bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of associations between adverse drug reactions and clinical outcomes in anlotinib treatment against medullary thyroid carcinoma (MTC): A subgroup analysis based on the ALTER01031 trial.
Authors: Chi Yihebali , Gao Ming , Tang Pingzhang , Zheng Xiangqian , Xu Zhengang , Li Dapeng , Chen Xiaohong , Ge Minghua , Zhang Yuan , Guo Zhuming , Wang Jun , Chen Jie , Zhang Jiewu , Cheng Ying , Li Zhendong , Liu Hui , Qin Jianwu , Zhu Jingqiang , Cheng Ruochuan 
Published: May 2020

e18518 Background: Anlotinib demonstrated favorable efficacy in a randomized, placebo-controlled phase 2b trial (ALTER01031, NCT02586350) for MTC which was published in 2019 ASCO annual meeting. Similar with other anti-angiogenesis drugs, hand-foot syndrome (HFS), hypertension and proteinuria were the major adverse drug reactions (ADRs) observed in this trial. We explored the association between common ADRs and the clinical outcomes with anlotinib in this subanalysis. Methods: Patients in the anlotinib group of ALTER01031 were divided into different groups according to the development of ADRs including HFS, hypertension or proteinuria. Kaplan-Meier method was used to estimate median PFS (mPFS) for patients in different groups. The mPFS for patients with or without dose reduction were also evaluated. Results: A total of 62 patients received anlotinib in ALTER 01031. HFS of any grade was observed in 39 patients with a mPFS of 28.5 months, which was longer than in those without HFS (14.0 months, P = 0.079). The hazard ratio for progression was 0.540 (95% CI 0.252, 1.158) although statistical difference was not reached. Similarly, more survival benefit was also observed in 29 and 38 patients who experienced hypertension and proteinuria, with mPFS of 28.5 months and 22.4 months respectively. While the mPFS for patients without corresponding ADRs were only 17.0 months (HR = 0.648 [95% CI 0.320, 1.314], P = 0.237) and 14.0 months (HR = 0.738 [95% CI 0.331, 1.65], P = 0.421). Median PFS had not been reached in 20 patients with dose reduction while was recorded as 17.0 months in those without (HR = 0.707 [95% CI 0.335, 1.496], P = 0.392). Conclusions: This analysis indicated a trend of greater PFS benefit for MTC patients treated with anlotinib who experienced HFS, hypertension or proteinuria although no statistical differences were observed. A possible positive association was also observed between dose reductions and better clinical outcomes. Clinical trial information: NCT02586350.
Peripheral immunological response to treatment with checkpoint inhibitor in recurrent/metastatic nasopharyngeal carcinoma.
Authors: Kwong Dora Lai Wan , Kam Ngar-Woon , Luk Ho-Yin , Hung Tae Yang Desmond , Yim Man Kim , Lee Victor Ho-Fun 
Published: May 2020

e18519 Background: A better understanding of peripheral cellular phenotypes in association with checkpoint inhibitors (CPI) responsiveness in recurrent/metastatic NPC could profoundly impact our knowledge of NPC immunopathology. Methods: Blood were collected from 11 patients with recurrent/metastatic NPC who received CPI (pembrolizumab) after failing second-line chemotherapy. Response to pembrolizumab was assessed by imaging and EBV DNA. Patients who achieved CR/PR were considered responsive and those with SD/PD were considered non-responsive. Four patients in the responsive group also had baseline blood before pembrolizumab. PBMC were freshly isolated and stored until analysis. For surface staining, cells were rested overnight at 37°C before resuspended in BD Brilliant stain with 2.5ng/µl Fc block for 15mins. Cells were then co-stained: 7-AAD, CD19-BV510, CD3-Alexa Fluo 700, CD4-BV510, CD279(PD-1)-BB515, CD197(CCR7)-BV421, CD45RO-APC, CD45RA-Pe-Cy5, CD8-APC-H7, CD27-PE, CD95-PE-Cy7, incubated on ice for 30mins. Samples were washed and acquired on NovoCyte Quanteon. Immune phenotypes were correlated with clinical response. Results: We found that: 1) %CD3 was upregulated in responsive group; 2) CD4/CD8 ratio did not directly stratify drug responsiveness; 3) frequency of PD1-expressing CD8+ T cells was significantly reduced in responsive group; 4) lower frequency of CCR7+PD1+CD8+ T cells in responsive group, suggesting that these may be highly differentiated and have the ability to move into peripheral sites in response to inflammatory chemokines; 5) frequency of naïve and TEMRA CD8+ T cells, but not Tscm was upregulated in responsive group; 6) finally, an interesting finding of sustained CD19+ subsets was observed in non-responsive group. Conclusions: Our results suggest that peripheral blood analysis may provide valuable insights into NPC patients’ responses to PD-1-targeted therapies. [Table: see text]
Comparison of treatment costs for pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma based on KEYNOTE-040 clinical trial.
Authors: Yeh Justin , Guddati Achuta 
Published: May 2020

