bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of radiation treatment failure in head and neck cancer with differential immune infiltrate.
Authors: Abdelhakiem Mohamed , Bao Riyue , Ferris Robert L , Pickering Curtis R. , Skinner Heath Devin 
Published: May 2020

6558 Background: Previously we have shown that PD-L1 expression is associated with treatment failure in Head and Neck Cancer (HNSCC) treated with radiation. We have further evaluated the effect of pre-treatment immune infiltrate on treatment failure following radiation. Methods: A total of 75 patients with HPV negative HNSCC treated with surgery and post-operative radiation were included in this study. Pre-treatment tumors were examined via RNA-Sequencing utilizing an Illumina platform. These data were then subjected to immune profiling utilizing publicly available software (xCell) to infer relative enrichment of immune cell infiltrate per sample. Each immune cell type detected at any level in at least 15 tumors was then evaluated for effect on loco-regional recurrence using Cox-regression analysis. Clinical variables included in this analysis include tumor stage, nodal stage and treatment site. Survival analysis was performed utilizing the method of Kaplan Meier, with log rank statistics used to test for significant comparisons. Results: The majority of HNSCCs analyzed in this study were from the oral cavity (65.3%), followed by the larynx and hypopharynx (28%) and oropharynx (6.7%). The total median dose of radiation delivered was 60 Gy (range: 36-79.2) and median follow up in living patients was 80.5 months (range: 7-190). On univariate analysis, no measured clinical variable was significantly associated with loco-regional recurrence (LRR). Similar to our previous studies in other HNSCC cohorts treated with radiation, PD-L1 expression was negatively associated with LRR (p = 0.005). Additionally, multiple immune cell infiltrates were negatively associated with LRR including: Th2 helper cells (p = 0.007), CD8+ central memory T cells (p = 0.02), immature dendritic cells (p = 0.037), CD4+ memory T cells (p = 0.043). In a multivariate model including these immune cell subsets, Th2 helper cells, CD8+ central memory T cells and immature dendritic cells remained significantly negatively associated with LRR following radiation. Conclusions: This analysis demonstrates the importance of pre-treatment immune infiltrate on outcomes in HNSCC and points to potential avenues to explore to augment response to radiation.
Prognostic value of radiological extranodal extension detected by computed tomography for predicting outcomes in head and neck squamous cell cancer patients treated with radical chemoradiotherapy.
Authors: Mahajan Abhishek , Chand Ankur , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Sable Nilesh , Ahuja Ankita , Menon Nandini Sharrel , Agarwal Jaiprakash , Laskar Sarbani Ghosh , D'Cruz Anil , Chaturvedi Pankaj , Chaukar D. , Pai P. S. , Pantvaidya Gouri , Thiagarajan Shivakumar , Vaish Richa , Rane Swapnil , Prabhash Kumar 
Published: May 2020

6560 Background: As per the AJCC 8th edition ENE/ECS is the most important predictor for N staging of HNSCC and is one of the key predictor of outcomes. Because ENE/ECS is based on pathological findings after surgery and it is difficult to predict outcomes for locally advanced squamous head and neck cancer (LASHNC) treated radically with CCRT. We hypothesized that ENE assessed by CT imaging (rENE) may directly correlate with outcomes in LASHNC treated radically with CCRT. Methods: This open-label, investigator-initiated, phase 3, randomized trial was conducted from 2012 to 2018. Adult patients with LASHNC who were fit for radical chemoradiation were randomized 1:1 to receive either radical radiotherapy (66-70 grays) with concurrent weekly cisplatin (30 mg/m2) (CRT) or the same schedule of CRT with weekly nimotuzumab (200 mg) (NCRT). 536 patients were accrued,182 were excluded due to non-availability DICOM CT scan, 354 patients were analysed for rENE (based on 6 criterion for metastasis and 3 for rENE). Near equal distribution of patients was achieved in CRT arm (170 patients) and NCRT arm (184 patients). There were 181 (51.1%) oropharynx and 173(48.9%) larynx and hypopharynx patients. We evaluated association of radiological ENE and clinical outcomes.The endpoints were disease-free survival (DFS), duration of locoregional control (LRC), and overall survival (OS). Results: There were 244(68.9%) patients with radiologically metastatic nodes, out of which 140(57.3%) had rENE. There was no significant association between rENE and CRT (p value 0.3) or NCRT (p value 0.412). The median follow-up was 33.0 months (95%CI 30.7-35.2 months). Complete response was achieved in 204 (57.6%) cases, PR/SD in 126(35.6%) cases and PD in 24(6.8%) cases. rENE positive patients had poor overall 3-year survival (46.7%), poor DFS (48.8%) and LRC (39.9%) than rENE negative cases (63.6%, 87%, 60.4%). rENE positive cases had 1.71 times increase chances of incomplete response than rENE negative cases. Overall stage, clinical positive node, response, rENE and site were the only significant factors for predicting OS, DFS and LRC. Conclusions: In conclusion, pre-treatment rENE can be regarded as an independent prognostic factor for survival (OS, DFS, LRC) in patients with LASHNC treated radically with CCRT. Pre-treatment rENE is not only associated with CCRT response but is also associated with poor prognosis and hence rENE, as an imaging biomarker, can stratify responder’s vs non-responders. Clinical trial information: CTRI/2014/09/004980 .
