bluuebunny/crossref_metadata_2025_split huggingface dataset:
PDL-1 expression in oral squamous cell carcinoma and implications for treatment.
Authors: Srinivasalu Vijay Kumar , Subramaniam Narayana , Iyer Subramania , Nambiar Ajit , Koyakutty Manzoor , Thankappan Krishnakumar , Das Manjula , Dhar Sujan Kumar , Balasubramanian Deepak , Keechilat Pavithran 
Published: May 2019

e17527 Background: PDL-1 expression has been shown in multiple tumours to be a key factor in treatment response and immunogenicity. In oral squamous cell carcinoma (OSCC), its role is controversial; the expression levels, prognostic significance and therapeutic relevance are unclear. This study was performed to determine the incidence of PDL-1 expression in OSCC, and to determine its correlation with demographic, clinical and pathological features, recurrence and survival. Methods: PDL-1 IHC (Dako kit) was determined on 64 samples of OSCC obtained during curative intent resection. PDL-1 expression levels were determined in tumour (T) and tumour infiltrating lymphocytes (TILs). Statistical analysis was performed. Results were validated on the mRNA-seq data from the Cancer Genome Atlas (TCGA) for head and neck squamous cell carcinoma (HNSCC). Results: 64 patients were included in the final analysis with a mean age of 54 years. < 1% expression was the most common for T (92%) and TILs (56%). Tumour PDL-1 expression < 1% had higher risk of lymphovascular invasion (LVI) (p = 0.044) and bone invasion (p = 0.010). TIL PDL-1 expression < 1% was more common in patients ≤45 years (p = 0.023) with higher chances of local recurrence (p = 0.020) and reduced local recurrence free survival (p = 0.047). For the TCGA data, low ( < 1%) PDL-1 expression was associated with a significant reduction in OS and DFS in the young (≤45 years) (p = 0.0078 and 0.0089 respectively), but not for older patients ( > 45 years) (p = 0.21 and 0.88 respectively). Conclusions: PDL-1 expression in OSCC was low. TIL PDL-1 expression < 1% was more common in those ≤45 years, and associated with a higher chance of local recurrence and poorer survival. The role of PDL-1 expression in prognosis of OSCC is controversial, with our data being the first to correlate low PDL-1 expression and poorer outcomes with younger patients. These results were validated by the TCGA data for HNSCC across multiple subsites. Further study is required to determine if this pathway plays a significant role in local control and survival.
Predictive score for recurrence after complete resection in locally advanced oral cavity squamous cell carcinoma.
Authors: Lu Hsueh-Ju , Tseng Szu-Wen , Peng Chih-Yu , Tseng Hsien-Chun , Hsin Chung-Han , Huang Wei-Shiou , Wu Ming-Fang , Yang Muh-Hwa , Chang Mu-Hsin 
Published: May 2019

e17536 Background: Early progression, usually defined disease-free interval (DFI) less than six months after completing adjuvant platinum-based chemoradiotherapy (CRT), has very poor outcome for oral cavity squamous cell carcinoma (OCSCC). But there are no biomarkers to predict such early progression. Methods: Locally advanced OCSCC patients, after complete surgical resection and followed-up platinum-based adjuvant CRT, were retrospectively enrolled from Chung Shan Medical University Hospital (CSMUH, training cohort) and Taipei Veterans General Hospital (TPE-VGH, validating cohort) in Taiwan. Clinicopathologic variables of patients with DFI < or ≥ 6 months were compared by using the χ2 test. The Cox proportional hazards model was applied to identify independent factors for DFI. Survival was estimated using the Kaplan-Meier method and log-rank test. Results: A total of 350 high-risk OCSCC patients were enrolled, including 146 patients in training cohort and 204 in validating cohort. In multivariate Cox regression, pN > 0, extracapular spread, and depth of invasion ( ≥ 1cm) were independent factors for DFI in training cohort. If each factor scored one point, the scoring system could effectively predict early progression that sensitivity/specificity/area under curve (AUC) of training and validating cohort were 57.7%/91.2%/0.771 and 58.1%/83.9%/0.730, respectively (the cutoff level ≤ 2 or > 2). DFI between lower- (score 0–2) and high- (score 3) risk groups were also significantly different in both training (median DFI, 59.6 vs. 4.5 months, P < 0.001) and validating cohorts (NA vs. 9.3 months, P < 0.001). Conclusions: The established score system was effective to predict early progression after adjuvant CRT for locally advanced OCSCC.
Risk of second primary neoplasia in patients with oropharyngeal carcinoma: Role of HPV status in the outcome.
Authors: Lopez-Pousa Antonio , Lopez V Montserrat , Garcia Jacinto , Farre Nuria , Gallego Rubio Oscar , Majercakova Katerina , Camacho Daniela , Borrell Maria , Molto Consolacion , Riudavets Mariona , Terés Raul , Bujosa Aida , SULLIVAN IVANA GABRIELA , Quer Miquel , Leon Xavier 
Published: May 2019

