bluuebunny/crossref_metadata_2025_split huggingface dataset:
A proteomic signature associated with prognosis in HPV-related locally advanced oropharyngeal squamous cell carcinoma (LA-OPSCC).
Authors: Liu Jia (Jenny) , Jackson Christopher , Anees Asim , Noor Zainab , Williams Steven , Porceddu Sandro , Liu Howard , Ladwa Rahul , Whitfield Joseph , Reddel Roger R , Zhong Qing , Panizza Benedict J , Robinson Phillip J 
Published: June 2023

6055 Background: Although HPV-related LA-OPSCC is associated with better prognosis than HPV-negative disease, ~30% of cases relapse despite curative-intent chemoradiotherapy. New prognostic biomarkers are needed to rationalise curative-intent treatment without compromising efficacy. We aimed to develop a proteomic signature associated with risk of recurrence from diagnostic biopsies of patients with HPV-positive OPSCC. Methods: We analysed 139 formalin fixed paraffin embedded archival core biopsy specimens from 124 patients with HPV-related (p16 IHC positive) T1-4N0-3M0 LA-OPSCC tumours. All patients were treated with definitive chemoradiotherapy at the Princess Alexandra Hospital (Brisbane, Australia) between 2007-2019. The cohort included 50 patients with recurrence less than five years from diagnosis and 74 age/performance-status matched patients with no recurrence. Proteomic analysis was performed utilizing data-independent acquisition mass spectrometry (DIA-MS). A proteomic prognostic signature associated with recurrence free survival (RFS) at five years was the primary endpoint of interest. It was developed using a computational pipeline comprising an initial univariate Cox model step, followed by multiple runs of multivariate Cox models with Least Absolute Shrinkage and Selection Operator (LASSO) regularization, and then a final step of recursive feature selection. Results: A total of 7,597 proteins were quantified and 665 were differentially expressed proteins between tumour and normal adjacent tissues. There were 5,199 proteins remaining in the tumour samples after filtering. RFS was significantly (q-value < 0.05) associated with 252 proteins, whose functions are enriched in adaptive and innate immunity and MAPK6/MAPK4 signalling pathways. A 16-protein signature associated with RFS stratified patients into low, intermediate, or high-risk groups (C-index = 0.885, p < 0.0001). The 16-protein signature outperformed clinico-pathological covariates including age, stage, ECOG and smoking history with the highest area under the receiver operating characteristic curve (AUROC 0.95). Conclusions: DIA-MS-based proteomics on core biopsies can be used to risk stratify HPV-related OPSCC patients. A 16-protein signature associated with RFS was successfully identified as a basis for future studies. Validation of this proteomic prognostic signature in independent cohorts is required and may be used to inform future clinical trials to better tailor upfront therapy.
Spatial relationships and immune subsets in the tumor immune microenvironment of head and neck cancers.
Authors: Henry Leanne E. , Krishnan Santhoshi , Patil Siddhi , Bellile Emily , Perera Chamila D. , Li Shiting , Qin Tingting , Taylor Jeremy M.G. , Rao Arvind , Chinn Steven B. , Rozek Laura S. , Sartor Maureen A. 