Detection of somatic mutations in saliva of patients with oral cavity squamous cell carcinoma.
Authors: Izumchenko Evgeny , Hasina Rifat , Hariharan Arun K , Shanmugam Ashwini , Irusappan Sivaraj , Maji Shiuli , Bahadur Urvashi , Veeramachaneni Vamsi , Bettadapura Radhakrishna , Ravichandran Aarthi , Hariharan Ramesh , Gupta Vaijayanti , Rao Vishal Uchila Shishir , Bagadia Ritvi K , N.M.L Manjunath , Lingen Mark W. , Agrawal Nishant 
Published: May 2020

6562 Background: Oral cavity squamous cell carcinoma (OCSCC) frequently presents as clinically advanced disease with poor prognosis. When diagnosed at early stages, survival rates approach 80%, underscoring the need for validated, cost-effective detection methods. OCSCC is driven by the serial acquisition of genetic alterations. Tumor-defining somatic mutations are attractive biomarkers and hence their presence in saliva may be associated with malignancy as shown in a few proof-of-concept studies, including our previous work. Based on this premise, we present a low-cost, accurate, next generation sequencing (NGS) test with high clinical utility aimed at detecting mutations in the saliva for early diagnosis and potential screening of OCSCC. Methods: We have designed a custom NGS panel that covers exons of 7 most frequently mutated genes in OSCC. This minimal gene set derived from the analysis from 3 public datasets, predicted incidence of at least one somatic aberration in 89% of patients. We recruited 91 treatment-naïve OCSCC patients and profiled DNA from tissue and matched pre-operative saliva using this test. We also tested DNA from 12 subjects with premalignant lesions with high-grade oral dysplasia and matched saliva. Results: Using stringent variant calling criteria, at least one somatic variant was detected in 88 (96%) of the 91 primary tumors. 90.9% of the matched saliva were concordant, with only a minor decrease in early stage disease. Tumor-specific mutations (≥5% AF) in driver genes were detected in 10 (83.3%) dysplastic lesions, suggesting that driving clonal events may occur early in disease development. Interestingly, in 3 matched saliva of the dysplastic samples, the same mutations were detected. To ensure a variant is not a false positive call, we performed a vigorous multistep analytical validation of this saliva-based test: (i) independent re-sequencing of 24 saliva confirmed 94% reproducibility; (ii) no functionally relevant variants were detected in saliva from 12 of 13 healthy subjects without history of tobacco and alcohol usage; (iii) reproducibility, sensitivity, and specificity were confirmed using a positive control with 7 loci at 0.25% AF across 8 independent saliva sequencing runs and a certified negative control and was found to be on par with droplet digital PCR. Conclusions: These data highlight the feasibility of saliva-based testing for early diagnosis of OCSCC and premalignant lesions.
SNOW: Sitravatinib and nivolumab in oral cavity cancer (OCC) window of opportunity study.
Authors: Oliva Bernal Marc , Araujo Daniel Vilarim , Chepeha Douglas Brian , Prawira Amy , Spreafico Anna , Bratman Scott Victor , Shek Tina , de Almeida John R , Hansen Aaron Richard , Hope Andrew J. , Goldstein David Paul , Weinreb Ilan , Perez-Ordonez Bayardo , Pugh Trevor John , Ohashi Pamela S , Wang Ben X , Irish Jonathan Crawford , Der-Torossian Hirak , Chen Isan , Siu Lillian L. 
