bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative effectiveness of linvoseltamab versus standard-of-care (SOC) treatment (tx) in real-world patients (pts) in the United States (US) with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).
Authors: Kumar Shaji , Weisel Katja C , Ma Qiufei , Hampp Christian , Humblet Olivier , Shokoohi Mostafa , Bonar Nicolle , Spin Paul , Harnett James , Ge Wenzhen , Jalbert Jessica J , Sobel Rachel E , Kroog Glenn Scott , Rodriguez-Lorenc Karen , Jagannath Sundar 
Published: June 2024

7561 Background: Pts with TCE RRMM have poor outcomes and a high unmet need, with no established SOC tx. LINKER-MM1 (NCT03761108) is a single-arm, Phase 1/2 study investigating linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody, in pts with RRMM who were previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody, or were triple-class refractory (TCR) to these tx. The aim of this study was to contextualize LINKER-MM1 by comparing outcomes with linvoseltamab vs a real-world (RW) external control arm (ECA). Methods: A RW ECA was derived from 2 US electronic health record databases (COTA, Guardian Research Network) of pts who started a new line of therapy (LOT) after classification as TCE or TCR and met key eligibility criteria for LINKER-MM1. Eligibility was assessed at the initiation of each new LOT, and all eligible LOTs were included in the ECA. Data in Phase 2 pts who received linvoseltamab 200 mg in LINKER-MM1 were included (data cutoff: Sep 8, 2023). Inverse probability of tx weighting (IPTW) was used to reduce imbalances between the RW and LINKER-MM1 cohorts. Key prognostic factors were identified using a systematic review and rank ordered by an international committee of MM experts (Kumar et al., 2023). Outcomes included overall response rate (ORR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). An independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments prior to conducting comparative analyses. Results: Comparative analyses were performed in 105 pts in the linvoseltamab cohort and 101 RW pts (137 LOTs). Following IPTW, the distribution of cytogenetic risk, age, TCR status, Eastern Cooperative Oncology Group Performance Status, and platelet count were balanced between the 2 cohorts (absolute standardized mean difference <0.10). After adjustment, pts receiving linvoseltamab had significantly improved ORR, PFS, TTNT, and OS vs the RW ECA (see table). Conclusions: Linvoseltamab significantly improved outcomes vs RW SOC in the US, highlighting its potential as a highly effective tx in pts with TCE RRMM. [Table: see text]
Predicting response of patients with NSCLC to immunotherapy using innate immune fitness (IIF) profiling.
Authors: Lindley Robyn Alice , Hall Nathan E , Mamrot Jared 
Published: June 2024

8038 Background: Aberrant activity of AID/APOBEC deaminase enzymes can cause 'off-target' somatic mutations in cancerous cells. Mutations associated with deaminases and other mechanisms can be quantified using metrics relating to motif usage, strand bias, transitions/transversions, codon context, and amino acid changes. Collectively, these metrics form an Innate Immune Fitness (IIF) profile (US Patent 20200370124). The aim of this project was to conduct IIF profiling on a cohort of Non-Small Cell Lung Cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICI), and use the IIF profiles to build and evaluate a predictive model. Methods: Whole exome and progression-free survival (PFS) data was obtained from Rizvi et al. 2015, Hellmann et al. 2018, Miao et al. 2018, Fang et al. 2019, Frigola et al. 2021, and Ravi et al. 2023 (n = 515). IIF profiles were generated using CRIS (v5.0.0; GMDx Genomics Ltd). Patients were classified as a ‘Responder’ (PFS > 12 months or Complete Response; n = 148) or ‘Non-Responder’ (PFS ≤ 12 months; n = 367). Machine learning models were generated using the H2O.ai AutoML platform and evaluated using multiple rounds of cross-validation. Patient response predictions were collated for each patient and a consensus ‘IIF Score’ was calculated. Multivariable analysis of IIF Score, TMB (10mut/Mb) and PD-L1 TPS ( < 1%, 1% - 50%, > 50%) was conducted using a Cox proportional-hazards model. Results: The predictive accuracy of IIF Scores was 76% (Sensitivity = 58%; Specificity = 83% , NPV = 83% , PPV = 58%) with a Hazard Ratio (HR) of 0.39 (0.29-0.53; p < 0.001; corrected for TMB and PD-L1). In comparison, the predictive accuracy of TMB was 67% (Sensitivity = 53%; Specificity = 79% , NPV = 79% , PPV = 44%), HR = 0.77 (0.59-1.00; p = 0.049; corrected for IIF Score and PD-L1). ‘PD-L1 > 50%’ accuracy was 53% and HR = 0.64 (0.44-0.94; p = 0.023; corrected for IIF Score and TMB). The Area Under the Curve (AUC) for IIF Score was significantly higher than TMB (0.77 vs 0.70; DeLong test: p < 0.001). Conclusions: IIF Score was the strongest predictor of patient response to ICI. Despite the inherent limitations of combining data from multiple cohorts, IIF Score outperformed TMB and PD-L1 in predictive accuracy, HR and AUC. With a Negative Predictive Value of 83%, these results support the use of IIF Score as a biomarker for identifying ICI Non-Responders in NSCLC patients. Research Sponsor: GMDx Genomics Ltd.
