found that PALB2mut was associated with better ORR (50% versus 18.3%, P = 0.016) on immunotherapy, and mOS in the PALB2mut group was significantly better than that in the PALB2wt group (Not reach versus 21 months, HR = 0.3, 95%CI 0.13−0.68, P = 0.002). However, in the subgroup receiving PD-L1 inhibitor treatment, no ORR benefit was found in the PALB2mut group (66.67% versus 56.76%, P = 1), and there was no difference on mOS between PALB2mut and PALB2wt (Not reach versus 31 months, HR = 0.45, 95%CI 0.11−1.8, P = 0.254). Conclusions: PALB2 mutations was associated with a higher TMB and TNB level. PALB2 may serve as a positive predictor of immunotherapy (CTLA4 inhibitor therapy) in patients with advanced melanoma and their clinical value warrants further investigation.
CCND1 amplification profiling identifies a subtype of melanoma associated with poor survival and an immunosuppressive tumor microenvironment.
Authors: Chen Yu , Jun Liu , Lin Jing , Wang Xuefeng , Zheng Xiao-bin , Gao Xuan , Chen Gang , Xiong Jiani , Lan Bin , Chen Chuan-ben , Si Lu , Xia Xuefeng 
Published: June 2021

e21552 Background: Melanoma is generally regarded as an immunogenic type of tumor that will respond to immune checkpoint therapy. However, melanoma tumors with CCND1 amplification respond poorly to checkpoint therapy. Further understanding of how CCND1 amplification modifies the effect of checkpoint therapy is necessary to design future clinical trials. Methods: We used the data from the Geneplus Institute (n = 302), The Cancer Genome Atlas (TCGA) (n = 367),and the Memorial Sloan Kettering Cancer Center (MSKCC) (n = 350) to identify the incidence of CCND1 amplification and the relationship between CCND1 amplification and survival in melanoma patients and explored molecular mechanisms. Results: The frequency of CCND1 amplification co-occurring with BRAF V600, NRAS, NF1, and KIT mutations was low in these three cohorts. Data from TCGA did not show a statistically significant correlation between CCND1 amplification levels and prognosis of melanoma patients irrespective of immune checkpoint inhibitors (ICIs). In contrast, we found opposite results using the MSKCC cohort where CCND1 amplification was an unfavorable prognostic factor for melanoma patients. This was especially true for patients received ICIs who were harboring a high tumor mutation burden (TMB). The TCGA data showed that CCND1 amplification were related to a higher proportion of immunosuppressive cells (Treg cells and M2 macrophages) and a lower proportion of immunity boosting cells (follicular helper T-cells, naive B-cells, CD8+ T-cells). Furthermore, GSEA analysis from the TCGA database suggests that the signaling pathways such as oxidative phosphorylation, reactive oxygen species, adipogenesis, fatty acid metabolism, DNA repair, and myc targets were differentially enriched in melanoma tumors with CCND1 amplification. Finally, we found that angiogenesis related molecules (HIF1A, VEGFA, VEGFR1, FGF2, FGFR1, FGFR4, HGF, PDGFA, PDGFRA, ANGPT1, and ANGPT2) were remarkable decreased in a CCND1 High Amplification group from the TCGA database. Conclusions: Melanoma with CCND1 amplificationis an independent genomic subtype associated with a poor prognosis, an immunosuppressive TME, activated oxidative and lipid metabolism, and down-regulated angiogenesis. Taken together, avoiding ICIs and antiangiogenic agents, while employing CDK4/6 inhibitors alone or in combination with ICIs, targeting oxidative and lipid metabolism pathway may be effective and promising therapeutic strategies for melanoma patients harboring CCND1 amplification.
Development and validation of an improved pathologic nodal classification system for cutaneous melanoma.
Authors: Nguyen Anthony Tuan , Luu Michael , Nguyen Vina , Hamid Omid , Faries Mark B. , Gharavi Nima M. , Lu Diana J. , Mallen-St. Clair Jon , Ho Allen S. , Zumsteg Zachary Stephan 
Published: June 2021