e18524 Background: Pembrolizumab has been approved by the FDA for the treatment of recurrent and refractory squamous cell cancer of the Head and Neck. This approval was based on the favorable results noted in the pembrolizumab arm of the KEYNOTE-040 clinical trial which compared pembrolizumab with the standard of care (methotrexate/cetuximab/docetaxel). This study aims to compare the financial aspects of these treatment arms in the setting of their relative clinical advantages in terms of increased overall survival by applying current pricing of the drugs and treatment for side effects. Methods: Data published from the KEYNOTE-040 study was used to generate a model incorporating the cost of each drug in both arms. The incidence of side effects was also extracted from the published data. The cost of treatment of side effects was extracted from previously published data and used for cost estimation in the model. The number of years added in terms of overall survival was calculated for the entire experimental arm and the cost of each such year was calculated. This model assumes that all drugs were supplied at the cost indicated at the retail price advertised by their producers. The cost was adjusted for inflation to the current year. Results: Based on current pricing, 248 patients in the control arm which involved methotrexate /cetuximab /docetaxel incurred an estimated total cost of $2,918,185 over 24 months. The total cost for the pembrolizumab arm based on current pricing was $36,744,819 for 247 patients over 24 months. The cost of management of adverse effects was $383,910 vs. $18,728 (Std. of care vs. Pembrolizumab). The total cost averaged over all patients in both arms was $13,314 vs. $ 148,840. There is an inverse relationship between drug cost and management of adverse side effects in both arms. Conclusions: Treatment with pembrolizumab confers an increase in overall survival but the cost of the incremental gain appears to be high. The model makes several assumptions including the distribution of cost over the patient population in both arms and extrapolates it to the cost in US dollars. It is very likely that the quality of life was superior in the pembrolizumab arm but it was not incorporated into our model. Justification of the continued use of pembrolizumab must be weighed against the long term survival benefits accrued by its usage in the context of a different and possibly better quality of life.
Neoantigen-based vaccination as a practical measure for head and neck cancer treatment.
Authors: Zheng Xiao-bin , Chen Chuan-ben , Chen Yu , Hao Shiguang , Jun Liu , Xiong Jia-ni , Lin Jin , Xu Yaping , Guan Yan-Fang , Li Yi , Huang Yingying , Yi Yuting , Xia Xuefeng 
Published: May 2020

e18528 Background: The view that neoantigens serve as potential vaccine targets has arisen in the last decade. Clinical and computational efforts have been done to increase the practicality of its application in real world. With these advances, we conducted a retrospective study on a Chinese population to explore the clinical feasibility of neoantigen-based vaccines for head and neck cancer treatment. Methods: Tumor and normal samples were profiled using a 1021-gene panel. Sequencing data were pre-analyzed according to our in-house standard procedures. Class I HLA typing was completed using OptiType v1.0. Curated somatic mutations in coding regions (SNVs and non-frameshift Indels with an allele frequency ≥ 5%) were collected and altered peptides produced by these mutations were analyzed using NetMHCpan v4.0. Peptides with an IC50 < 500 nM were considered potential binders, and especially, those with an IC50 < 50 nM were considered strong binders. An altered peptide was considered a neoantigen if IC50 altered is < IC50 wildtype. Results: We analyzed a total of 243 patients and detected 114 unique HLA alleles. By carrier percentage, the top three alleles are C*01:02 (44%), B*46:01 (36%), and A*11:01 (33%). In total, 743 mutations were deemed eligible for neoantigen prediction and 223 unique neoantigens were found. Of these neoantigens, 67 (carried by 21% of patients) were strong binders, among which 26 (carried by 9% patients) exhibited a great fold change (≥ 5 folds) of binding affinity. Moreover, the neoantigens in these patients are unique, as only two neoantigens were shared. A search for shared neoantigens revealed a combination of mutation PIK3CA p.E542K and HLA A*11:01, which was detected in 0.54% of all patients. Additionally, 43.6% (106/243) of patients were diagnosed with nasopharyngeal carcinoma, among whom 42% (44/106) possessed predicted neoantigens, including 15 patients with strong-binder neoantigens. Conclusions: (1) Neoantigen-based vaccination is a practical measure to treat patients with head and neck cancer, as indicated by the percentage of patients harboring strong-binder neoantigens. (2) Off-the-shelf neoantigen vaccines may not be practical, given the result that the most common combination of a neoantigen-producing mutation and the corresponding HLA was only found in 0.54% of all patients.
Are the demographics of recurrent oropharyngeal and oral cavity squamous cell carcinoma changing?
Authors: Means Jeffrey , Stram Douglas , Katzel Jed Abraham 
Published: May 2020