Signatures of early plasticity in the histological transformation of lung cancer.
Authors: Rakhade Swanand , Chen Monica F , Quintanal-Villalonga Alvaro , Sabet Amin , Manoj Parvathy , Chaudhary Ojasvi , Xu Tianhao , Masilionis Ignas , Falcon Christina J. , Egger Jacklynn V. , Nawy Tal , Mazutis Linas , Chaligne Ronan , Yu Helena Alexandra , Pe'er Dana , Rudin Charles M. , Chan Joseph Minhow 
Published: June 2024

8042 Background: Tumor plasticity, especially histological transformation, is an emergent mechanism of therapeutic resistance. Lung adenocarcinoma (LUAD) can transform to small cell lung cancer (SCLC), a more aggressive tumor type of neuroendocrine (NE) histology, leading to EGFR inhibitor resistance and a more aggressive disease phenotype. TP53 and RB1 loss are enriched but insufficient for NE transformation, and it remains unknown what additional molecular changes underlie plasticity. We use single-cell RNA sequencing (scRNA-seq) to profile the intratumoral transcriptional heterogeneity of NE transformation across multiple time points. Methods: We performed 10X scRNA-seq in patient samples to create an atlas of NE plasticity (47 transformed and admixed LUAD-SCLC, 10 EGFR/RB1/TP53 mut LUAD, 17 de novo SCLC, 4 normal lung). Our pipeline performed ambient RNA removal, outlier filtering, normalization, and batch correction. Tumor cells from transformed and admixed LUAD-SCLC tumors were divided into the LUAD compartment prior to transformation (pre-transformed LUAD) and the transformed SCLC compartment based on acquisition of NE marker expression. We performed copy-number inference, pseudotime analysis, and estimation of differentiation potential to establish dynamic changes in phenotypic and subclonal architecture across longitudinal timepoints. Results: We captured 12,105 (9%) pre-transformed LUAD cells from transformed and admixed LUAD-SCLC tumors. Canonical squamous cell carcinoma genes (KRT5, KRT6A, TP63, SERPINB4) were found to be enriched in this pre-transformed LUAD compartment. By projecting a force-directed layout of cells from these samples, we modeled the transition between LUAD, LUSC, and SCLC cell types. Genetic pathways promoting angiogenesis, inflammatory signaling, epithelial-to-mesenchymal transition, and RAS/RAF signaling were highly overexpressed during LUAD-LUSC transformation. Furthermore, we show that macrophages from transforming LUAD-LUSC tumors exhibit a pro-fibrotic phenotype. CNV inference revealed distinct subclonal populations in pre-transformed LUAD tumors. Subclones with high CNV burden and high differentiation potential represented early plastic cells whose lineage could be traced to matched longitudinal post-transformation samples. Conclusions: There is remarkable intratumoral heterogeneity within transforming LUAD. Squamous transformation, mediated by early RAS/RAF signaling, may represent a precursor to SCLC transformation. Identifying early hallmarks of plasticity can help stratify patients at high risk for transformation and reveal therapeutic vulnerabilities.
Nuclear receptor subfamily 4A2: Novel role and a potential therapeutic lead in cancers.