e21563 Background: Given recent therapeutic advances and evolving patterns of lymph node (LN) evaluation for cutaneous melanoma, accurate and precise LN staging is needed to guide adjuvant treatment and future investigations. Current staging was developed primarily for patients undergoing completion LN dissection (CLND) for node-positive disease and do not produce LN classification groups with continuously increasing mortality. Thus, we developed and validated an improved LN classification system for cutaneous melanoma. Methods: Retrospective cohort analysis of 105,785 patients with cutaneous melanoma who underwent surgery from 2004 to 2015 in the National Cancer Database. Extent of LN dissection (sentinel LN biopsy [SLNB] and/or CLND) was available for patients diagnosed 2012 onward. Multivariable models were generated with number of positive LNs modeled using a non-linear restricted cubic spline function. Recursive partitioning analysis (RPA) was used to derive a modified LN classification system based on LN variables independently associated with overall survival (OS). The proposed LN classification system was validated in 85,499 patients from SEER-18. Results: Number of positive LNs (1-2 LN+: hazard ratio [HR] 2.48 per LN, 95% CI, 2.37-2.61, P< 0.001; ≥3 LN+: HR 1.10 per LN, 95% CI, 1.07-1.13, P< 0.001), clinically detected metastases (HR 1.35, 95% CI 1.27-1.42; P< 0.001), and in-transit metastases (HR 1.48; 95% CI 1.34-1.65; P< 0.001) were associated with OS. An RPA-derived LN classification system using these variables demonstrated continuously increasing mortality risk for each proposed LN classification group (HR: 1.83, 2.72, 3.79, 4.56, 6.15, and 8.25 for the proposed N1a-N3b groups, Table, P< 0.001). By contrast, AJCC 8E produced a more haphazard mortality profile (HR: 1.83, 3.81, 2.59, 2.71, 4.51, 3.44, 6.06, 8.15, and 6.90 for N1a-N3c). As a sensitivity analysis, the proposed system continued to accurately predict outcomes when we excluded patients undergoing CLND for microscopic LN metastases. Lastly, we validated this system for OS and cause-specific mortality in SEER-18 ( P< 0.001). Conclusions: A modified and simplified LN classification system can accurately predict mortality in cutaneous melanoma in an era of increasing use of SLNB without CLND and should be considered for future staging systems.[Table: see text]
Comorbidity affects Вcl-2 levels in mitochondria in C57BL/6 mice with transplantable B16/F10 melanoma.
Authors: Neskubina Irina V. , Frantsiyants Elena M. , Bandovkina Valeria A. , Cheryarina Natalia D. , Shikhlyarova Alla I. , Surikova Ekaterina I. , Kaplieva Irina V. , Nemashkalova Ludmila A. , Pozdnyakova Viktoria V. , Przhedetskiy Yuriy V. , Przhedetskaya Viktoria Yu. , Ilchenko Maria G. , Agarkova Elena I. , Maksimova Natalia A. , Khokhlova Olga , Zakharova Natalia A. , Kit Oleg I. 
Published: June 2021

e21581 Background: Overexpression of the Bcl-2 protein inhibits apoptosis and promotes carcinogenesis. Stress causes signaling leading to cell buffering with Bcl-2 protein above acceptable levels. The purpose of the study was to analyze the influence of comorbidity – chronic neurogenic pain (CNP) – on the Bcl-2 levels in mitochondria of cells of melanoma, the heart, skin and brain in female mice with growing tumors. Methods: Female С57ВL/6 mice were divided into groups: intact group (n = 21); control group with a CNP model – bilateral sciatic nerve ligation (n = 21); group M – B16/F10 melanoma (n = 63); CNP+M group – B16/F10 melanoma was transplanted 3 weeks after the CNP model creation (n = 63). The concentration of Bcl-2 (ng/mg of protein) was determined in mitochondrial samples by ELISA (Thermo Fisher Scientific, Austria). Statictical analysis of results: Statistica 10.0. Results: CNP decreased the Bcl-2 level in heart mitochondria by 1.3 times (p < 0.05), but increased it in skin and brain mitochondria by 5.8 and 1.3 times, respectively. Similar changes were observed in melanoma growth 1 week after its transplantation: Bcl-2 levels decreased in heart mitochondria by 1.3 times, and increased in the skin and brain by 8.9 and 1.3 times, respectively. After 2 weeks of the tumor growth, Bcl-2 in brain mitochondria decreased by 1.7 times, and it started declining in the skin by the 3rd week – by 4 times, compared to intact females. Bcl-2 in tumor mitochondria exceeded the values in the skin by more than 4 times throughout the experiment. Tumor growth in presence of CNP caused a decrease in Bcl-2 in brain mitochondria by 2.4 times after 3 weeks, and in the heart and skin – by 2 and 1.7 times, respectively, after 2 weeks. Bcl-2 in tumor mitochondria in presence of CNP was lower than in the intact skin on average by 1.8 times throughout the experiment. Conclusions: CNP as a comorbidity caused a modulating effect on the mechanisms of survival and apoptosis of cells both in the tumor and in the main organs providing the vital functions of the body - the brain and heart, and also affects the target organ of melanoma - the skin. The results demonstrated the ability of comorbidity to change levels of Bcl-2 in mitochondria depending on the stage of tumor development.
Successful allografting for relapsing pediatric ALL: The results of two decades.
Authors: Zulfikar O. Bulent , Koc Basak 
Published: June 2021

