bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 1 clinical trial of DB-020 intratympanic injections administered prior to high dose cisplatin chemotherapy to reduce ototoxicity.
Authors: Rischin Danny , O'Leary Stephen John , Hart Christopher David , Diwakarla Chandra Sai , Seetharamu Nagashree , Lee John , Raines Shane , Quigley Tera , Wolff Heather M , Lapuerta Pablo , Panizza Benedict J 
Published: June 2023

6043 Background: Hearing loss with cisplatin (CP) chemotherapy is common. DB-020 is a formulation of thiosulfate for intratympanic (IT) injection being developed to reduce CP ototoxicity. The primary objective of this Phase 1 study was to evaluate the safety and tolerability of repeated IT injections of DB-020. A secondary objective was to compare hearing changes with DB-020 vs. placebo. Methods: Subjects scheduled for at least 3 cycles of CP and cumulative exposure of ≥280 mg/m2 were randomized to blinded, bilateral, IT injection with DB-020 (12% or 25%) in one ear and placebo in the other, once every 3 or 4 weeks, up to 3 hours before receiving CP. Subjects with moderate or severe hearing loss at baseline were excluded. Ototoxicity was defined by American Speech-Language-Hearing criteria: ≥20 dB threshold increase at any one test frequency, or ≥10 dB threshold increase in any two adjacent frequencies, or loss of response at three consecutive frequencies where responses were previously obtained. Severe ototoxicity was ≥20 dB threshold increase in any two adjacent frequencies. A pre-specified interim analysis evaluated safety, ototoxicity (with Mcnemar’s test using the last observation carried forward), and average threshold shifts (from air conduction audiometry, analyzed with a mixed model with repeated measures). Results: Nineteen subjects were randomized, with mean age of 57 years (84% male and 100% white) and mean cumulative CP dose 248 mg/m2. Most (95%) had head and neck cancers (5% had lung cancer). Seventeen subjects had both baseline and follow-up audiometry, and 16/17 had baseline audiograms within 5 dB of the median threshold for age-matched controls. Free CP systemic levels were similar to reference values. Ear pain (15/19 subjects, 78.9%) and tinnitus (8/19 subjects, 42.1%) were common. Ear pain was more common in DB-020 treated ears, and tinnitus was more common in placebo treated ears. There were no tympanic perforations, no serious adverse events in the category of ear and labyrinth disorders, and no deaths. Ototoxicity was significantly more common and more severe in placebo treated ears (Table). As the overall study objectives were met at this interim analysis, no further enrollment was pursued. Conclusions: In this initial clinical trial experience there was no significant safety signal, and DB-020 IT injections showed a meaningful reduction in cisplatin ototoxicity. These results warrant further clinical development. Clinical trial information: NCT04262336 . [Table: see text]
Association between locoregional failure and NFE2L2/KEAP1/CUL3 pathway mutations in NRG/RTOG 9512: A randomized trial of hyperfractionation vs. conventional fractionation in T2N0 glottic squamous cell carcinoma (SCC).
Authors: Guan Li , Torres-Saavedra Pedro A. , Zhao Xiaobei , Major Michael B. , Holmes Brittany J. , Nguyen Ngan , Kumaravelu Parasakthy , Hodge Tim , Diehn Maximilian , Zevallos Jose , Emami Bahman , Sagar Stephen M. , Morrison William H. , Schultz Christopher J. , Caudell Jimmy J. , Jones Christopher U. , Yom Sue S. , Harris Jonathan , Le Quynh-Thu , Hayes David N. 