e17544 Background: Patients with HPV-positive oropharyngeal cancer (OPC) have better prognosis and a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor and its relationship with toxic habits. Methods: This study includes patients from a prospective data-base: 484 OPC patients were treated from 1991 to 2017 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. The mean follow-up of patients included in the study was 4.9 years (SD 5.1 years). We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. Results: Ninety-nine (20.5%) out of 484 OPCs included in the study were HPV-related. During the follow-up period, 127 patients with HPV-negative tumors (33.0%) and 19 patients with HPV-positive tumors (19.2%) had a SPN. Considering only the tobacco/alcohol-related SPNs, 106 of the patients with HPV-negative tumors (27.5%), and 12 patients with HPV-positive tumors (12.1%) had a tobacco/alcohol-related SPN (P < 0.0001). Five-year and 10-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 61.0% versus 81.5%, and 37.6% versus 73.8%, respectively (P < 0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates were 66.6% versus 86.8% and 45.9% versus 83.5% for 5-year and 10-year survival rates, respectively (P < 0.0001). The frequency of tobacco/alcohol-related SPNs occurrence throughout the follow-up period for patients with HPV-negative OPC was 27.5%, for patients with HPV-positive tumors with a previous history of severe tobacco and/or alcohol use was 21.4%, and for patients with HPV-positive tumors without a history of severe tobacco and/or alcohol consumption it was 8.5% (P < 0.0001). Conclusions: HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. HPV-related OPC patients without previous history of severe tobacco and/or alcohol use have a significant low risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption
Multiplexed digital PCR for detection of HPV in tissue samples from oropharyngeal cancer patients.
Authors: Kumar Sunil , Chera Bhishamjit S. , Beaty Brian , Marron David , Jefferys Stuart , Amdur Robert , Sheets Nathan , Dagan Roi , Hayes David N. , Weiss Jared , Grilley-Olson Juneko E. , Zanation Adam M. , Hackman Trevor , Blumberg Jeffrey , Patel Samip , Weissler Mark Christian , Parker Joel S. , Tan Xianming , Mendenhall William M. , Gupta Gaorav 
Published: May 2019

e17552 Background: p16 immunohistochemistry (IHC) is a commonly used method for identifying HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). However, p16 overexpression in a minority of HPV negative OPSCC can give rise to false positive results. In contrast, HPV nucleic acid testing lacks adequate sensitivity for routine diagnostic testing. The goal of this study was to investigate whether a multiplexed digital PCR assay can detect and quantify HPV DNA in p16 positive OPSCC treated with definitive chemo-radiotherapy (CRT). Methods: Formalin-fixed paraffin embedded (FFPE) residual diagnostic biopsy specimens were collected from 57 patients. Macrodissection was performed to ensure tumor cellularity > 70%. Extracted genomic DNA was analyzed by next generation sequencing (NGS) using a hybrid capture assay (UNCSeq) targeting > 200 cellular genes and HPV 16/18 genomes. We also designed, validated, and implemented an multiplexed droplet digital PCR (dPCR) assay to detect and quantify HPV DNA (strains 16, 18, 31, 33 and 35) in tissue samples, relative to a genomic control locus (chromosome 6). Results: HPV strain 16 DNA was identified in 50 patients (87.7%), whereas 5 patients (8.8%) had HPV DNA from an alternative high-risk strain (18/31/33/35). HPV DNA was undetectable in 2 patients, indicating a false positive rate of 3.5% for p16 IHC testing in this cohort. HPV DNA copy number per diploid genome equivalent varied significantly across samples, with a median value of 19.7 (range 0.23-1712). A significant correlation was observed between the copies of HPV detected by dPCR and NGS (R2 = 0.5853, p < 0.0001). Evidence for HPV integration was detected by NGS in 23 out of 56 evaluable tumors (42%). There was a trend towards a higher prevalence of HPV integration in tumors with less than 10 HPV copies per diploid genome relative to cancers with > / = 10 HPV copy number (63% versus 34%, p = 0.07). Conclusions: Multiplexed digital PCR demonstrates excellent sensitivity for detection and typing of HPV DNA in diagnostic FFPE specimens from patients with p16 positive oropharyngeal cancer. HPV copy number varies significantly across samples, with a possible association with HPV integration status. Future investigations of potential correlation between HPV copy number, integration status, and clinical outcomes are warranted. Clinical trial information: NCT02281955, NCT03077243.
A phase II study of concurrent nimotuzumab and intensity-modulated radiotherapy in elderly patients with locoregionally advanced nasopharyngeal carcinoma.
Authors: Cao Caineng , Hu Qiaoying , Chen Xiaozhong 
Published: May 2019