e22000 Background: The prognosis of children and adolescents with acute lymphoblastic leukemia (ALL) has dramatically improved. This success is associated with both by multiagent chemotherapy regimens and by definition of clinical, biological and treatment response that allow the administration of risk-adapted therapy, including allogeneic hematopoietic stem cell transplantation (HSCT). In treatment of relapsed and resistance ALL, allogeneic HSCT continues to play a major curative role. In the present study, we desciribed the patients who underwent HSCT in our clinic in the last 21 years. Methods: From 1999 to 2020, 147 patients who diagnosed with ALL and treated with the COG protocols at the Istanbul University Oncology Institute were retrospectively reviewed and 17 of them relapsed. HSCT was applied 7 of the relapsed cases and also 3 resistant cases who had suitable matched donors. The demographic features, laboratory findings and treatment responses of 10 patients were recorded from the patients’ medical records. Results: All 10 patients were B-ALL with median diagnosis age of 79.5 months (range: 32-195) and 5 were male. Characteristics of patients given in Table 1. HSCT was performed due to late relaps in 7 patients. Three of the 7 relaps were only bone marrow and other 4 had combined. Patient #2 had both breast, conjunctiva and bone marrow for the 1st relaps and only conjunctiva for the 2nd one and this patient had also t(9;22) in the 1st relaps. Patient #3 had bone marrow+central nervous system relaps and patient #7 had bone marrow for the 1st relaps and testis and bone marrow for the 2nd one. Other 3 had poor response to treatment and Minimal Residual Disease (MRD) was high in End of Introduction (EoI) and End of Consolidation (EoC)). All patients had allogeneic HSCT and 8 are alive. Conclusions: HSCT remains the standard-of-care treatment for ALL patients who carry high-risk features predicting leukemia recurrence and for those experiencing high-risk first relapse or multiple relapses. Additionally, defining the indications of HSCT are dynamic and it could change according to treatment options as well as new molecular and biological findings. It is important to identify the patients who have high relapse risk and HSCT should have priority in patients whom MRD is high in EoI and EoC.[Table: see text]
Comprehensive genomic and transcriptomic profiling of pediatric malignancies using the Tempus xT Next-Generation Sequencing Assay to identify clinically meaningful alterations.
Authors: Toll Stephanie , Kwiatkowska-Piwowarczyk Aneta , Schaeffer Jeff , Schwarzbach Anna Ewa , Thomas Stefanie Marie , Kaneva Kristiyana 
Published: June 2021

e22002 Background: Our understanding of the genomic makeup of childhood cancers has accelerated over the past decade largely due to next-generation sequencing (NGS) utilized to identify genetic drivers, aid diagnostics and risk stratification, and detect therapeutic targets. Here, we present the genomic and transcriptomic landscape of pediatric malignancies tested with a broad NGS panel at a large commercial CLIA/CAP laboratory, Tempus Labs. Methods: We used the Tempus LENS platform to analyze DNA- and RNA-seq data from a cohort of 150 de-identified records of patients with pediatric cancer aged 0 to 18 years who underwent NGS with the Tempus xT platform. Results: The cohort included 139 solid tumors, 46 of which were central nervous system (CNS) tumors, and 11 hematologic malignancies. A total of 115 samples (77%) had at least one clinically meaningful pathogenic somatic variant detected, with TP53 variants being the most common (n=26; 17.3%). Gene fusions, most commonly EWSR1-FLI1 and KIAA1549-BRAF, were observed in 31 cases (20.7%). Matched tumor/normal testing revealed at least one incidental pathogenic germline variant in six patient records, with two cases harboring two distinct variants. Four cases had tumor mutational burdens (TMBs) greater than 10 mutations/megabase, including two that also exhibited high microsatellite instability (MSI). Conclusions: The Tempus xT tumor/normal-matched platform detects clinically meaningful genomic alterations in pediatric cancers important for diagnosis, prognosis, therapeutic target identification, and incidental germline findings. We continue to accumulate and structure data to meet the need for a large, accessible pediatric cancer clinical and molecular dataset. [Table: see text]
Clinical value of Next Generation Sequencing in Chinese pediatric soft tissue sarcoma: A multicenter data.
Authors: Lu Suying , Sun Feifei , Yuan Xiuli , Huang Junting , Wang Juan , Guo Haixia , Zhen Zijun , Zhu Jia , Sun Xiaofei , Que Yi , Zhang Lian , Wang Chen , Wang Dan , Zhang Yizhuo 
Published: June 2021