Published: June 2023

6054 Background: Radiotherapy (RT) is the primary treatment for patients with T2N0 glottic SCC. ~30% of these patients experience locoregional relapse despite dose escalation. Mutations in the NFE2L2/KEAP1/CUL3 pathway have been linked to radioresistance preclinically and in small retrospective studies. We tested the hypothesis that patients with T2 glottic SCCs having these mutations would show radioresistance and more local (LF) and locoregional failures (LRF) when treated with RT compared to those without, using samples from a phase III trial. Methods: Of 250 randomized patients with T2N0 glottic SCC receiving definitive RT in RTOG 9512, 119 had available biospecimens that were subjected to amplicon-based next generation sequencing (appropriate to low-input DNA from biopsy specimens) to assess for presence of NFE2L2/KEAP1/CUL3 mutations without regard to outcomes. The association between binary mutation status and LF, LRF, disease-free survival (DFS), and overall survival (OS) was assessed using (cause-specific) Cox models (2-sided alpha of 0.05). LR/LRF rates were estimated by the cumulative incidence method and DFS/OS rates by the Kaplan-Meier method. Results: Nineteen of 119 patients (16.0%; 95% confidence interval [CI] 9.4, 22.6) had mutations in the NFE2L2/KEAP1/CUL3 pathway. Patient and tumor characteristics were similar between those with and without mutation.There were 32 LF, 37 LRF, and 80 DFS events, and 52 deaths. Patients with mutation compared to those without had significantly higher LF and LRF rates (Table). Median DFS was 0.9 years (95% CI 0.4, not reached) for the mutation group compared to 4.2 years (95% CI 3.2, 6.4) for those without. The hazard ratio (HR) for DFS was significantly higher for the mutated compared to the non-mutated group in the first 2 years after randomization but declined thereafter (Table), likely due to limited events after 2 years in the mutation group. There was no significant difference in OS between the two groups (HR = 0.76; 95% CI 0.35, 1.6; p = 0.48). Conclusions: NFE2L2/KEAP1/CUL3 pathway mutations may predict radiation treatment failure in T2N0 glottic cancer. They may also be a prognostic biomarker for DFS, but the current evidence supports the harmful effect of these mutations only during the first 2 years from randomization. Clinical trial information: NCT00002727 . [Table: see text]
Clinical validity of TTMV-HPV DNA liquid biopsies for the diagnosis and surveillance of HPV-associated oropharyngeal carcinoma.
Authors: Roof Scott A. , Ferrandino Rocco , Chen Sida , Kappauf Catharine , Barlow Joshua , Gold Brandon , Westra William , Berger Michael , Teng Marita S , Khan Mohemmed N , Bakst Richard Lorne , Sindhu Kunal K. , Genden Eric Michael , Chai Raymond L , Posner Marshall R. , Misiukiewicz Krzysztof 
Published: June 2023

6060 Background: While there are several HPV biomarker assays, a commercially available assay evaluating tumor tissue modified viral DNA (TTMV-HPV DNA) (NavDx, Naveris Inc, Natick, MA) has shown impressive results in clinical trials and small cohort studies. Our aim was to establish the clinical efficacy of plasma TTMV-HPV DNA testing in the diagnosis and surveillance of HPV-associated OPSCC in a contemporary, real-world clinical setting. Methods: In this retrospective analysis, we evaluated the accuracy of the TTMV-HPV DNA assay in detecting HPVOPSCC in the diagnostic (pre-treatment) and surveillance phases of care between April 2020 and October 2022. For the diagnostic cohort, patients with OPSCC and at least one TTMV-HPV DNA measurement prior to initiation of primary therapy were included in the analysis. For the surveillance cohort, all TTMV-HPV DNA tests performed 3 months after completion of primary therapy for pathologically confirmed HPV-associated OPSCC were evaluated, regardless of pre-treatment TTMV-HPV DNA testing. Patients with suspected recurrence, but without pathologic confirmation, were excluded. HPV status was defined utilizing positive p16 staining on immunohistochemistry (93.2% diagnosis; 97.9% surveillance) or HPV polymerase chain reaction/in situ hybridization (79.6% diagnosis; 89.7% surveillance). Results: In the diagnostic cohort, 163 patients were included. The cohort included mostly men (87%) with median age 63, of which 93.3% had HPVOPSCC versus 6.7% had HPV negative OPSCC. The sensitivity in pre-treatment diagnosis was 91.5%; its specificity was 100%. In the surveillance cohort, 591 tests conducted in 290 patients were evaluated. 23 patients had pathologically confirmed recurrences. The assay demonstrated 79.2% sensitivity and 100% specificity in detecting the recurrences. Positive predictive value was 100% and negative predictive value was 98.2%. The median lead time from positive test to pathologic confirmation was 28 days, 6/18 (30%) had lead time >50 days (maximum 507 days). Conclusions: The commercially available NavDx TTMV-HPV DNA assay demonstrated 100% specificity, and therefore excellent positive predictive value, in both diagnosis and surveillance. However, the sensitivity was lower, 91.5% for the diagnosis cohort and 79.2% for the surveillance cohort, signifying that a negative value may require further work-up. Further studies will be required to determine the optimal timing of testing and how results should inform treatment decisions. [Table: see text]
Peripheral blood epigenetic immune-profiling and survival outcomes with anti-programmed death (PD)-1 based therapy in recurrent/metastatic (R/M) squamous cell carcinoma of head and neck (SCCHN).