Authors: Kumar Mudasir Ahmad , Basit Aga , Masoodi Tariq , Chaudhary Sanjib , Assad Assif , Bhat Muzafar Rasool , Shah Zubair A. , Al-Shabeeb Akil Ammira S. , Bhat Ajaz Ahmad , Batra Surinder K. , Macha Muzafar Ahmad 
Published: June 2024

e18017 Background: Perineural invasion (PNI) is a pathological process where cancer cells infiltrate surrounding nerve tissues, markedly increasing the risk of cancer recurrence, metastasis, post-surgical complications, and associated pain. Alarmingly, PNI is prevalent in 80 - 100% of Head and Neck Squamous Carcinoma (HNSCC) and Pancreatic Ductal Adenocarcinoma (PDAC) cases. In these tumors, nerve invasion often occurs as a distinct route of metastasis, bypassing the usual lymphatic or vascular routes. Despite the rigor of surgical interventions and post-operative radiation, PNI-associated tumors recurrently manifest, emphasizing an urgent need to elucidate the underlying molecular interplay between tumor cells and nerves. Methods: Our study focuses on the Nuclear receptor subfamily 4A2 (NR4A2) transcription factor, known for its pivotal roles in cellular homeostasis and response to pathological conditions. Results: Comprehensive analyses employing tissue microarrays, curated public datasets, and cell lines unveiled a consistent overexpression of NR4A2 in HNSCC and PDAC tumor cells compared to their normal counterparts. Intriguingly, genome-wide chromatin immunoprecipitation (ChIP) sequencing with an NR4A2-specific antibody highlighted an enrichment of genes linked to neuronal guidance, suggesting a probable NR4A2-mediated mechanism underpinning PNI. Further, an in-depth analysis of these ChIP-enriched neuronal genes using The Cancer Genome Atlas (TCGA) confirmed their heightened expression in HNSCC and PDAC tumor tissues relative to healthy tissues. Advancing our research with graph neural networks and sophisticated bioinformatics, we identified two potent lead compounds targeting NR4A2. Preliminary Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) assessments of these compounds indicate favorable safety and efficacy profiles for clinical application. We are currently conducting comprehensive evaluations of these compounds, deciphering their molecular mode of action and therapeutic potential in cell culture and animal models. Conclusions: To sum up, our findings reveal a yet unknown role of NR4A2 in the landscape of PNI in HNSCC and PDAC. The AI-driven discovery and ensuing validation of NR4A2-centric inhibitors present a novel therapeutic avenue to curb cancer progression, prevent metastasis, and potentially improve patient outcomes.
Clinical utility of circulating tumor tissue-modified viral HPV DNA testing in HPV-driven oropharyngeal cancer arising in women.
Authors: Russial Olga , Raben Adam , Shah Sophia , Kegelman Timothy 
Published: June 2024

e18032 Background: HPV+OPSCC is rare in womenand may indicate a different biology. The purpose of this study was to evaluate the clinical utility of circulating tumor tissue modified viral (TTMV)-HPV DNA testing in women with HPV+ OPSCC, and to compare the results to our male cohort. Methods: A total of 88 TTMV-HPV DNA tests were collected on 23 women with OPSCC, treated with curative intent. 87% pts (20/23) had pre-treatment TTMV testing. Initial HPV status was assessed by p16 marker IHC and then by TTMV-HPV DNA assay. There were 22/23 pts with p16+ by IHC. One pt with p16- IHC had a positive pre-Tx TTMV score of 185. Post treatment TTMV testing was performed at 3-month intervals. The pre-Tx TTMV median score was 1047 normalized frags/ml. (range: 7-16909). Median number of surveillances TTMV tests were 2.5 (range 1-7). Test results were correlated with imaging to assess clinical utility. Results: 23 women were included. Median age 65.9 (Range: 49-79). Median follow-up was 25.6 months (Range 1.4-52.7). There were 20 pre-treatment tests, 19/20 pts were p16+ IHC. 14 TTMV tests were true positive, with a per-test and per-patient sensitivity of 76.5% (95% CI: 56.3 – 96.6%). For p16+ males, the per-test sensitivity was 54/59, 91.5%, (95% CI: 84.4 – 98.6%) and the per-pt sensitivity is 50/55, 90.9% (95% CI: 83.8 – 98.5%). Fisher’s exact test was used to determine if there is a relationship between biological sex and pre-treatment sensitivity. The per-test p-value was 0.0575, and the per-pt p-value was 0.1119. 5 pts with p16+ IHC had negative baseline TTMV tests, one of which had TTMV-HPV16 DNA subsequently confirmed by FFPE. Clinical staging included T1-T2 (N=19; 82.6%), T3-T4 (N=4, 17.4%), N0-N1 (65.2%: N0=3, N1=12), N2-N3 (34.8%: N2=7, N3=1). There was no correlation between pre-treatment TTMV score and T stage. There was a significant difference in pre-treatment score for pts with N0 vs N+ (Mann-Whitney U test, p = 0.0392). However, the N0 group only had 3 tests, compared to 15 tests in the N1/N2/N3 group. The median score of the N0 group was 7 and the median score of the N1/N2/N3 group was 371. All TTMV tests resolved to zero after treatment completion. 9/14 (64.3%) TTMV scores resolved within 3 months after treatment completion. These pts had post treatment imaging and clinical examination without evidence of disease. We have not observed to date any rise in TTMV-HPV ctDNA in this cohort. Conclusions: This is the first single institutional report evaluating the clinical utility of TTMV-HPV DNA in a female cohort treated for HPV+ OPSCC. Utilization of this testing in a female population appears feasible in a community-based hospital setting. All pts had TTMV resolution after treatment and remained undetectable without recurrence. Despite the apparent trend toward lower sensitivity in females, the difference was not statistically significant and warrant further investigation in a larger multi-institutional study.