Published: May 2020

6569 Background: Sitravatinib (receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) is predicted to increase M1-type tumor-associated macrophages (TAMs) and decrease MDSCs in the tumor microenvironment. SNOW is a window-of-opportunity study evaluating the immunogenic and antitumor effects of preoperative sitravatinib and nivolumab in patients (pts) with OCC. Early results demonstrated the combination was safe and active (Oliva et al, SITC 2019). Biomarker analyses and updated results are presented. Methods: Pts with untreated T2-4a, N0-2 or T1>1cm-N2 OCC are eligible. All pts receive oral sitravatinib 120mg daily from day (D) 1 up to 48h pre-surgery and 1 dose of Nivolumab 240mg on D15. Surgery planned between D23-D30. Standard of care adjuvant radiotherapy given based on clinical stage. Tumor pictures, fresh tumor biopsies, blood samples taken at baseline, D15 and pre-surgery. Tumor flow cytometry and multiplex immunofluorescence staining performed on all biopsies to study changes in immune-cell populations. Tumor whole-exome sequencing (WES) performed on baseline biopsies. Results: As of Jan 31st 2020, 10 out of 12 planned pts were enrolled. Study treatment was well-tolerated: only 1 pt had grade (G) >3 toxicity (hypertension) and 1 pt required surgery delay due to G2 thrombocytopenia. None had intraoperative complications. 1 pt had wound infection and tracheostomy bleeding 11 days post-surgery, possibly-related to study drugs. All pts had tumor reduction, 9/10 had pathological downstaging, including 1 complete response (Table). All had clear margins with no extranodal extension; none required adjuvant chemotherapy. All pts are alive with no recurrence (median follow-up= 69 weeks). Lower % of MDSCs and increased % of M1-TAMs and M1:M2 ratio trend was seen at D15 and pre-surgery, with stronger effect in major responders. Best responders (Pts S1-S2) had higher % of PD-L1+ TAMs at baseline. Tumor WES revealed an HRAS G12D mutation in pt S2 and a BLM mutation (DNA repair) in pt S6 (no downstaging). Conclusions: Pharmacodynamic analyses support the antitumor and immune effects of sitravatinib and nivolumab in OCC. Immune pathological response assessment and transcriptomics are on-going. Clinical trial information: NCT03575598 . [Table: see text]
Dose and volume de-escalation for HPV-associated oropharyngeal cancer: Long-term follow-up of the OPTIMA trial.
Authors: Rosenberg Ari , Agrawal Nishant , Pearson Alexander T. , Seiwert Tanguy Y. , Gooi Zhen , Blair Elizabeth A. , Cursio John , Howard Adam , Chin Jeffrey , Foster Corey Christian , Kochanny Sara , Lingen Mark W. , Haraf Daniel J. , Vokes Everett E. 
Published: May 2020

6575 Background: Human papilloma virus (HPV) associated oropharyngeal cancer is associated with a favorable prognosis, but standard multimodality treatment is associated with substantial treatment related toxicity. A de-escalation treatment paradigm that optimizes oncologic outcomes while reducing toxicity is needed. We sought to further expound on our published OPTIMA data with long-term follow-up and additional pts subsequently treated using the OPTIMA treatment paradigm. Methods: Long-term follow-up of our institutional de-escalation OPTIMA trial (NCT02258659) and retrospective review of additional patients treated subsequently per OPTIMA outline was performed. Pts were classified as low-risk (LR) (≤T3, ≤N2B, ≤10PYH) or high-risk (HR) (T4, ≥N2c, > 10PYH). Pts received induction chemotherapy (IC) of 3 cycles of dose dense carboplatin and nab-paclitaxel (OPTIMA) or paclitaxel (subsequently treated). LR with ≥50% response received low-dose radiotherapy (RT) to 50 Gy. LR with 30-50% response or HR with ≥50% response received intermediate-dose chemoradiotherapy (CRT) to 45Gy. All others received full-dose CRT to 75Gy. Results: 108 pts consented and 107 were treated (61 on study; 46 subsequently) from October 2014 through November 2019. 1 pt transferred care post-enrollment. Median follow-up was 36 months (interquartile range 17-45). Median age was 63 years (range 33-84) and 95% were male. 47% were LR and 53% were HR. ≥50% tumor shrinkage occurred in 78/107 (73%) of pts overall, and 37/51 (73%) among LR; 41/56 (73%) among HR. 82% of pts received de-escalated (C)RT. Overall, 94% of pts were alive at last follow-up (98% LR; 89% HR). 3 pts (2 HR and 1 LR) developed disease recurrence (2.7%), with 2 local recurrences and 1 distant recurrence. Likelihood of G-tube placement was 3% in low-dose RT, 35% in intermediate-dose CRT, and 84% in full-dose CRT. Conclusions: IC followed by risk-adapted dose and volume de-escalated treatment for HPV+ oropharyngeal cancer demonstrates excellent oncologic and functional outcomes with long-term follow-up. Supported by Celgene, Alinea benefit supported by Grant Achatz/Nick Kokonas, and National Cancer Institute of the National Institutes of Health (NIH) through Grant Number P30 CA14599. Clinical trial information: NCT02258659 .
