bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reality check for precision oncology in squamous cell lung cancer.
Authors: Bakhtyar Maham , Bhatti Sajjad Akbar 
Published: June 2023

e21221 Background: Squamous cell lung cancer (SqCLC) is the second most common type of pulmonary malignancy after lung adenocarcinoma. Therapeutic advances in Precision Oncology have significantly improved outcomes in subsets of patients with lung adenocarcinoma. However, a significantly different mutational landscape has limited the success of Precision Oncology in SqCLC. Still, NCCN guidelines recommend considering molecular testing in SqCLC, preferably with broad-based molecular profiling like next-generation sequencing (NGS), aiming to identify candidates for FDA-approved targeted therapy. We aim to evaluate the percentage of SqCLC potentially eligible for targeted therapy using NGS by analyzing data from The Cancer Genome Atlas (TCGA). Methods: We filtered cases with a SqCLC diagnosis from the TCGA database. These cases were screened for DNA/RNA alterations in the 9 NCCN-guidelines recommended genes, including EGFR/ALK/ROS1/BRAF/MET/RET/HER2/NTRK/KRAS. Each unique alteration in the genes mentioned above was then analyzed in the oncoKB database to predict clinical benefit with level 1 and 2A evidence from FDA-approved targeted therapy. We then calculated the percentage of patients with SqCLC tested with NGS who could assess approved matched targeted therapy. Results: We identified 501 unique cases of SqCLC diagnosis in the TCGA. In the 9 NCCN-recommended actionable genes, 206 alterations were detected. We reviewed the clinical implication and utility of each of these alterations in the OncoKB database, and only 5 alterations were consistent with level 1/2A clinical benefit from a matched targeted therapy. These included 2 cases with L861Q and one each with EGFR L858R, EGFR E746_A750 exon 19 deletion, and G222C missense in the ERBB2 gene. Conclusions: The percentage of squamous cell cases which are potential candidates for FDA-approved targeted therapy was relatively low, 0.1% (5/501). While next-generation sequencing will not affect the standard of care treatment options for most SqCLC patients, clinicians can use this information to counsel patients for enrollment in clinical trials. [Table: see text]
Clinical outcomes for immunotherapy beyond progression in patients with advanced non-small cell lung cancer.
Authors: Jia Wenxiao , Wang Min , Zhu Hui , Wu Gang 
Published: June 2023

e21222 Background: No definite conclusion has yet to be reached for immunotherapy beyond progression(IBP)as the second-line treatment for advanced NSCLC patients with negative driver genes. Therefore, a retrospective study was conducted to evaluate the efficacy of IBP in this population and investigated whether the cycles, best response and progressive mode of first-line immunotherapy could affect the results. Methods: The clinical data of patients with advanced NSCLC whose response was evaluated as progressive disease (PD) after receiving a PD-1/PD-L1 inhibitors as first-line therapy were retrospectively collected and the patients were assigned to the IBP and non-IBP groups. The overall survival (OS), progression-free survival (PFS) were evaluated between the two groups. The survival effects of cycles, best response and progressive mode of first-line immunotherapy were also evaluated. Results: Between January 2019 and January 2022, a total of 121 patients was evaluated as PD after first-line immunotherapy in our institution; 53 (43.8%) patients were included in the IBP group and 68 (56.2%) patients were included in the non-IBP group. The OS and PFS were no significantly different between the two groups. Further analysis revealed the OS was prolonged with the prolongation of first-line medication cycle. The median OS was 15.4m (15.4 vs 10.8 p= 0.029), 16.1m (16.1 vs 10.8 p= 0.021), 16.3m (16.3 vs 10.9 p= 0.015) for patients with ≥4, ≥6, ≥8 cycles in first-line immunotherapy, respectively. The advantages of OS and PFS were also seen in the subgroup of PR (best response) and local progression of first-line immunotherapy. Conclusions: The clinical outcomes of IBP were similar to those of non-IBP in patients with PD after first-line immnuotherapy in advanced NSCLC. But more cycles, PR as best response and local progression in first-line was benefit.
CAROLINE study: Incidence and characterization of melanoma in French Polynesia.
Authors: Epaillard Nicolas , Auclin Edouard , Hirigoyen Elodie , Bermond Luc , Bonnet Anouck , Loiselet Pierre , Chastenet Mathilde , Herve Robert , Mengue Sylvie , Dutin Jean Philippe , Honoré Charles , Gustin Pierre , Mahjoubi Linda 
Published: June 2023