Authors: Sehgal Kartik , Zhang Ze , Shirai Keisuke , Butler Rondi , Lee Min Kyung , Molinaro Annette , Wiencke John Kirk , Koestler Devin , Salas Lucas A , Christensen Brock C , Kelsey Karl , Haddad Robert I. 
Published: June 2023

6062 Background: Most patients with R/M SCCHN do not derive durable benefit from standard-of-care anti-PD-1-based therapy. The currently utilized biomarker, PD-ligand-1 combined proportion score is limited by the availability and heterogeneity of tumor samples. There is an unmet need to develop easily accessible peripheral blood-based biomarkers for response to immunotherapy. Methods: We are conducting a prospective multi-center study to identify peripheral blood derived DNA-based methylation biomarkers measured in patients with R/M SCCHN on treatment with FDA-approved anti-PD-1 based therapy. DNA isolated from these samples undergo bisulfite conversion, methylation profiling using Illumina EPIC microarray, and cellular deconvolution to generate peripheral blood immune profiles (PMID 35140201), including granulocytic (g) and monocytic (m) myeloid derived suppressor cell (MDSC) scores. Associations between baseline peripheral blood immune profiles before the start of treatment with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier curves and Cox proportional hazards models adjusted for age and sex. Additionally, logistic regression models adjusted for age and sex were utilized to investigate the baseline immune profiles between subgroups of patients who received anti-PD-1 monotherapy with durable clinical benefit for at least 1 year (Group A) versus progression or death within 100 days (Group B) from start of therapy. Results: 61 patients with R/M SCCHN who received anti-PD-1 based therapy as of Oct 31, 2022, were eligible for this preliminary analysis. Mean (SD) age of the entire population was 66.4 (11.8) years, 82% were male. gMDSC score was the only immune parameter with a statistically significant association with PFS (HR 2.6 (1.40 – 4.87) independent of age and sex, with higher scores stratified by median value associated with shorter PFS (Median PFS: 75 days vs. 145 days). Memory CD4 T cells, total CD4 T cells, percentage of T regulatory /CD4 cells, and absolute memory B cells were significantly associated with OS in this population, independent of age and sex (Table). Among the subgroup treated with anti-PD-1 monotherapy, Group A with durable benefit (n = 7, 86% male, mean age: 64.7 years) had significantly higher proportion of CD4 naïve/total CD4 cells (p = 0.03), and significantly lower gMDSC (p = 0.015) & mMDSC (p = 0.000049) scores, compared with Group B (n = 27, 78% male, mean age: 66.4 years). Conclusions: Peripheral blood DNA-based epigenetic immune profiling can recognize clinically relevant methylation biomarkers of benefit from anti-PD-1 therapy before the start of treatment. [Table: see text]
Radiotherapy alone versus concurrent or adjuvant chemoradiotherapy for nasopharyngeal carcinoma patients with negative Epstein-Barr virus DNA post-induction chemotherapy.
Authors: Kong Fang-Fang , Pan Guang-Sen , Du Cheng-Run , Zhang Zhen , Hu Chaosu , Ying Hong-Mei 
Published: June 2023

6064 Background: Induction chemotherapy (IC) plus concurrent chemoradiotherapy has been recommended as the standard treatment for locoregionally advanced nasopharyngeal carcinoma(LA-NPC). However, concurrent chemotherapy was associated with increased toxicities, poor tolerance, and low completion rates. The aim of this study was to compare the efficacy and toxicity of IC+ radiotherapy (RT) and IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) in patients with negative post-IC EBV DNA. Methods: A total of 547 NPC patients with negative plasma EBV DNA post-IC were included. Patients were classified into the IC+RT group and the IC+ concurrent or adjuvant chemoradiotherapy (IC+CCRT/AC) group. Locoregional relapse-free survival (LRFS), distant metastasis-free survival (DMFS), overall survival (OS), and progression-free survival (PFS) were estimated and compared using the Kaplan-Meier method. Propensity-score matching (PSM) was performed to balance the variables. Results: The median follow-up time was 37 months. The 3-year LRFS, DMFS, OS, and PFS rates for the whole group were 92.2%, 92.4%, 96.4%, and 84.4%, respectively. There was no significant difference in LRFS, DMFS, OS, and PFS between the IC+RT and the IC+CCRT/AC group both before PSM (3-year rates of 91.1% vs. 92.6%, p = 0.94; 95.6% vs. 91.5%, p = 0.08; 95.2% vs. 96.8%, p = 0.80; 85.9% vs. 84.0%, p = 0.38) and after PSM (90.7% vs. 92.7%, p = 0.77; 96.8% vs. 93.7%, p = 0.29; 94.5% vs. 93.9%, p = 0.57; 84.7% vs. 85.6%, p = 0.96). Multivariate analysis demonstrated that treatment schedule was not an independent predictor for survival rates. Patients in the IC+RT group had fewer treatment-related acute toxicities and better tolerance. Conclusions: IC+RT displayed similar survival outcomes as IC+CCRT/AC for NPC patients with negative post-IC EBV DNA. Our current data seems not to support the routine use of concurrent or adjuvant chemotherapy after IC for unselected patients.