e18537 Background: In the current era of human papillomavirus (HPV)-related oropharyngeal cancer and decreasing alcohol and tobacco use, the demographic factors associated with recurrent head and neck cancer may be evolving. We evaluated clinical and demographic factors in a cohort of patients with recurrent and non-recurrent Oral Cavity (OC) and Oropharyngeal Squamous Cell Carcinoma (OPSCC) in order to evaluate which factors are associated with tumor recurrence and how these factors are modified by HPV status. Methods: From a cohort of 3201 patients diagnosed with OC and OPSCC at Kaiser Permanente Northern California between 1/1/2008 and 6/30/2019, 235 recurrent cases were identified. Clinical and demographic factors were extracted from electronic medical records. We calculated frequencies of demographic and clinical factors stratified by recurrence and HPV status, and reported p-values using the chi-square test for independence. Results: HPV-related cases were more likely to be male (84% vs. 64%), younger (80% ≤70 years old vs. 55%), have fewer comorbidities (61% with non-cancer Charlson index < 1 vs. 47%), and higher cancer stage (88% with a stage > 1 vs. 42%) than HPV-unrelated cases. Recurrent HPV-unrelated cases were more likely to be Asian (14% vs. 8%), and from higher income census tracts (75% from tracts with median household income > $60,000 vs. 66%) than recurrent HPV-related cases. Chi-square p-values of < 0.001. Recurrence and HPV status did not appear to be associated with prior smoking and alcohol abuse. Conclusions: Our cohort verifies that HPV-related OPSCC patients are more likely to be younger, male, and with lower Charlson scores, while recurrent HPV-unrelated OC and OPSCC may be more common among Asians and individuals from higher-income census tracts. This may have important implications for future clinical trial design and surveillance for recurrence. [Table: see text]
Prediction of local recurrence in oral squamous cell carcinoma using immune markers.
Authors: Pierssens Damiana , Mulder Frans , Van Den Hout Mari , Sluijpers Niels , Kessler Peter , Kremer Bernd , Speel Ernst-Jan M. 
Published: May 2020