e21505 Background: Epidemiology of metastatic melanoma in French Polynesia has never been described. Yet melanoma is known to be associated with sun exposure. The aim of this monocentric study was to assess the epidemiology of metastatic melanoma in French Polynesia. Methods: Here we analyzed data of all patients diagnosed with metastatic melanoma from January 2015 to December 2020 in the only public hospital in French Polynesia and described epidemiological, survival findings and molecular characteristics. Clinical, molecular and radiological data were collected. Results: Out of 69 patients, the majority were male (74%) and median age was 65 years old. Patients were more often native from French Polynesia (59%) and Metropolitan France (32%), 80% of patients were living in Tahiti Island. Most patients had metastatic cutaneous melanoma and only 3 had metastatic uveal melanoma. A total of 37 patients had an available BRAF molecular profile and 35% were BRAF mutated. 28% were metastatic at diagnosis. First line treatments were nivolumab (31%) and pembrolizumab (15%). The ORR was 45.88% (15/33) and 2 patients had CR. Overall, the median OS was 12.2 months [95% CI, 8.64- 43.27]. Conclusions: Most patients with metastatic melanoma were from Tahiti Island and there were no major disparities between the other archipelagos. Yet facilities of access to care may vary from geographical zones. Massive prevention is still crucial.
Immunotherapy and radiotherapy in metastatic uveal melanoma: Results from a single institute study.
Authors: Guan Jian , Teh Bin S. , Schefler Amy , Bernicker Eric 
Published: June 2023

e21507 Background: Metastatic uveal melanoma carries a poor prognosis, especially for patients who are not eligible for Tebentafusp. Unlike cutaneous melanoma, checkpoint inhibitors have limited effect on uveal melanoma. The observation of Abscopal effect has inspired this study of adding radiotherapy to boost the efficacy of immunotherapy. Methods: We performed a retrospective study in Houston Methodist Hospital to evaluate the efficacy of combining immunotherapy with radiotherapy including either SBRT or Y-90 treatment. Clinical outcomes were determined by assessing best overall response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), progression-free survival(PFS) and overall survival. Results: A total of 8 patients were included for this study, among which one patient had previously progressed on immunotherapy. The median follow-up period was 19 months. The best overall response rate (ORR) and disease control rate (DCR) were 25% and 75% in patients received dual-modality combination treatment (including one complete response and one partial response). The PFS and overall survival in dual-modality combination treatment group were 5.4 months (95% CI, 1.1 to 14.9 months) and 18.7 month (95% CI, 11.1 to 23.9 months), respectively. Fifty percent of patients experienced grade 3-4 treatment-related adverse events. Conclusions: The combination of radiotherapy and immunotherapy is active in metastatic uveal melanoma with sustained response in selected patients. A randomized prospective trial may be required to confirm the benefits of dual-modality combination treatment.[Table: see text]
Adjuvant polypeptide vaccines for high-risk uveal melanoma.
Authors: Gaughan Elizabeth Mary , Lucchesi Nicholas , Jin Ruyun , Slingluff Craig L. 
Published: June 2023