Immunotherapy for local/regional control of locally advanced orbital and periocular squamous cell carcinoma.
Authors: Esmaeli Bita , Fan Janet , Goldberg Hila , Lu Tracy , Akhave Neal , Guimaraes de Sousa Luana , Ferrarotto Renata 
Published: June 2024

e18034 Background: Periocular squamous cell carcinoma can be of eyelid skin, ocular surface (bulbar) or palpebral conjunctival, or of lacrimal sac/nasolacrimal duct mucosal origin, is relatively rare, and presents unique anatomic considerations due to proximity to the eye and inherent risk to ocular structures associated with high dose radiation therapy. We herein report on 17 patients with orbital or periocular SCC who were treated with immunotherapy (IO) to decrease surgical morbidity or to avoid high dose radiation therapy. Methods: Retrospective review of all previously unreported patients with orbital, conjunctival, or periocular SCC who were treated with IO either in the neoadjuvant setting prior to surgery or for treatment of periocular SCC with perineural spread into the orbit and skull base. Results: 17 patients, 12 men and 5 women (Age range: 44-92; median=70 years old) with orbital (n=6), conjunctival (n=5), or lacrimal sac/duct (n=2) squamous cell carcinoma (SCC), or periocular SCC with perineural spread into the orbit and skull base (n=4) who were treated with IO either as single drug (n= 11) or in combination with chemotherapy (n= 6 ). In all patients either cemiplimab or pembolizumab was used. In 13 patients IO was used in the neoadjuvant setting prior to planned surgery. In 4 patients with perineural spread as they had non surgically resectable disease, IO was used to avoid high dose radiation therapy with its inherent significant risk of ocular toxicity. Overall, 3 patients achieved complete response, 10 patients achieved partial response, and 4 patients had stable disease, using RECIST criteria. One of 5 patients with conjunctival SCC also had nodal metastasis at presentation and achieved a dramatic complete response of both the conjunctival tumor and the nodal metastasis and managed to avoid surgery altogether. This patient had a very high tumor mutation burden (TMB). One patient developed diabetic ketoacidosis as a side effect of IO; otherwise the adverse effects were low grade. Conclusions: IO either as single drug or in combination with chemotherapy has a fairly high response rate in patients with ocular adnexal, conjunctival or orbital SCC and in patients with periocular SCC with perineural spread in the orbit and skull base. Future prospective trails using IO for orbital and ocular adnexal SCC should be planned and should aim to correlate molecular data such as TMB with response.
Differential sensitivities of primary tumor and lymph nodes to induction chemotherapy and definitive radiotherapy in nasopharyngeal carcinoma.