Published: June 2023

6061 Background: The tumor microenvironment provides important insights into cancer behavior and its response to treatment. In particular, the cellular composition and spatial arrangement of tumor immune infiltrates are associated with patient prognosis and survival. We optimized and employed a novel method using readily available hematoxylin and eosin (H&E) slide images, termed the G-cross score, which reflects immune cell infiltration levels and their proximity to tumor cells. The G-cross score is calculated by estimating the probability distribution of immune cells, of any type, within a certain distance from a tumor cell, with higher scores indicating greater immune cell infiltration. However, because G-cross scores are calculated from H&E slides, the method is unable to distinguish among immune cell types. Using head and neck squamous cell carcinoma (HNSCC) patients having both G-cross scores and bulk RNA-seq data, we determined which subset of tumor-infiltrating immune cell types best correlate with G-cross scores, and its predictive and prognostic value. Methods: G-cross scores were calculated for 425 HNSCC samples from University of Michigan, of which 64 had paired bulk RNA-seq data. We applied the cell-type deconvolution tool, CIBERSORTx, to identify immune cell type proportions based on RNA-seq data. G-cross scores were correlated against cell-type deconvolution results, immune cell activation expression signatures, and validated gene expression-based radiosensitivity index scores. Pearson's correlation coefficient and p-value using HPV status as a covariate in a linear model was calculated for each comparison. For survival and recurrence analysis, Cox proportional hazards multivariate regression was performed using the entire 425 sample cohort. Results: G-cross scores were significantly correlated with total T cells (R = 0.52, p = 4.63✕10-5), B cells (R = 0.33, p = 2.08✕10-2), and dendritic cells (R = 0.46, p = 7.71✕10-4), but not macrophages or mast cells. G-cross scores also had a positive correlation with T cell activation (R = 0.46, p = 2.17✕10-4) and B cell activation (R = 0.53, p = 1.24✕10-4) and were correlated with radiation sensitivity (R = -0.44, p = 6.67✕10-4). Survival analysis showed higher G-cross scores were associated with a longer time to recurrence and improved overall survival (p = 3.0✕10-4). Conclusions: G-cross scores are mainly driven by T cell and dendritic cell levels among tumor-infiltrating lymphocytes and are correlated with B and T cell activation. Importantly, G-cross scores also correlate with gene expression profiles associated with response to radiotherapy as well as time to recurrence and overall survival. G-cross scores may be an important biomarker of radiation response and indicative of protective immune subsets for HNSCC patients.
The impact of genetic predisposition to depression on quality of life in patients with head and neck cancer immediately post-treatment: A longitudinal study.
Authors: Henry Melissa , Chen Lawrence , Meaney Michael , Rosberger Zeev , Frenkiel Saul , Hier Michael , Zeitouni Anthony , Kost Karen , Mlynarek Alexander , Richardson Keith , Deamond Haley , Lang Jacob , Silver Jennifer , Ducharme Laurence , Mascarella Marco Antonio , Sadeghi Nader , Sultanem Khalil , Shenouda George , Cury Fabio , O'Donnell Kieran 
Published: June 2023

6063 Background: The primary aim of this study was to investigate the contribution of genetic predisposition to depression, through polygenic risk scores (PRS), on quality of life levels in patients with head and neck cancer (HNC) immediately post-treatment period (i.e., 3 months post-diagnosis). Methods: Prospective longitudinal study of 223 consecutive adult patients with HNC (72% participation) newly diagnosed with a first occurrence of primary HNC, including saliva samples analyzed using the Illumina PsychChip, psychometric measures, Structured Clinical DSM Interviews, and medical chart reviews. Results: Level of quality of life at 3 months on the FACT-G+H&N was predicted by (r2 = 0.51, r2 adj. = 0.33, p = 0.001) the polygenic risk score for depression (standardized b = -0.28, p = 0.01) and a previous history of suicidal ideation (standardized b = -0.25, p = 0.04). Other variables were non-significant in the analyses: sociodemographic (i.e., age, sex, education, living alone), psychosocial (i.e., SCID current and past diagnoses (trend), past history of abuse), and medical variables (i.e., cancer stage and site, HPV status, functional status/ECOG, treatment). Conclusions: Our results outline the importance of attending to genetic predisposition and past history of suicidal ideation as markers for quality of life compromise immediately post-treatment in patients with head and neck cancers. Strategies are needed to address psychosocial vulnerability early-on as part of pre-habilitation in the treatment of patients with head and neck cancer.
One-year reductions in cisplatin-related chronic kidney disease (CKD) in patients with head and neck (HNC) cancer treated with avasopasem manganese: A prespecified analysis from the phase 3 ROMAN trial.
Authors: Allen Bryan G. , Spitz Douglas R. , Mapuskar Kranti A. , Zepeda-Orozco Diana , Beardsley Robert Alan , Kennedy Eugene Paul , Anderson Carryn M. 