e21509 Background: Due to biologic differences, uveal melanoma patients are often excluded from clinical trials for cutaneous melanoma; however, many antigens are shared between the two melanoma subtypes. Thus, our vaccine trials at the University of Virginia (UVA) have allowed enrollment of high-risk uveal melanoma patients, who have substantial risk of relapse without FDA-approved adjuvant therapy available. For the present study, we hypothesized that the vaccines would be well-tolerated and immunogenic in this population. We examined the clinical, immunogenicity and safety outcomes of subjects with uveal melanoma enrolled in our adjuvant vaccine clinical studies. Methods: Patients were identified through participation in an adjuvant vaccine study at UVA between 2012-2022. Ten patients received the 6-Melanoma-Helper Peptide (6-MHP) vaccine through Mel-65 and Mel-66 clinical trials (NCT03617328 and NCT04364230) and one patient received the 12-peptide MELITAC vaccine through the Mel-58 clinical trial (NCT01585350). Clinical outcomes included relapse-free (RFS) and overall survival (OS) and trial toxicity reporting. Immunogenicity was assessed by ex vivo interferon-gamma ELISpot assay of peripheral T cells. OS and RFS were reported by Kaplan-Meier survival analysis and compared by log rank test between groups. Results: Of the 11 identified patients, nine were male (82%) and two were female (18%), with a median age of 64 years. All patients were high risk by molecular testing, the majority by Castle Bioscience DecisionDx-UM. Five were PRAME positive, five PRAME negative, and one not reported. In the cohort, three patients had uveal melanoma recurrence and one subject died from metastatic disease during the evaluation period. The 5-year RFS and OS were 71% (95% CI 43-100) and 80% (95% CI 52-100), respectively. Two patients experienced dose-limiting, grade 3 toxicities to the vaccine, requiring early trial discontinuation, including one grade 3 injection-site reaction and one grade 3 uveitis. Nine patients experienced grade 1-2 toxicities, mostly injection-site reactions and constitutional symptoms. Of nine patients with available immunogenicity data, five (55%) had direct antigen-mediated immune response to vaccine. Two patients’ responses are pending. Patients with immunogenic response had a non-significant trend toward better RFS and OS (both p = 0.22). The 3-year RFS and OS were 100% for subjects with T cell response and the RFS and OS were 50% (95% CI 13-100) for patients without T cell response. Two of the relapsed patients did not have an immune response to vaccine, and response data were not available for the third. Conclusions: Melanoma polypeptide vaccines are immunogenic and safe in patients with uveal melanoma. Our early data suggests the possibility of early benefit with direct antigen response, though longer follow up and further study will be needed to investigate these findings.
Patterns of care delivery and outcomes in patients with melanoma brain metastases treated with ipilimumab/nivolumab.
Authors: Haykal Tarek , Ferreira Michelle , Lowe Melissa , Hanks Brent Allen , Fecci Peter E. , Kirkpatrick John P. , Vaios Eugene John , Reitman Zach , Salama April K.S. 
Published: June 2023

e21510 Background: Patients (Pts) with metastatic melanoma presenting with brain metastases (MBM) have a high morbidity and mortality risk. The combination of ipilimumab/nivolumab (I/N) has demonstrated high intracranial response rates in selected, asymptomatic pts, suggesting there is a subset of pts who may be able to forgo or delay intracranial therapies. There is currently limited real world data on how many pts with MBM are successfully treated with this approach. We sought to explore our clinical experience at Duke University with combination immune checkpoint inhibitors for pts with MBM. Methods: An electronic database search was conducted for all metastatic melanoma pts treated with PD-1 therapies between 2015 and 2021. Pts treated with combination ICIs for brain metastases were included. The primary outcome was overall survival (OS). Secondary outcomes were need for local therapies (radiation (RT): stereotactic radiosurgery or whole brain radiation therapy or craniotomy), and immune related adverse events (irAEs). Results: Between 2015 and 2021, 66 pts with MBM received I/N, with a median follow-up of 30.4 months. Median age was 68, 60.6% were male and 61% had a BRAF mutation. 38 pts were asymptomatic. Of the 28 symptomatic patients 61% were on corticosteroids at the time of I/N initiation. 56% of pts received local therapy prior to start of I/N, 17% during and 18% after discontinuing I/N. 53% of pts were initiated on I/N as first line systemic therapy for MBM. 56% of patients had to discontinue I/N after one cycle because of high-grade irAEs. 13.8% of patients that received RT to the brain developed radionecrosis. Median OS was 25.6 months in the overall cohort, with a 1 year OS of 63%. There was a trend towards a higher risk of death for symptomatic versus asymptomatic patients HR:1.96 [95% CI: 0.96, 3.97; P:0.06]. Of the 38 asymptomatic patients, only 6 patients did not receive local therapies with either RT or craniotomy. Two of these patients died from melanoma progression, one from intra-cranial progression, the other from both intra-cranial and extra-cranial progression, and 4 remain alive without evidence of progression. Conclusions: The majority of pts with MBM are ultimately treated with multimodality therapy. Advances in systemic therapies have provided meaningful clinical benefit that could allow a limited number of asymptomatic patients to forgo local therapy, but currently few pts are treated in this manner.
Predicting immunotherapy outcomes of melanoma patients before treatment by intestinal microbiota.
Authors: Wang Tao , Liu Yang , Wang Qian , Xiao Shanshan 
Published: June 2023