e17562 Background: The purpose of this study was to evaluate the feasibility of concurrent nimotuzumab to intensity-modulated radiotherapy (IMRT) in elderly patients with locoregionally advanced nasopharyngeal carcinoma (NPC). Methods: According to the eighth edition of the American Joint Committee on Cancer staging system, elderly patients with stage III–IVA NPC were given concurrent nimotuzumab (200 mg/week, starting 1 week before IMRT) with IMRT. They completed a geriatric assessment tool (function, comorbidity, cognition, psychological state, social activity/support, and nutritional status) before initiation of protocol therapy. Results: Thirty patients [median age of 70.5 (65-95) years] with stage III (60%), and IVA (40%) NPC were enrolled between March 2017 and November 2018. The mean scores on the comorbidity scale and instrumental activities of daily living scale were 7 (range, 1 to 12) and 12 (range, 8 to 14), respectively. Grade 3 mucositis occurred in 10 (33%) patients and 1 (3%) patient had grade 3 radiotherapy-related dermatitis. Grade 3 pneumonia occurred in 3 patients (10%) and no patients had nimotuzumab-related acneiform rash. There were 20 complete responses and 10 partial responses 1month after the completion of IMRT. Conclusions: Concurrent administration of nimotuzumab and IMRT is effective and well-tolerated for elderly patients with locoregionally advanced NPC. Clinical trial information: NCT03025958.
Single institute analysis of squamous cell carcinoma of the head and neck treated with concurrent chemoradiation with either cisplatin versus cetuximab.
Authors: Jeong Il Seok , Kim Matthew , Nguyen Anthony L. , Mo Huan , Hayton Bruce , Xu David , Cao Huynh Le 
Published: May 2019

e17571 Background: Squamous cell carcinoma of the head and neck (SCCHN) is currently the sixth most common cancer in the world and is linked to tobacco, alcohol and human papillomavirus (HPV). Cisplatin (Cs)-based concurrent chemoradiation is currently the standard treatment for locally advanced disease with a desire for organ preservation. In 2006, cetuximab (Cx) with radiation was approved as another option for this indication. We performed a single institute retrospective analysis to explore the difference in efficacy between Cs and Cx regimens with respect to P16 and smoking status. Methods: We retrospectively reviewed pts in Loma Linda University Medical Center (LLUMC) with locally advanced SCCHN who received concurrent chemoradiation with either Cx or Cs as first-line treatment from 2006 to present. We excluded patients with nasopharyngeal cancers, and patients having surgery as first line of treatment. Overall survival (OS) and disease free survival (DFS) with respect to p16 status and smoking status are the two primary endpoints. Results: Based on our study criteria, 115 out of 1545 screened pts qualified. The average age at diagnosis was 60 years. 75.7% were males and 24.3% were females. Median follow-up is 26 months. There are overall 55 DFS events and 23 OS events. Comparing between smokers (S, n = 44) and non-smokers (NS, n = 42), there is no significant difference in OS (NS: HR = 0.73 [0.28-1.92], p = 0.52) while the DFS was significantly better in the NS (NS: HR = 0.53 [0.29-0.98], p = 0.043). The overall median OS of the P16-pos pts (n = 49) is not reached while that of P16-neg pts (n = 12) is 36 mo (P16-neg: HR = 6.431 [1.71-24.13], p = 0.0058). The overall median DFS of the P16-pos pts is not reached while that of P16-neg pts is 6.5 mo (P16-neg: HR = 5.39 [2.32-12.54], p < 0.001). Overall, the median OS of Cx is 132 mo while that of Cs is not reached (Cs: HR = 0.38 [0.16-0.90], p = 0.027). The median DFS is 30 mo for Cs and 25 mo for Cx. Within P16-pos population, there are 4 OS events in Cx (n = 18) while 0 in Cs (n = 31)(p = 0.0062, favors Cs); there are 5 DFS events in Cx while 9 in Cs (Cs: HR = 1.17 [0.39-3.51], p = 0.78). The median OS and DFS for both groups are not reached. Conclusions: Our analysis of retrospective single institute data shows that positive P16 significantly associates with better OS. These findings are consistent with previous reports. Compared to Cx, the Cs regimen significantly associates with a better OS but not DFS in both overall and P16-pos populations.
Potential role of botanical drug APG-157 as immune adjuvant in patients with oral squamous cell carcinoma.
Authors: Shin Daniel Sanghoon , Srivatsan Eri , Nasser Hassan , Tosevska Anela , Jacobs Jonathan , Pellegrini Matteo , Wang Marilene 
Published: May 2019