Authors: Wang Juan , Cheng Yanshuang , Sun Ji , Zhong Yahua , Wu Qiuji 
Published: June 2024

e18037 Background: Risk factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy and their impact on clinical outcome in nasopharyngeal carcinoma (NPC) patients are undetermined. Methods: During June 2017 to June 2022, 105 NPC patients treated with comprehensive induction chemotherapy and concurrent chemoradiotherapy in our institute were eligible for analysis. Logistic regression analysis was used to identify factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy (IC). Correlation and regression analysis were used to investigate whether there was a linear relationship between the sensitivity to induction chemotherapy and the efficacy of chemoradiotherapy. COX regression models were used to find prognostic factors, and Kaplan-Meier survival analysis was used to compare prognostic differences among groups with different induction chemotherapy sensitivities. Results: The median patient follow-up time was 26.0 (95%CI: 23.0-34.0) months. Grouped according to the response of the tumor primary site and lymph nodes to induction chemotherapy, we identified potential risk factors associated with different response patterns: primary tumor non-responsive and lymph node non-responsive, performance status (PS) score (OR: 3.824, 95% CI: 1.005-14.558, p = 0.030) ; primary tumor non-responsive but lymph node responsive, hemoglobin level (OR: 1.033, 95% CI: 1-1.067, p = 0.039) ; primary tumor responsive but lymph node non-responsive, N stage (OR: 2.297, 95% CI: 0.103-0.857, p = 0.014), white blood cell count (OR: 1.32, 95% CI: 1.025-1.699, p = 0.030); lymphocyte count (OR: 3.499, 95% CI: 1.196-10.241, p = 0.018) and blood urea nitrogen (OR: 1.416, 95% CI: 1.055-1.901, p = 0.021); primary tumor responsive and lymph node responsive, N stage (OR: 2.02, 95% CI: 1.044-3.907, p = 0.033), red blood cell count (OR: 0.369, 95% CI: 0.157-0.865, p=0.018) and lymphocyte count (OR: 0.359, 95% CI: 0.151-0.856, p = 0.015). Tumor response 6 months after chemoradiotherapy was significantly associated with tumor response after induction chemotherapy (p = 0.037). Similarly, lymph node response 3 months after chemoradiotherapy was significantly associated with lymph node response after induction chemotherapy (p = 0.043). White blood cell count (HR: 1.327, 95% CI: 1.035-1.701, p = 0.026) and neutrophil count (HR: 1.405, 95% CI: 1.049-1.882, p = 0.022) was risk factors associated with progression free survival. Conclusions: In this study, we identified PS score and hemoglobin as potential factors associated with differential sensitivities of primary tumors and lymph nodes to induction chemotherapy in NPC. However, our study found the efficacy of induction chemotherapy could predict the efficacy of chemoradiotherapy or progression free survival.
Health disparities in acute myeloid leukemia: A decade-long analysis of Afro-Caribbean patients in a safety net New York City hospital.
Authors: Thida Aye Mon , Erdinc Burak , Homsy Sylvester , Jafri Firas Muhammad , Chiu Edwin , Gonsky Jason Parker 
Published: June 2024

e18515 Background: Acute Myeloid Leukemia (AML) in the Afro-Caribbean population is associated with poor outcomes due to disparities in health insurance and access to healthcare resources, among other factors, when compared to survival data in the national SEER database. This study reviews clinical characteristics and treatment outcomes of a cohort of 51 Afro-Caribbean patients who were diagnosed with AML and treated in the past 10 years in a urban safety net hospital in Brooklyn, New York. Methods: This is a retrospective review of patients diagnosed and treated for AML at New York City Health and Hospitals/Kings County from 2012 to 2022. Electronic Health Data was reviewed for clinicopathologic data and treatment outcomes. Analysis was performed through descriptive statistics with specific focus on insurance status and survival outcomes. Results: Our AML patient cohort had a mean age of 66, with 84% of patients identifying as Afro-Caribbean, and 51% being female. In this cohort, the AML risk stratification distribution based on 2022 European LeukemiaNet Risk classification includes 21 (41%) patients in the adverse-risk group, 23 (45%) patients in the intermediate-risk group, and 7 (14%) patients in the favorable-risk group. Of the 36 patients with molecular analysis data, 9 (25%) harbored a mutation in FLT3-ITD. Healthcare disparities are evident in insurance coverage, as 58% of patients lacked medical insurance, 19% had Medicare/Medicaid, and 23% had private insurance. At the time of this retrospective chart review, 35% of patients lacked any follow-up information, including appointments or status updates regarding their condition, vital status, or engagement with healthcare, possibly due to missed appointments, transfers, mortality, or other reasons. Of the 27 patients who were deemed transplant eligible, three (11%) successfully completed allogeneic bone marrow transplant. Reasons for non-transplantation include lack of a compatible donor, inadequate social support, insurance-related challenges, or patient refusal. Patients who completed induction and consolidation treatment with documented follow-up had a 23% survival rate at the five-year mark, compared to 31.7% overall survival rate reported in SEER data from 2013 to 2019. Conclusions: Our study highlights persistent healthcare disparities in Afro-Caribbean AML patients leading to poor survival outcomes. Despite treatment advancements, challenges related to insurance coverage, social support, follow-up care, and access to restricted, advanced care remain. Addressing these disparities calls for targeted interventions to enhance access and support systems for this vulnerable population.