e22005 Background: To uncover the genomic characteristics as well as to, within the scope of pediatric soft tissue sarcoma (psts), assess the clinical value of Next Generation Sequencing (NGS), we present the first report of genomic profiles in Chinese psts. Methods: Tumor tissue, as well as peripheral blood from 41 psts patients, were collected in Sun Yat-Sen University Cancer Center, Shenzhen Children's Hospital and Nanfang Hospital. Samples were sequenced in a CLIA/CAP-accredited laboratory with a targeted NGS panel (Onco PanScan plus; GenetronHealth.inc) consisted of all exons of 831 cancer-related genes and mRNA of 395 genes. Bioinformatics analysis was conducted using a build-in computational pipeline. Results: A total of 41 samples consisted of five major histology types including rhabdomyosarcoma (RMS) (n = 11), fibrosarcoma (n = 4), Ewing's sarcoma (n = 4), INI1-deficient mesenchymal tumor (n = 4), and other mesenchymal tumors (n = 18). All patients were with doubtful diagnosis,advanced, relapsed, or refractory sarcoma, of which 85% samples were from initial diagnoses. In totally, we identified 116 somatic aberrations and 4 pathogenic or likely pathogenic germline mutations, with a median tumor mutational burden of 0.47/Mb (0–6.57). Genomic analysis revealed frequent alterations in TP53 (10%), NTRK fusion (10%), PAX3/7 fusion (8%), and ARID1A (7%). ARID1A (18% vs. 0%) and TP53 (18% vs. 3%) mutations were found with higher frequency compared with pediatric RMS data in a previous study (Jack et al 2014). ARID1A mutation was only reported in a RMS case report (Cramer et al 2017). Furthermore, the mutation of ARID1A potentially match PARP inhibitors, which may provide more therapeutic options. In addition, NGS aided pathologic diagnosis in 63% (26/41) patients. The proportion of confirmed diagnosis, differential diagnosis, and the excluded diagnosis was 41.5%, 12.2%, and 9.7%, respectively. Druggable alterations were detected in 39% patients (Table). Four patients received the treatment recommended by genetic testing, three of them with NTRK fusion were recruited in a matched clinical trial could be evaluated and showed partial remission upon Larotrectinib. Conclusions: We discovered ARID1A mutations, which potentially sensitive to PARP-inhibition, were at a higher incidence in Chinese RMS. This study demonstrated the value of NGS test in guiding the clinical practice of psts in Chinese population. [Table: see text]
Localized osteosarcoma analysis of very poor responders subgroup (Huvos I).
Authors: Longhi Alessandra , Carella Antonio , Broll Valquiria , Palmerini Emanuela , Cesari Marilena , Paioli Anna , Hakim Rossella , Gambarotti Marco , Righi Alberto 
Published: June 2021

e22010 Background: Osteosarcoma is a malignant primitive bone tumor whose prognosis is not changed since 4 decades, after the introduction of neoadjuvant chemotherapy with Methotrexate, Cisplatin, Doxorubicine and Ifosfamide. Histologic response to preoperative chemotherapy is a significant prognostic factor. Huvos I (necrosis ≤ 50%) has worst prognosis . Previous studies reported a 3 years EFS of this Huvos I patients around 25% (Tsuda Y,2020). In order to evaluate if survival has changed in recent years in this unfavourable prognostic group we evaluated the outcome of osteosarcoma patients with Huvos I. Methods: from our Pathology archieves we retrieved all cases of localized osteosarcoma treated at Rizzoli with neoadjuvant chemotherapy who reported an histologic necrosis below or equal to 50% (Huvos I grade) after preoperative chemotherapy MAP (Ethical C. Approval 917/2020/Oss/IOR). Results: from 2003 to 2019 we had 70 cases of localized osteosarcoma with Huvos I necrosis after neoadjuvant chemotherapy ( MAP in 66 and MAPI in 4) evaluable. Median age 21,5 (3-70); M:F = 44:26. 10/70 had axial localization vs extremity(60), subhistotype distribution:46 osteoblastic,11 chondroblastic, 7 fibroblastic, 5 teleangectatic, one not classified. In 24 cases PgP was available(14 PgP positive). With a median follow up of 86.7 ms (IQR 41-136) 43/70 had already relapsed. The median EFS was 25 ms (95% CI 15-42) and the 3 yrs EFS was 40.6% (95% CI 29-52). The 3 yrs overall survival was 80% (95%CI 68-88) and median OS was not reached. Axial tumor site was associated with significant inferior EFS (P = .004). Conclusions: these data confirm the poor prognosis of patients with necrosis ≤50% and the need of new drugs to improve their survival in this sub-group.