e17572 Background: Natural botanical drugs, such as curcumin, resveratrol and related flavonoids, are under clinical studies. Previous pilot study of curcumin, a polyphenol, for normal and patients with oral squamous cell carcinoma (OSCC) showed significant inhibition of inflammatory cytokines in saliva. Phase I investigation was performed on APG-157 to evaluate the potential utility an as oral drug for the treatment of OSCC. Methods: A double-blind, randomized, placebo-controlled phase I clinical trial was conducted with a botanical preparation containing a combination of curcumin related polyphenol molecules (pharmaceutical name APG-157). 12 Subjects with oral cancer and 13 normal control subjects were recruited. Two doses of the drug, 3x100 mg and 3x200 mg, were tested. The drug was administered orally each hour for 3 consecutive hours. Blood and saliva were collected pre-treatment and 1, 2, 3, and 24 hours post-treatment. Salivary cells and supernatants were analyzed for the expression of cytokines by multiplex ELISA and microbial content by 16S RNA sequence. Pre- and post-treatment tumor biopsies of one subject were studied for expression using the RNA seq and immunofluorescence (IF). Results: This study did not reveal any toxicity and there was a dose dependent inhibition of inflammatory cytokines, IL-1β, TNF-alpha and IL-8 in the salivary supernatant of cancer subjects treated with the drug. Tumor RNA-seq revealed down regulation of gene ontologies of cell adhesion, cell cycle and cell division and up regulation of generation of precursor metabolite/energy in the post-treatment tumor sample. Microbiome study showed significant decrease in Bacterioides after 24 hours of treatment. There was also a trend of decreasing Bacteroides among other cancer subjects treated with APG-157. IF showed a marked increase in the number of CD4, CD8 T cells in post-treatment tumor. PD-L1 expression was up-regulated in the post-treatment tumor sample. Conclusions: APG-157 is found to be safe and toxicity was not observed. The drug has shown a decrease in inflammatory cytokines. Moreover, there was a markedly increased CD4, CD8 T cells infiltration on a subject and decreased Bacteriodes microbial population after APG-157 treatment suggesting that it might have potential synergistic effect with immune checkpoint blockade immunotherapy. Decreased expression of cell growth related genes and increased expression of growth inhibitory genes pointed to a potential anti-tumor activity of APG-157.
Chemotherapy in the management of olfactory neuroblastoma/esthesioneuroblastoma: An analysis of the surveillance, epidemiology, and end results (SEER) 1973-2015 database.
Authors: Cranmer Lee D. , Chau Bonny 
Published: May 2019

e17573 Background: Olfactory neuroblastoma (ON) is a malignant tumor of nasal cavity arising in sensory neuroectodermal olfactory cells. Chemotherapy (CT) has been proposed as an adjunct to primary local therapy. Here, we investigated the role of CT in primary ON treatment. Methods: SEER was searched for ON (ICD-3 9522). Inclusion criteria were (1) unique cases; (2) primary nasal cavity tumor; (3) staging information; and (4) ability to derive Kadish stage. Abstracted covariates included sex, age, tumor grade, nodal status, year of diagnosis, derived Kadish stage, and treatment (surgery, radiotherapy (RT), CT). Outcomes included disease-specific (DSS) and overall (OS) survival. In SEER, CT and RT are classified as Yes vs No/Unknown. Uni- and multi-variable Cox analyses assessed CT treatment on DSS and OS, controlling for covariates noted above. To account for proportional hazards violations, such variables were either stratified or time-varying. Multiple imputation addressed missing data. A p < 0.05 was designated for statistical significance. Analyses were conducted using Stata ver 12. Results: 797 ON cases were included. In univariable analysis, CT treatment (yes vs no/unknown) was associated with inferior DSS (HR 2.81, 95% CI 2.11 3.74, p < 0.001) and OS (HR 2.03, 95% CI 1.63 2.54, p < 0.001). In multivariable analyses, CT was again associated with inferior DSS (HR 1.74, 95% CI 1.21, 2.51, p = 0.003) and OS (HR 1.71, 95% CI 1.26, 2.32, p = 0.001). Limiting analysis to those with local/regional disease treated with local therapy (surgery and/or radiation), CT remained associated with inferior outcomes [DSS (HR 2.78, 95% CI 1.63, 4.74, p < 0.001) and OS (HR 2.17, 95% CI 1.45, 3.27, p < 0.001)]. Sensitivity analyses ruled out chemotherapy misclassification as an explanation for our results. Conclusions: Our analysis does not support the use of chemotherapy to improve either DSS or OS in primary ON treatment. We controlled for known ON prognostic factors available from SEER. Other prognostic and treatment selection factors could exist for which we did not control. Chemotherapy may also beneficially affect outcomes other than DSS or OS. While concerns have been expressed regarding CT treatment misclassification in SEER, our analyses did not identify such misclassification as an explanation.
Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population.
Authors: Liu Jie , Li Huizheng , Du Rong , Fang Nan , Zhang Jingbo , Tang Yu , Wang Jianwei , Wu Qixi 
Published: May 2019

e17574 Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.