e21512 Background: To find the appropriate patients that can benefit from immunotherapy is very important in precision medicine. Biomarkers such as PD-L1, TMB and MSI attracted a lot of attentions in immunotherapy. Emerging biomarkers such as intestinal microbiota and others also showed promising predictive/prognosis values in the clinical studies. The purpose of this study was to evaluate new prediction models based on intestinal microbiota data from the melanoma patients before treatment. Methods: This study enrolled 41 microbiome 16S patients from published datasets. Firstly, survival analysis was performed on the response group (R) and non-response group (NR). Species in all the samples were included to perform univariate cox regression analysis, and the differences of intestinal microbiota between R and NR groups were evaluated by alpha and beta diversities. The specific differential microbiota was obtained by Student's t-test and LEfSe and further screened by the best performance of the five machine learning methods. To find the minimum set of the microbiota species, logistic regression and ROC curve were used. Analyses of KO data included PCA, differential and KEGG enrichment analysis. Significantly enriched pathways were scored by ssGSEA. The spearman correlations between ssGSEA scores and final microbiota species were calculated. Results: The non-response (NR) group had shorter PFS. Univariate cox regression analysis on all the samples identified 36 species which might be associated with prognosis. Alpha and beta diversities showed the R and NR groups were significantly different. Student's t-test identified 52 differential species and LEfSe identified 72 OTUs. Most of the microbiome enriched in R group belonged to firmicutes, while those enriched in NR group belonged to firmicutes, bacteroides and proteobacteria. We then constructed five machine learning models to predict PD1 immunotherapy responses of the melanoma patients and finally identified 25 species. Logistic regression and ROC curve identified the minimum set of the microbiota species including methanobrevibacter smithii, schaalia odontolytica, cuneatibacter caecimuris. A total of 119 differentially expressed KO genes were obtained by differential analysis, and those genes were mainly enriched in 25 pathways. Spearman correlation analysis found that those three microbial species were mainly associated with 12 pathways which might influence the classification of the two groups. Conclusions: In this study we identified three microbial species which might contribute to the classification of the R and NR patient groups. The models based on intestinal microbiota data can predict immunotherapy outcomes of melanoma patients.
Intrathecal anti-PD-1 treatment in patients with metastatic melanoma (MM) with leptomeningeal disease (LMD): Real-world data and evidence.
Authors: Zhen Junjie , Zhang Xiaoshi , Cai Linbo , Chen Linbin , Lai Mingyao , Li Dandan , Wang Hui , Ding Ya , Yang Yanying , Li Jingjing , Wen Xizhi 
Published: June 2023

e21516 Background: LMD is one of the most severe complications of melanoma and has an extremely poor prognosis. Over the past decade, the incidence of LMD is increasing with improved treatment strategies and prolonged survival. This real-world study aims to evaluate the safety and efficacy of intrathecal anti-PD-1 treatment in MM patients with LMD. Methods: MM patients with LMD diagnosed by MRI and/or cerebrospinal fluid (CSF) cytology were assigned to intrathecal nivolumab infusion 20mg once every 2 weeks (n = 4) or pembrolizumab 20mg once every 3 weeks (n = 3). The patients received a median of 4 cycles of treatment (range 2–7 cycles). Efficacy and safety analyses were performed on all the treated patients. Results: Between June 2022 and December 2022, 7 patients were treated, including 3 cutaneous, 2 acral and 2 primary leptomeningeal melanoma. All patients presented linear or small nodular enhancement of leptomeningeal on MRI. Four patients had concurrent parenchymal brain metastases. The tumor cells were found in 5 patients by CSF cytology, and pathologic diagnosis was obtained by leptomeningeal biopsy in 2 patients. According to RANO-LM criteria, 4 patients responded to treatment with symptom improvement and reduction or disappearance of linear enhancement on MRI, while 3 patients developed progressive disease. The median overall survival (OS) was 39.7 months after initial diagnosis and 24 weeks after LMD. With a median follow-up of 13.3 weeks (range 9.4–20.3 weeks), the median intracranial progression-free survival (IPFS) and median OS for intrathecal anti-PD-1 were 16.1 and 20.3 weeks, respectively. All treatment-related adverse events were grade 1-2, including headache (grade 1, n = 1; grade 2, n = 2) and low back pain (grade 1, n = 1). Conclusions: In this real-world study, intrathecal anti-PD-1 treatment was found to be well tolerated and effective in metastatic melanoma patients with LMD.
Imaging response to immune checkpoint inhibitors in patients with advanced melanoma: A retrospective observational cohort study.
Authors: Gupta Mehul , Stukalin Igor , Goutam Siddhartha , Meyers Daniel E. , Heng Daniel Yick Chin , Cheng Tina , Monzon Jose Gerard , Navani Vishal 
Published: June 2023