Published: June 2023

6066 Background: Cisplatin-induced acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD) are associated with increased production of reactive oxygen species, notably superoxide, in conjunction with alterations in mitochondrial electron transport chain complex activities in tubular epithelial cells (Mapuskar et al. Antioxidants 2021;10:1329). These pathologies can be targeted and thereby inhibited by increasing superoxide dismutase activity, which converts superoxide to hydrogen peroxide. The investigational new drug avasopasem manganese (AVA), a selective dismutase mimetic, ameliorated cisplatin-induced kidney injury in mice (Mapuskar et al. Redox Biol 2019;20:98). Preclinical results also demonstrate that AVA does not interfere with cisplatin anticancer activity (Mohanty et al. Cancer Res 2018;78[13_suppl]:Abstract 2929). Consistent with this, a retrospective analysis of 1- and 2-year kidney function of a limited subset of patients treated in a randomized, placebo (PBO)-controlled phase 2b trial of AVA to reduce severe oral mucositis (SOM) from radiotherapy and cisplatin (CRT) suggested that AVA prevented or reduced cisplatin-related CKD compared to PBO (Steinbach et al. J Clin Oncol 2020;38[15_suppl]:Abstract 12071). Methods: The ROMAN phase 3 trial (NCT03689712; ITT n = 407) of CRT in combination with AVA or PBO demonstrated improved incidence, duration, and onset of SOM by AVA (n = 241) vs PBO (n = 166) (Anderson et al. J Clin Oncol 2022;40[16_suppl]:Abstract 6005). In ROMAN, prospectively defined follow-up of serum creatinine (sCr) and estimated glomerular filtration rates (eGFR) were assessed every 3 months for 1 year following 7 weeks of CRT. Results: At 1-year follow-up, AVA was associated with significant improvements in preservation of eGFR ( P= 0.0008) and sCr ( P= 0.006) levels vs PBO. Grade 3+ CKD (eGFR < 60 mL/min) results through 12 months show 10% AVA vs 20% PBO (relative risk 0.55, P= 0.0043). Regarding cisplatin schedule, patients receiving Q3W therapy show grade 3+ CKD of 12% AVA vs 22% PBO; patients receiving QW therapy show AVA 9% vs PBO 19%. During treatment, nominal reduction of the incidence of AKI adverse events (0.8% AVA vs 3.6% PBO) was also observed. Conclusions: At 1-year follow-up, AVA appears to reduce cisplatin-related CKD in the study population and may also reduce cisplatin-related AKI during treatment. These results carry significance beyond CRT for HNC, potentially impacting platinum-containing regimens in other cancers. Clinical trial information: NCT03689712 .
Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin and radiotherapy in locoregionally advanced nasopharyngeal carcinoma: A single arm, open label, phase II clinical trial.
Authors: Fangzheng Chen , Deng Ying , Yang Fang , Wang Meng-Yao , Yin wen-Jing , Liu Jin-Quan , Chen Dong-Ping , Qi Bin 
Published: June 2023

6067 Background: To evaluate the efficacy of induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy in locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Methods: This is a prospective, single-arm, open-label, phase II trial. Patients with aged 18-65 years, newly diagnosed stage III-IVa (except T3-4N0) nasopharyngeal carcinoma were enrolled. Eligible patients received induction chemotherapy with docetaxel (60 mg/m² intravenously on days (D) 1, 22 and 43), Nedaplatin (60 mg/m² intravenously on D 1, 22 and 43) and fluorouracil (600 mg/m² per day as a continuous 120 hours (h) infusion on D 1-5, 22-26 and 43-47) every three weeks for three cycles, thereafter received intensity-modulated radiotherapy (IMRT) concurrently with nedaplatin (100mg/m2 intravenously on D 1, 22 and (or) 43) every three weeks for two or three cycles. The primary end point was objective response rate (ORR). The secondary end points included overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS) and local recurrence-free survival (LRFS). Results: Between March 2020 and June 2021, a total of 32 patients with LA-NPC were enrolled. With a median follow-up duration of 14.0 months (IQR 11.7-16.3), 32 patients (100%) achieved ORR at three months after treatment. The 12-month PFS was 95.7% (95% CI 87.3% to 100%) and the 12-month OS was 100%. The most common grade 3 or 4 adverse events during induction chemotherapy were neutropenia (3 [9.4%]), diarrhea (3 [9.4%]) and hepatoxicity (3 [9.4%]), followed by leucopenia (2 [6.3%]) and fatigue (1 [3.1%]). The most common grade 3 or 4 adverse events during concurrent chemotherapy were mucositis (3 [9.4%]), leucopenia (1 [3.1%]), neutropenia (1 [3.1%]) and thrombocytopenia (1 [3.1%]). All of these adverse events were manageable. Conclusions: Induction chemotherapy with nedaplatin, docetaxel and 5-fluorouracil followed by concurrent nedaplatin combined with radical radiotherapy showed promising antitumor activity and manageable toxicities in patients with LA-NPC. Further phase III randomized controlled trials are warranted to validate our findings. Clinical trial information: NCT04834206 .
