bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction gemcitabine cisplatin followed by chemoradiation in locally advanced nasopharyngeal cancer.
Authors: Usman Sadaf , Rasheed Sara , Raza Ali , Hussain Raza , Jamshed Arif 
Published: September 2018

6027 Background: The current standard of treatment in locally advanced nasopharyngeal cancer is concurrent chemoradiation, however recent addition of induction chemotherapy in the already established regimen has presented an attractive alternative approach. We report on survival with induction Gemcitabine and Cisplatin (GC) followed by chemoradiation (CRT) in the treatment of advanced nasopharyngeal carcinoma. Methods: Between 2005 and 2015, 300 patients (M 70%: F 30%) with histologically confirmed nasopharyngeal carcinoma. Histological subtypes WHO I 4% (13) and WHO III 96% (287). AJCC (7th edition) stage was Stage III 28% (85) and Stage IV 72% (215) patients. IC included a 2 drug combination; intravenous gemcitabine 1000 mg/m2 on day 1 and 8 and cisplatin 75 mg/m2 on day 1 only. Radiotherapy was given as a phase treatment to a total dose of 70 Gy in 35 fractions. Concurrent three weekly cisplatin (75 mg/m2) was administered to all patients. Results: Median follow up time was 30 months. The 5-year overall survival (OS), loco regional control (LRC) and relapse free survival (RFS) rates were 70% (95% CI 6.43 – 7.52), 69% (95% CI 6.52 – 7.64) and 52% (95% CI 5.25 – 6.34) respectively. One hundred and seven patients failed treatment; local or loco-regional 39% (42), regional 16% (17) and distant 45% (48). Conclusions: We conclude that induction gemcitabine and cisplatin followed by chemo-radiation is an effective regimen in management of nasopharyngeal carcinoma, meriting further investigation in randomized clinical trials.
Premilinary survival results and potential beneficiaries for locally advanced nasopharyngeal carcinoma treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy.
Authors: Feng Mei , Lang Jinyi , Li Lu , Huang Yecai , Xu Peng , Qi Yunxiang , Li Fang , Wang Weidong 
Published: September 2018

6030 Background: Neoadjuvant is a promising chemotherapy modality for recurrent nasopharyngeal carcinoma (NPC). However, there is still controversy for locally advanced NPC. We study the survival results of locally advanced NPC treated with neoadjuvant chemotherapy followed by concurrent chemoradiotherapy (NACT) retrospectively, and to explore the potential beneficiaries. Methods: 147 stage III-IVa+b NPC treated with IMRT were included and divided into two groups. NACT group (76) received 2-3 cycles of neoadjuvant chemotherapy with TP or TPF, and then 2-3 cycles of platinum-based chemoradiotherapy (CCRT). CCRT group (71) received 3 cycles of platinum-based chemoradiotherapy. TNM stage, age and whole blood count before treatment were all collected. The stratified analysis was used for distinguishing the potential beneficiaries. Results: median follow-up time was 30 months. For all patients, the 3-year LRRFS, DMFS and OS in NACT and CCRT were 94.5%, 96.8%; 85.8%, 82.8% and 81.6%, 83.4% respectively ( p> 0.05). For stage III patients, the 3-year LRRFS, DMFS and OS were 95.2%, 97.3%; 91.4%, 84.6% and 86.3%, 82.1% respectively ( p= 0.38, p= 0.15, p= 0.58). Though there was no statistical significance, DMFS in NACT was better than it in CCRT. However, for stage IV, the survival rate had no significant difference. The incidence of grade 3-4 bone marrow suppression was higher in NACT ( p= 0.007), and the other toxicities were similar. Univariate analysis showed the percentages of neutrophil and neutrophil-to-lymphocyte ratio (NLR) were significantly correlated with OS ( p= 0.031, p= 0.049). N and clinical stage were the adverse prognostic factors for OS ( p= 0.025, p= 0.007) and DMFS ( p= 0.018, p= 0.001). Clinical stage was the prognostic factors for OS and DMFS in multivariate analyses ( p= 0.019, p= 0.01). Conclusions: NACT had a comparable survival results and tolerable toxicity with CCRT for locally advanced NPC. Stage III might be the potential beneficiaries from NACT, especially for DMFS. Percentages of neutrophil and NLR might be the new adverse prognostic factor for OS. Clinical stage was still the prognostic factor for OS and DMFS.
Aspirin use and survival in head and neck squamous cell cancer (HNC) patients.
Authors: Rafei Hind , Lumley Catherine , Han Jim , Kaffenberger Thomas M. , Maxwell Jessica H. 
Published: September 2018