Prospective study of integrating post-radiotherapy [18F] fluorodeoxyglucose-positron emission tomography/computed tomography scan and plasma Epstein-Barr virus DNA in surveillance of locoregionally advanced nasopharyngeal carcinoma.
Authors: Tang Lin-Quan , Liu Li-Ting , Yang Zhen-Chong , Shen Jia-Yi , Luo Mei-Juan , Hu Ying-Ying , Lu Zi-Jian , Xiao Bei-Bei , Yang Jin-Hao , Lv Xiao-Fei , Jia Guo-Dong , Guo Shan-Shan , Chen Qiu-Yan , Fan Wei , Mai Hai-Qiang 
Published: June 2023

6072 Background: To evaluate the role of [18F] fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan at 12-weeks after the end of Radiotherapy (RT) integrated with plasma EBV DNA in surveillance and standardized implementation of locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This prospective study was conducted in patients with stage III-IVa LA-NPC. FDG-PET/CT examination and plasma Epstein-Barr virus (EBV) DNA measurements was performed pretreatment and at 12-weeks after the end RT. The primary study endpoint was the negative predictive value (NPV) and other supporting diagnostic test characteristics of 12-weeks FDG-PET/CT for the surveillance of residual locoregional disease and new distant metastasis. Results: From June 2018 to December 2019, 506 eligible patients were enrolled and entered follow-up (median,45 months). At 12 weeks after the end of RT, there were 22 (4.3%) patients have residual locoregional disease, 30 (5.9%) patients developed distant metastasis and 6 (1.2%) patients presented both residual locoregional disease and distant metastasis. The NPV of 12-weeks FDG-PET/CT for overall residual diseases and distant metastasis was 96.3% (95% confidence interval [CI], 94.0%-97.8%) with sensitivity of 72.4% (95%CI, 58.9%-83.0%), specificity of 93.3% (95%CI, 90.5%-95.4%), positive predictive value (PPV) of 58.3% (95%CI, 46.1%-69.6%) and accuracy of 90.9% (95%CI, 88.4%-93.4%). In EBV DNA-based risk subgroups, the NPV of 12-weeks PDG-PET/CT was 96.8% (95%CI, 94.5%-98.2%) in patients with undetectable 12-weeks plasma EBV DNA and 87.0% (95%CI, 65.3%-96.5%) in patients with detectable 12-weeks plasma EBV DNA. Conclusions: 12-weeks PDG-PET/CT was reliable in the surveillance of LA-NPC and could help optimize the follow-up strategy and provide implications for timely and effective therapeutic regimen, especially for patients in different EBV DNA-based risk groups. Clinical trial information: NCT03601390 .
CT radiomic signature to predict overall survival and chemotherapy benefit in stage I and II HPV-associated oropharyngeal carcinoma.