e18538 Background: The local recurrence rate of oral squamous cell carcinomas (OSCC) hardly decreases despite the best possible treatment. Partly, this is caused by the presence of (pre)malignant cells in the surrounding tissue, which can develop into a new malignancy in time. Histological recognition of these cells in resection margins appears to be difficult during routine practice. The aim of this study was to determine whether or not the presence of immune cells in OSCC resection margins may predict the development of a recurrence in these patients. Methods: Thirty-four patients with firstly diagnosed, radically resected primary OSCC with histopathological confirmed tumor-free margins (treated between 1993 and 2003) were included. Nine patients out of the 34 patient developed a locoregional recurrence within 5 years. Formalin-fixed paraffin-embedded tissue sections of 34 resection margins were subjected to immunohistochemistry for CD45, CD3, CD4, CD8, PD-L1 and PD-1 expression in immune cells, after which a quantitative analysis of the largerst distribution of CD45-, CD3-, CD4-, CD8-, PD-L1 and PD-1 positive lymphocytes on each resection margin has been photographed. The highly immunostained surface in relation to the total surface has been measured up to 100μm below the squamous epithelium. This analysis has been performed using QWin software (Leica). All data were analyzed using GraphPad Prism (version 7.05 for Windows, GraphPad Software, La Jolla California USA, www.graphpad.com). Results: Only CD3 and CD8 had a moderate correlation (Spearman = 0.68). A high expression of CD45 (≥7.7% ) and CD4 (≥5,4%) was strongly correlated with a worse disease-free survival (p = 0.0054 and p < 0.001, respectively), as was a low CD3 expression (≤5,9%) (p = 0.0211). PD-L1 and PD-1 expression analysis did not show a significant association with recurrence risk. Conclusions: A high amount of CD45-, and CD4- and a low amount of CD3-positive immune cells in OSCC resection margins may predict local recurrence.
Prevalence of herpes simplex virus I, II, cytomegalovirus, Epstein–Barr virus and human papillomavirus (6, 11, 16 and 18) in normal oral mucosa and OSCC patients in Saint-Petersburg (Russia).
Authors: Kutukova Svetlana , Beliak Natalia P. , Ivaskova Julia V. , Chuhlovin Alexey B. , Yaremenko Andrey I. , Ermakova Tatiana S. 
Published: May 2020

e18539 Background: The objective of our study was to evaluate the prevalence of DNA of HSV I, II, CMV, EBV, HPV6.11, HPV16, HPV18 in normal oral mucosa and oral squamous cell carcinoma (OSCC), and determine this association with long-term treatment outcomes and patient survival. Methods: The study included 116 patients with OSCC (stage I-IVB who received standard treatment) and 50 healthy volunteers, median age 60.0 yrs (95% CI 58.0-64.0). Using real-time PCR (polymerase chain reaction), freshlyfrozen samples of the tumor and normal mucous membranes of the cavity were analyzed. mouths, which, after collection, were placed in an EDTA solution and frozen at 20°C. Results: In 54 (46.55%) OSCC and 17 (34.00%) normal mucous viral DNA was not found (p = 0.13). The occurrence of DNA (OSCC vs. normal) of the following viruses was the same in both OSCC and normal mucosa: HSV I, II: 2 (1.72%) vs. 2 (4.00%) (p = 0.38); EBV: 40 (34.48%) vs. 15 (30.00%) (p = 0.57); CMV: 5 (4.31%) vs. 2 (4.00%) (p = 0.93); HPV6.11: 16 (13.79%) vs. 6 (15.00%) (p = 0.84); HPV16: 12 (10.34%) vs. 2 (4.00%) (p = 0.18). HPV18 DNA: 20 (17.24%) vs. 24 (48.0%) (p <0.0001) was found significantly less frequently in the OSCC group. In addition, EBV + HPV18: 7 (14.00%) vs. 5 (4.31%) (p = 0.0270) was more common vs. OSCC in the group of healthy volunteers; CMV + HPV18: 2 (4.00%) vs. 0 (p = 0.0302). In the OSCC group, patients with stage III disease were more often virus-positive (p = 0.0137); the pterygo-maxillary fold region (p = 0.0438); with partial keratinization of cells (p = 0.05). PFS in the HPV18 (+) OSCC group was 38.5 months (95% CI 11.00-66.0) and 23.5 m higher than the group of HPV18 (-) patients (HR = 0.63; 95% CI 0.39-1.03; p = 0.0399). In virus-negative patients, PD was more often recorded: 12 (24.00%) vs. 2 (3.03%) (p = 0.0006). In the group of virus-positive patients, OS and PFS, even with non-radical treatment, were significantly higher than virus-negative patients with radical treatment. OS: vir (+)/non-radical = 69.0 mo vs. vir (-)/radical = 15.0 mo (HR = 0.22; 95% CI 0.11-0.47; p <0.0001). PFS: vir (+)/non-radical = 56.0 mo vs. vir (-)/radical = 11.0 mo (HR = 0.20; 95% CI 0.09-0.45; p <0.0001). Conclusions: The association of OSCC with viral DNA, especially HPV18, is a favorable prognosis of the disease and a longer OS and PFS, even when radical treatment is not possible.
PD-L1 in combination with CD8+TIL and HIF-1α are promising prognosis predictors of head and neck squamous cell carcinoma.
Authors: Yu Jinming , Zhou Zihan , Mu Dianbin , Zhang Dexian , Zhang Xianbin , Ding Xingchen , Yang Jia , Bai Xinbin , Yu Jinming 
Published: May 2020