6042 Background: The phosphatidylinositol-3-kinase (PI3K) signaling pathway is the most common genetic alteration in HNC, particularly in oropharynx cancers (OPC). Up-regulation of the PI3K pathway enhances the production of prostaglandins inhibiting apoptosis in cancer cells. We hypothesized that aspirin (ASA) improves survival in HNC patients (pts) by counteracting the effects of prostaglandins. Methods: This is an IRB-approved retrospective cohort study of 584 veterans with HNC treated at the Washington DC Veterans Affairs Medical Center between 1995 and 2015. Charts were reviewed for clinical-pathologic and treatment data; recurrence/distant metastases; cause of death; and for the number, date and dose of ASA prescriptions. Pts who filled more than one prescription, excluding refills, after diagnosis of HNC were considered ASA users. All others were considered non-ASA users. The Kaplan-Meier method and log-rank test were used to compare disease-free survival (DFS) and disease-specific survival (DSS) between users and non-users. Results: 332 pts met inclusion criteria. Primary subsites included oropharynx (n = 146), larynx (n = 105), oral cavity (n = 62), and hypopharynx (n = 19). 86 pts were ASA users after diagnosis (25.9%) and more likely to be older (p = 0.002), African American (p = 0.03), never-alcohol users (p = 0.044), and have early stage cancer (I/II; p < 0.0005) compared to non-ASA users. Among all HNC pts, ASA users demonstrated significantly better 5-year (y) DSS (82%) compared to non users (43%; p = 0.009). 5-y DFS was also significantly higher among users (72%) vs non users (39%; p < 0.001). Among the OPC pts, 5-y DSS was higher for ASA users (74%) vs non users (41%; p = 0.024). 5-y DFS was also better for users (72%) vs non users (39%; p = 0.004). For stages III and IV, 5-y DFS was significantly higher among ASA users (64%) vs non users (44%; p = 0.035). 5-y DSS was higher as well in users (69%) vs non users (44%) but p = 0.098. On multivariate analysis, aspirin use remained an independent prognostic factor associated with improved DSS and DFS when accounting for age, race, gender, subsite, stage, tobacco and alcohol use. Conclusions: Aspirin use following diagnosis and curative treatment of HNC is associated with improved DSS and DFS.
Predicting response to radical (chemo)radiotherapy (R-CRT) with circulating HPV DNA and tumor DNA (ctDNA) analysis in locally-advanced head and neck squamous cell carcinoma (LAHNC).
Authors: Bhide Shreerang , Lee Jen , Garcia-Murillas Isaac , Cutts Ros , Hurley Tara , Grove Lorna , Nutting Christopher , Newbold Kate , Turner Nicholas C. , Harrington Kevin 
Published: September 2018