Authors: Song Bolin , Yang Kailin , Viswanathan Vidya Sankar , Lee Jonathan , Stock Sarah , Fu Pingfu , Saba Nabil F. , Koyfman Shlomo A. , Lewis James S. , Madabhushi Anant 
Published: June 2023

6073 Background: Chemoradiation is the standard of care for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). However, not all patients would benefit from chemotherapy, especially patients with low-risk characteristics. We aim to develop and validate a prognostic and predictive radiomic image signature (pRiS) to inform survival and chemotherapy benefit in stage I and stage II HPV-associated OPSCC. Methods: Radiographic scans for 491 patients with stage I and stage II HPV-associated OPSCC were acquired from 4 independent sources and divided into three cohorts D1-D3. D1 comprised computed tomography (CT) scans from 60 radiotherapy treated patients and was used to identify prognostic features via a LASSO Cox model to predict overall and disease-free survival. The prognostic performance of pRiS was evaluated on two test sets (D2, n = 162; D3, n = 269) using concordance index (C-index). An integrated nomogram was developed to demonstrate the incremental value of the pRiS to the existing clinical factors for individualized survival estimation. Patients from D2 and D3 who received either radiotherapy alone or chemoradiation were used to validate pRiS as predictive of added benefit of chemotherapy. Results: Seven radiomic features were selected to construct the image biomarker pRiS, which was found to be prognostic of overall survival (OS) on univariate analysis in D2 (hazard ratio [HR] = 2.14, 95% confidence interval [CI], 1.1–4.16, p = 0.02) and D3 (HR = 2.74, 95% CI, 1.34–5.62, p = 0.006). Chemotherapy was associated with improved OS for high-pRiS patients in both D2 (radiation vs chemoradiation, HR = 4.47, 95% CI, 1.73–11.6, p = 0.002) and D3 (radiation vs chemoradiation, HR = 2.99, 95% CI, 1.04–8.63, p = 0.04). In contrast, chemotherapy did not improve OS for low-pRiS patients, which indicates these patients did not derive additional benefit from chemotherapy and could be considered for treatment de-escalation. Conclusions: The proposed radiomic signature was prognostic of patient survival and the binary pRiS group informed chemotherapy benefit for stage I and II HPV-associated OPSCC patients. [Table: see text]
Neoadjuvant chemoimmunotherapy for the treatment of locally advanced laryngeal and hypopharyngeal squamous cell carcinoma: A single-arm phase 2 clinical trial.
Authors: Chen Yanfeng , Yang Ankui , Mao Yan-Ping 
Published: June 2023

6077 Background: Standard treatment for patients with locally advanced laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC) is total laryngectomy, which seriously affects the quality of life. Neoadjuvant treatment with Nab-paclitaxel plus cisplatin(TP) has favorable efficacy with acceptable toxicity for laryngeal preservation in LHSCC. Programmed death 1 (PD-1) blockade plus chemotherapy has shown a survival benefit and recommended as the first-line treatment in recurrent or metastatic head and neck cancer, but the safety and activity in the combination of TP and PD-1 blockade in locally advanced LHSCC need investigation. Methods: In this single-center, single-arm, phase 2 trial, newly diagnosed pts with stage T3-4N0-3M0 laryngeal SCC or T2-4N0-3M0 hypopharyngeal SCC were recruited. Eligible patients received chemotherapy [Nab-paclitaxel 240 mg/m2 plus cisplatin 75 mg/m2] and toripalimab[240 mg, d1]every 3 weeks for 3 cycles. After induction treatment, patients achieving clinical partial response (cPR) or complete response (cCR) received definitive radiotherapy, while those with stable diseases(SD) and progression disease(PD) received surgery plus adjuvant radiotherapy. Toripalimab was given intravenously once every 3 weeks for up to 10 cycles, including 3 cycles before. The primary endpoint was the objective response rate (ORR) according to RECIST 1.1 by investigator assessment to neoadjuvant chemoimmunotherapy. The secondary endpoints included laryngectomy-free survival (LFS), disease failure-free survival (DFS)and overall survival OS at 2 years, quality of life (QOL) and toxic effects. Results: From October 2020 to May 2022，25 patients received neoadjuvant chemoimmunotherapy (median age 58 years; 23.9% men), 52% (13/25) and 48% (12/25) were hypopharyngeal and laryngeal squamous cell carcinoma. 80% (20/25) were clinical T3/4 and 64.0% (16/25) ≥N2. After neoadjuvant chemoimmunotherapy, 2 patients achieved CR, 21 achieved PR, with an ORR of 92%(23/25), 23 patients with CR/PR of the primary tumor received concurrent radiotherapy and immune maintenance therapy, 2 patients with SD/PD received laryngectomy. At a median follow-up of 17 months (range 8-27 months), 1-year DFS was 88.0% , 1-year OS was 96.0% , 1-year LPS was 92.0%, Respectively, only grade 1-2 adverse events occurred in 100% of patients, including loss of appetite (100%), anemia (92.0%), nausea (84.0%), vomiting (52.0%), hypothyroidism (16.0%), peripheral neuritis (20%), leukopenia (12.0%), rash (12.0%). Conclusions: Neoadjuvant treatment with TP plus toripalimab achieved impressive ORR and 1-year LPS rate with manageable toxicities in patients with LHSCC. Further follow-up is needed to confirm the long-term efficacy. Clinical trial information: ChiCTR2000033506 .