e21524 Background: The association of objective imaging response with first line immune checkpoint inhibitor (ICI) therapy regimes in advanced melanoma remains uncharacterized in a real-world context. We compared likelihood of objective response between patients receiving first line anti-programmed cell death protein 1 (anti-PD1) monotherapies (pembrolizumab or nivolumab), or combination nivolumab with the cytotoxic T-cell lymphocyte-antigen 4 inhibitor ipilimumab and outlined the association between objective response and baseline characteristics and survival outcomes. Methods: We conducted a multi-center retrospective cohort analysis of advanced melanoma patients receiving first line ICI therapy from 2013-2020 in Alberta, Canada. Best imaging response was assessed by Response Evaluation Criteria in Solid Tumors, Version 1.1. The primary outcome was likelihood of objective imaging response (complete or partial response) between patients receiving anti-PD1 monotherapy and those receiving combination nivolumab-ipilimumab. Secondary outcomes were the identification of baseline characteristics associated with non-response and the association of imaging response with overall survival (OS) and time to next treatment (TTNT) endpoints. Results: Of the 255 patients included, 49/255 (19.2%) had complete response 112/255 (43.9%) had partial response, 28/255 (11.0%) had stable disease, and 66/255 (25.9%) had progressive disease. Median OS was not evaluable (NE) (95% CI NE-NE) for complete responders, NE (95% CI 52.93 months-NE) for partial responders, 21.30 months (95% CI 15.20 months-NE) for stable disease, and 7.72 months (95% CI 5.77-10.6 months) for progressive disease (log rank p < 0.0001). A robust delineation of TTNT by imaging response was also seen. Likelihood of objective response was similar between patients treated with nivolumab-ipilimumab compared to those receiving anti-PD1 monotherapy (OR 1.87 95% CI 0.85-4.20, p = 0.124). Normal LDH level (OR 2.13; 95% CI 1.01-4.35, p = 0.047), non-mucosal primary site (OR 9.09; 95% CI 2.44-33.33, p < 0.001), and absence of BRAF V600E mutation (OR 3.23; 95% CI 1.39-7.69, p = 0.007) were independently associated with likelihood of objective imaging response in multivariable analysis. Conclusions: In this real-world analysis, we demonstrate no significant difference in likelihood of objective response between patients treated with anti-PD1 monotherapy and combination nivolumab-ipilimumab, and demonstrate that a normal LDH level, non-mucosal primary site, and absence of BRAF V600E mutation are associated with response. Imaging response was also strongly associated with both OS and TTNT irrespective of therapy received. These results may help inform treatment selection, and aid in counseling of advanced melanoma patients treated with first line ICI therapy in a routine clinical practice setting.
Cemiplimab in first line treatment for locally advanced and metastatic skin squamous cell carcinoma in Slovenia.
Authors: Ocvirk Janja , Sever Masa , Tomic Blaz , Mesti Tanja 
Published: June 2023

e21531 Background: Cemiplimab is a first PD1 inhibitor for treatment of locally advanced cutaneous squamous cell carcinoma (laSCC) and metastatic SCC (mSCC). The purpose of this study is to report outcomes of patients with SCC, treated with cemiplimab in routine clinical practice in Slovenia in twenty-month period. Methods: In this retrospective cohort study we analyzed medical records of patients with laSCC and mSCC inappropriate for surgery or radiotherapy treated with cemiplimab in first line between May 2020 and November 2022. The baseline characteristics, outcomes, immune related adverse events (irAE). Results: 28 patients were included, 24 with laSCC and 4 with mSCC, with a median age of 76.1 years. Of them, 18 % (5 patients) a concomitant autoimmune disease. The estimated median progression-free survival (PFS) was 4.4 months (95% CI: 1.5–7.3). The median overall survival (OS) was 7.3 months (95% CI: 4.6–9.9). Among 27 treated patients with an evaluable response, 3 (11 %) achieved complete response, 5 (19 %) achieved partial response, 6 (22 %) had stable disease and 13 (48 %) patients experienced a progressive disease. The overall response rate (ORR) was 30 %, and the disease control rate (DCR) was 52 %. A quarter of all patients had at least one immune related adverse events (irAEs). Only one patient had grade 3 event, there were no grade 4 and no fatal events. Higher response rate was achieved in patients with irAE – ORR was 43 % and DCR was 71 %. Seven patients are still on cemiplimab. Conclusions: Cemiplimab has shown meaningful efficacy with DCR of 52 % in patients with laSCC and mSCC in Slovenia. Patients developing irAE had higher response rate.