Recurrent or metastatic salivary gland tumor (MSGT) patients treated with selinexor, a first in class selective exportin-1 (XPO1) inhibitor.
Authors: Malone Eoghan Ruadh , Spreafico Anna , Weinreb Ilan , Jennings Sarah , Carlsson Lindsay , Noori Ahmad , Wang Lisa , Siu Lillian L. , Hansen Aaron Richard 
Published: May 2020

6586 Background: MSGT are rare with limited systemic treatments. This single institution, prospective study in recurrent or metastatic (RM) MSGT involved 2 phases: genomic profiling followed by treatment with either genomically-matched or unmatched therapy. Here we present the results of the unmatched arm for patients (pts) treated with S an oral selective inhibitor of XPO1 that leads to activation of tumor suppressor proteins and retention of oncoprotein mRNAs in the cell nucleus, inducing cancer cell apoptosis. Methods: Patients (pts) with RM-MSGT had archived paraffin embedded tumor samples profiled with targeted next generation sequencing, immunohistochemistry for androgen receptor (AR) and fluorescent in-situ hybridization for HER-2 and ALK. If no actionable mutations were identified or if no matched agents were available, pts with progressive disease could receive S (60mg given twice weekly Q28 days). The study had a simon-2 stage design; 1 partial response in the first 18 pts treated with S, would trigger an additional 7pts to receive S in stage 2. Results: Between July 2014 and April 2019 85 pts were enrolled on study: 73 had sequencing which identified 41 with no actionable mutations and 32 with actionable mutations. 18 pts (10F/8M, median age 61 years [40-79]) were treated with S and included adenoid cystic (n = 8), salivary duct (n = 4), acinic cell (n = 2) and other subtypes (n = 4). Of these 18, 4 pts had actionable aberrations: AR amplification (n = 2), mutations in SMARCB1 (n = 1) and CDKN2A (n = 1). 13pts were treatment naïve, 3pts and 2pts received 1 and 2 or more lines of treatment respectively prior to enrollment: androgen deprivation therapy (n = 2), chemotherapy (n = 3), early phase clinical trials (n = 3). The median number of cycles of S received were 3 (range: 1-19). The best response by RECIST was SD in 13pts (72%) (SD > 6 months (range: 6-18 months) in 5pts (28%); tumor reduction measured in 7pts (39%)), no PRs, PD in 3pts (17%), and 2pts (11%) were not evaluable for response due to insufficient duration of treatment coming off early due to toxicity. The median PFS (95% CI) was 7.6 (3.5-NA) months and the median OS (95% CI) was 15.4 (7.3-NA) months. The most common drug-related toxicities were grade 1-2 fatigue 14pts (78%), nausea 13pts (72%) and dysguesia 10pts (56%). 5 (28%) pts had a dose reduction and 6 (33%) in total had a dose interruption due to toxicity. Conclusions: Single agent antitumor activity was limited and the side effect profile was tolerable. No specific genomic aberration was associated with response to S. Clinical trial information: NCT02069730 .
A multicenter study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of taxotere/cyclophosphamide-induced febrile neutropenia in patients with early-stage breast cancer.