Induction chemotherapy with nanosomal docetaxel lipid suspension (NDLS), cisplatin, and fluorouracil in patients with locally advanced head and neck squamous cell carcinoma.
Authors: Biswas Ghanashyam , Ganta Ranga Raman , N Kharthik , Kantharia Rajesh , Bondarde Shailesh , Raghu Raman Ramaiyer , Mahajan Manoj , Ahmad Ateeq , Sheikh Saifuddin , Ali Shoukath M , Paithankar Mahesh , Patel Lav , Rajani Anil , Bunger Deepak , Chaturvedi Alok , Ahmad Imran 
Published: June 2023

6074 Background: Nanosomal docetaxel lipid suspension (NDLS), a polysorbate-80 and ethanol free formulation, was developed to overcome the toxicity issues and to improve disease outcomes associated with conventional docetaxel. We evaluated the safety and efficacy of NDLS based TPF (NDLS, cisplatin and 5-fluorouracil [FU]) induction chemotherapy in patients with inoperable/unresectable Locally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC). Methods: In this multicentric, single arm, open label, Phase IV clinical study, patients with inoperable/ unresectable LA HNSCC received induction chemotherapy with NDLS (75 mg/m2; Day 1), cisplatin (75 mg/m2; Day 1) and 5-FU (750 mg/m2/day for 5 days) based TPF regimen every 3 weeks (q3w) for 4 cycles followed by radiotherapy. The study outcomes were overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Fifty patients were enrolled in this study. Most of the patients belonged to the age group of 35-64 years (86%) and had a WHO performance status of 1 (66%). In the modified intent-to-treat (mITT) population ( n = 40), the ORR after NDLS based TPF induction chemotherapy was 42.5%, which increased to 60.0% after loco-regional therapy. In the per-protocol (PP) population ( n = 14), the ORR was 64.3%, which increased to 80.0% after loco-regional therapy (Table). At 2 years, the PFS and OS rates were 82.5% and 97.5%, respectively, in the mITT population and 85.7% and 100% respectively, in the PP population. The most common grade 3/4 adverse effects reported were neutropenia (10%), leukopenia (6%), febrile neutropenia (4%), asthenia (2%), diarrhea (2%), and thrombocytopenia (2%) respectively. Grade 3/4 infusion-related reactions, hyperglycemia or neuropathy were not reported. Conclusions: NDLS based induction chemotherapy was effective and well-tolerated in the treatment of inoperable LA HNSCC and showed high response rates. Clinical trial information: CTRI/2017/12/010938 .[Table: see text]
Neoadjuvant pembrolizumab, GX-188E, and GX-I7 in patients with human papillomavirus-16- and/or 18-positive head and neck squamous cell carcinoma: Single-arm, phase 2 trial with single cell transcriptomic analysis and artificial intelligence-powered spatial analysis.