e18545 Background: Currently, the tumor/node/metastasis (TNM) staging is the most widely used Head and neck squamous cell carcinoma (HNSCC) staging system. However, this classification only provides limit information for the prognosis of HNSCC. Recently, some studies suggest that the level of PD-L1 in tumor cells (TC-PD-L1) or in tumor microenvironment cells (TMC-PD-L1) is a promising biomarker for the prognosis of HNSCC patients. Therefore, in this study, we evaluated the prognostic value of TC-PD-L1, TMC-PD-L1, CD8+ TIL, HIF-1α. In addition, we investigated if incorporated these biomarkers into TNM stage could improve the prognostic value of TNM stage. Methods: A total of 63 patients who underwent surgical resection. The level of PD-L1, CD8+ TIL and HIF-1α was determined by immunohistochemical analysis. The survival of patients was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. The prognostic power of these parameters was evaluated by C-index. Results: We observed that the survival of patients, who had high level of PD-L1 in tumor cells, was significantly shorter than those who had low level of PD-L1. However, the survival of patients who had high level of PD-L1 in tumor microenvironment was significantly longer than patients with low level of PD-L1 in tumor microenvironment. In addition, high level of CD8+ tumor-infiltrating lymphocyte or low level of HIF-1α level suggests a better prognosis. Moreover, we observed that PD-L1 in combination with CD8+tumor-infiltrating lymphocyte and HIF-1α could significantly improve the prognostic effect of current TNM stage. Conclusions: The results of this study suggest that the level of PD-L1, CD8+TIL and HIF-1α is useful prognostic biomarkers for patients with HNSCC. Incorporated these biomarkers into current TNM stage of HNSCC improve the discriminatory capability of TNM stage.
Efficacy and safety of neoadjuvant chemotherapy (NACT) with paclitaxel plus carboplatin and oral metronomic chemotherapy (OMCT) in patients with technically unresectable oral cavity squamous cell carcinoma (SCC).
Authors: Kashyap Lakhan , Patil Vijay Maruti , Dhumal Sachin Babanrao , Noronha Vanita , Joshi Amit , Menon Nandini Sharrel , Prabhash Kumar 
Published: May 2020

e18550 Background: NACT regimen for patients with oral cavity scc is based on maximum tolerated doses (MTD). Combination of MTD and metronomic chemotherapy schedule will lead to initial debulking of tumor and subsequent inhibition of angiogenesis, this may produce synergistic effect and overcome the drug resistance of MTD schedule. We assessed the efficacy and safety of this combination as NACT in patients with technically unresectable oral cavity SCC. Methods: This is retrospective analysis of prospectively maintained data. Fourteen patients having technically unresectable oral cavity SCC received NACT with paclitaxel (175mg/m2) plus carboplatin (AUC5) 3 weekly (MTD schedule) and OMCT (methotrexate 9mg/m2 once a week, celecoxib 200mg twice daily and erlotinib 150mg once daily). Patient were assessed clinically and radiologically after minimum of two cycles for resectability. Radiological response was evaluated as per RECIST 1.1. We report response rate, resectability and tolerance of this NACT regimen. Results: Median age of the patients was 38 years. Twelve patients (85%) were male. Twelve (85%) and two (15%) patients had buccal mucosa and oral tongue primary respectively. AJCC 2017 stage IVA and IVB disease was present in 85% and 15% patients respectively. Reason for technical unresectabilty was skin edema above zygoma in five (36%), high infratemporal fossa involvement in five (36%), nodal encasement of major vessels in two (14%) and posterior extent of oral tongue tumor into oropharynx in two (14%) patients. Median number of NACT administered were three. The tumor of nine (64%) patients showed partial response and none of the patients had tumor progression. Tumor of nine patients (64%) were deemed resectable after NACT. Common grade 3/4 toxicities (CTCAE 5.0) were neutropenia in eight (57%), thrombocytopenia in three (21%), febrile neutropenia, hypokalemia and diarrhoea in two patients (14%) each. Conclusions: Paclitaxel and carboplatin along with OMCT is well tolerated and easily administered NACT regimen with high response rate and resectabilty in patients with technically unresectable oral cavity SCC.