Authors: Clemons Mark J. , Fergusson Dean , Joy Anil A. , Meza-Junco Judith , Price Hiller Julie A. , Mackey John Robert , Zhu Xiaofu , Ibrahim Mohammed FK , Basulaiman Bassam Mohammed , Awan Arif Ali , Sienkiewicz Marta , Vandermeer Lisa , Pitre Lacey D. , Nixon Nancy Alice , Hutton Brian , Pond Gregory Russell , Hilton John Frederick 
Published: May 2020

7001 Background: Docetaxel-cyclophosphamide (TC) adjuvant chemotherapy is commonly used in patients with early stage breast cancer (EBC). Due to the risk of febrile neutropenia (FN) with TC, primary prophylaxis with either ciprofloxacin (cipro) or granulocyte-colony stimulating factors (G-CSF) is recommended. Despite significant differences in costs (7-120 $US/course [cipro] vs. 2100-7000 $US/dose [G-CSF]) and toxicity profiles, optimal primary FN prophylaxis is unknown. We performed a pragmatic randomised trial comparing the superiority of G-CSF to cipro. Methods: EBC patients receiving TC chemo were randomized to receive cipro or G-CSF as primary FN prophylaxis. The primary outcome is a composite of either treatment-related hospitalisations or FN. Secondary outcomes included: chemo dose reductions, delays, discontinuations and incidence of C. difficile infections. Primary analysis was performed with the intention to treat (ITT) population. Results: 455 eligible patients were randomized to cipro (227) or G-CSF (228). 37/227 (16.3%) patients on cipro had a hospitalization, compared with 25/228 (11.0%) on G-CSF (Fisher’s exact test p-value=0.10). Relative risk (RR) of hospitalization for patients on G-CSF:0.68, 95%CI=0.42 to 1.09. Patients on cipro were statistically significantly more likely to be hospitalized for FN (30/227, 13.2%) vs 9/228 (4.0%) patients on G-CSF(p<0.001). RR of developing FN and being hospitalized for patients on G-CSF: 0.44, 95%CI=0.26 to 0.76. There was no significant difference between groups for chemo dose reductions, delays, and C. difficile rates. Twenty patients on cipro (8.8%) and 9 on G-CSF (3.9%) discontinued chemo early (p=0.036). RR of discontinuing chemo: 0.43, 95%CI=0.19 to 0.96. Conclusion: G-CSF was superior to cipro at reducing FN. While a trend towards reduced hospitalizations was also observed with G-CSF, it did not attain statistical significance. However, as 18 patients would need to be treated with G-CSF to prevent one hospitalization compared to cipro, this would suggest a cost of over $100000 $US to prevent a hospitalization. A formal cost-effectiveness analysis will be performed. Clinical trial information: NCT02173262, NCT02816112 .
Phase III randomized controlled trial of eRAPID (electronic patient self-Reporting of Adverse-events: Patient Information and advice)—An eHealth intervention during chemotherapy.
Authors: Velikova Galina , Absolom Kate , Warrington Lorraine , Morris Carolyn , Hudson Eleanor , Carter Robert , Gibson Andrea , Holmes Marie , Holch Patricia , Hulme Claire , Brown Julia 
Published: May 2020

7002 Background: Routine monitoring of patients’ symptoms can improve symptom management, quality of life (QOL) and survival. eRAPID is an online system for patients to report symptoms, uniquely providing automated severity-dependent advice (self-management or alerts for hospital contact). We evaluated eRAPID impact on patient experiences & clinical care. Methods: A prospective randomized two-arm parallel group trial (1:1 allocation Usual Care (UC): UC+eRAPID). Eligible patients started chemotherapy for colorectal, breast & gynecological cancers at Leeds Cancer Centre. In eRAPID arm, patients completed weekly online symptoms for 18 weeks. Primary outcome: QOL/symptom control (FACT-PWB Physical Wellbeing Scale) at 18 weeks. Secondary outcomes: process of care (admissions/ chemotherapy delivery), patient self-efficacy (Lorig Self-Efficacy Scale) & global QOL (EQ5D).Mixed effects repeated measures models were employed. Results: During Jan 2015-June 2018, we screened 1484 patients; 508/690 eligible patients (73.6%) consented & were randomized (256 eRAPID:252 UC). No statistically significant effect of eRAPID on FACT-PWB score was found at 18 weeks (difference in means 0.20 95% CI -0.81, 1.20; p = 0.699). There was a positive impactat 6 & 12 weeks (1.08, 95% CI 0.12, 2.05; p = 0.028 & 1.01, 95% CI 0.05, 1.98; p = 0.039).In responder analysis lower proportion of eRAPID patients had clinically meaningful deterioration 47.5% at 12 weeks vs 56.3% UC. Pre-planned subgroup analysis found no effect in metastatic disease, but better FACT-PWB in non-metastatic/adjuvant group at 6 & 12 weeks (1.45, 95% CI 0.32, 2.58; p = 0.011 & 1.13; 95% CI 0.07, 2.19; p = 0.036). eRAPID patients reported better self-efficacy (p = 0.007) & QOL EQ5D-VAS at 12 (p = 0.030) & 18 weeks (p = 0.010). There were no differences for admissions/chemotherapy delivery. 3314 online reports were completed, median per patient 14.0 (range 0-117). Emergency alerts were activated in 29/3314 cases (0.9%), self-management advice 2714/3314 (81.9%). Post-hoc analysesshowed high patient adherence was associated with clinicians’ use of the data, high baseline FACT-PWB & older age. High adherence patients had better FACT-PWB scores at 12 weeks. Conclusions: Online symptom monitoring with immediate advice improved symptom control early during adjuvant chemotherapy (6 &12 weeks), helping patient education & self-efficacy. The results support its utility as an improved model for patient care during adjuvant chemotherapy. Clinical trial information: ISRCTN88520246 .