Authors: Kim Hye Ryun , Kim Chang Gon , Koh June-Young , Hong Min Hee , Hong Hyun Jun , Kim DaHee , Sim Nam Suk , Yoon Sun Och , Kim Gamin , Lee Jung Eun , Son Wonrak , Lee Chang , Kim Kyung Hwan , Lee Jeong Seok , Yoo Donggeun , Ock Chan-Young , Koh Yoon Woo 
Published: June 2023

6075 Background: With the increasing prevalence of head and neck squamous cell carcinoma (HNSCC) associated with human papilloma virus (HPV) infection, effective treatment strategies for HPV-positive HNSCC are urgently needed. Here, we present the results of neoadjuvant checkpoint blockade of pembrolizumab, therapeutic HPV DNA vaccine of GX-188E, and long-acting interleukin-7 of GX-I7 for patients with resectable HPV-16 and/or 18-positive HNSCC. Methods: In this single-arm, phase 2 trial, patients with resectable HPV-16 and/or 18-positive HNSCC were enrolled. Patients were given pembrolizumab 200mg on day 1 and day 22; GX-188E 2mg on day 1, 8, and 22; and GX-I7 1200 ug/kg on day 8 before surgical resection. Major pathologic response (MPR; defined as residual viable tumor of less than or equal to 10%) was primary endpoint with null and alternative hypothesis of MPR rate ≤5% and ≥35%, respectively. Secondary objectives were safety, recurrence, and survival. Results: Of the 11 patients included, all underwent surgical resection after neoadjuvant treatment without delays in surgery or increased surgical complications. MPR was achieved in seven patients (63.6%) and pathologic complete response was achieved in four patients (36.3%), which met the primary endpoint. Single cell RNA sequencing of baseline and post-treatment paired specimens revealed that the proportion of follicular helper T cell cluster, featured with CXCR5 and BCL6 expression, was significantly increased among tumor-infiltrating immune cells, accompanied with the reinvigoration of CD8 T cell cluster toward less exhausted phenotypes, represented with the upregulation of TCF7 and CD28 expression. In addition, artificial intelligence-powered spatial analysis revealed that triple combination significantly increased the density of tumor-infiltrating lymphocytes, completely converting immune-desert and immune-excluded type of tumor to inflamed immune phenotype. Conclusions: Neoadjuvant pembrolizumab, GX-188E, and GX-I7 showed promising activity and manageable safety profile in patients with resectable HPV-16 and/or 18-positive HNSCC. Therapeutic induction of brisk immune responses significantly reshaped the tumor microenvironment and associated with pathologic regression, warranting further investigation of pembrolizumab, GX-188E, and GX-I7 for patients with HPV-positive HNSCC. Clinical trial information: NCT05286060 .
Association of biophysics-based biomarker with tumor volumetric response in breast cancer treated with immunotherapy.
Authors: Cook Daniel , Pfeiffer John R. , Peterson Joseph R. , Liadis Nicole , Biancalana Matthew , Lopez Dorys , Cole John A. , Antony Anuja K. 
Published: June 2023

608 Background: The treatment landscape of triple negative breast cancer (TNBC) has rapidly changed in recent years, with immuno-oncology (IO) therapies, such as immune checkpoint inhibitors, leading to improvement in patient outcomes. However, the number of patients who benefit is less than 15%, and the therapy itself can prompt severe immune-related adverse events. Breast cancer tumor volume measurements derived from magnetic resonance imaging (MRI) have proven to be a strong predictor of outcome (survival) in patients who either achieve pathological complete response (pCR) or have residual cancer burden (RCB) (ACRIN6657/CALGB150007 I-SPY1). Using an integrative computational approach, we developed both the TumorIO biomarker and the TumorIO Score to predict response to IO therapy in breast cancer patients. Here, we assess the volumetric response in IO-treated patients and its relationship with the TumorIO Score. Methods: We assessed the relationship between breast tumor volumetric response to IO therapy and the TumorIO Score, a previously developed metric that relates probability of IO responsiveness to spatially-resolved tumor biology. We grouped patients into TumorIO Score high vs. low populations, and compared final volumes assessed by MRI and percent response to therapy between groups. Results: We analyzed the volumetric response of IO-treated patients from the I-SPY2 trial and from an independent cohort (total n = 67). Over 96% of the IO-treated patients in the I-SPY2 trial (n = 55) had a greater than 90% volumetric response, while in the independent cohort (n = 12) only 50% of patients had greater than 90% volumetric response. Across both cohorts, 95.8% of patients with a high TumorIO Score achieved > 90% reduction in tumor volume. Additionally, we identified three patients in our cohort that appeared not to respond to IO therapy, who were later classified as progressor, pseudo-progressor, and non-responder patients. The TumorIO biomarker was able to differentiate these three patients, as it associates a unique distinctive biological phenomenon with either response or lack of response. Conclusions: The TumorIO Score provides a novel technology to address several challenges in neoadjuvant IO therapy, namely: predicting which patients are likely to have pCR in response to IO therapy, as well as identifying patients likely to have a substantial volumetric response to IO. Additionally, this method may facilitate subcategorizing patients likely to show radiological pseudo-progression prior to IO administration, although a larger cohort is needed to validate these findings.