6043 Background: Following R-CRT for human papilloma virus positive (HPV+) and negative (HPV-) LAHNC, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT findings even in the presence of a complete pathological response (pCR), which causes significant morbidity. We assessed the role of circulating tumor DNA analysis in identifying patients with true residual disease. Methods: We prospectively recruited development (DC, n=55) and test (TC, n=33) cohorts of LAHNC patients having R-CRT. For HPV+ tumors we developed a novel amplicon based next generation sequencing assay (HPV-detect) to detect circulating HPV DNA and for HPV- tumors we used personalised droplet digital PCR assays of somatic mutations. Circulating tumor DNA levels at 12 weeks post-R-CRT were correlated to residual disease assessed by PET-CT and surgery. Results: In the DC (27 HPV+), baseline HPV-detect demonstrated 100% sensitivity and 93% specificity, confirmed in the TC (20 HPV+). 37 HPV+ patients (DC&TC) had complete samples-set. 36 had a negative HPV-detect at end of treatment, including 6 patients who underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had pCR on surgical/biopsy specimen. 1 patient had positive HPV-detect and positive biopsy, indicating 100% agreement for HPV-detect and residual cancer. In a 10 HPV- patients with complete sample-set, there was 90% agreement between ctDNA and residual disease in HPV- tumors (3 ctDNA positive and tumor present, 1 ctDNA negative but tumor present, and 6 negative ctDNA negative tumor) with 80% sensitivity for residual disease and 100% specificity. Combined agreement between ctDNA testing (HPV+ and -) & residual disease was 98% (Table). Conclusions: Circulating HPV DNA quantified using HPV-detect and ctDNA identifies patients with residual disease post-R-CRT in LAHNC. Further studies are required to validate these findings. [Table: see text]
HPV status and survival in non-oropharyngeal squamous cell carcinoma of the head and neck.
Authors: Wookey Vanessa , Kusi Appiah Adams , Kallam Avyakta , Ernani Vinicius , Smith Lynette , Ganti Apar Kishor 
Published: September 2018

6046 Background: HPV positive squamous cell carcinoma of the oropharynx and tonsil has been associated with increased survival. However, the prognostic value of HPV status for other primary sites is unclear. We assessed the effect of HPV status on survival in patients with non-oropharyngeal head and neck squamous cell carcinoma at all stages. Methods: Data was obtained from the National Cancer Database (NCDB) to determine the effect of HPV status on overall survival (OS) in adults with non-oropharyngeal head and neck squamous cell carcinoma (gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx) using SAS software. Pearson’s Chi square test was used for comparisons by HPV status. The Kaplan-Meier method was used to estimate OS and differences were compared using a log-rank test. A multivariate Cox proportional hazards regression model analysis was performed to determine effects of individual variables on outcomes. Results: Patients with all stages of squamous cell carcinoma of the gum, lip, floor of mouth, tongue (excluding base), hypopharynx and nasopharynx diagnosed from 2010 to 2013 with complete HPV data were included (n = 13,908). In univariate analysis, HPV positivity, female gender, Asian race, primary site (lip, tongue, nasopharynx and hypopharynx), private insurance and any treatment (except for chemotherapy alone) were associated with increased OS, whereas increased age, Black race, higher Charlson-Deyo comorbidity score, hypopharynx primary, and higher AJCC stage were associated with worse OS. After adjustment for covariates, HPV positivity was associated with improved OS (HR 0.83, 95% CI 0.74-0.93; p < 0.001). Female gender, gum, lip, nasopharynx primaries, and private insurance on multivariate analysis predicted for improved OS, while age > 70, higher Charlson-Deyo score and higher AJCC stage were associated with worse OS. Conclusions: HPV positivity and female gender are good prognostic factors in squamous cell carcinoma of the head and neck, independent of primary site. Trials evaluating de-escalation of treatment should be considered for HPV positive tumors from non-oropharyngeal sites in the head and neck region.
Association of mannitol (MAN) with cisplatin (CIS)-induced nephrotoxicity (NTX) and cumulative CIS dose (CCD).
Authors: Ramalingam Sri , Szabo Aniko , Kilari Deepak , Bhosekar Chitra , Wong Stuart J. 
Published: September 2018

6051 Background: CIS is widely used in cancer therapy with CCD linked to survival outcome. CCD, however, is constrained by side effects—particularly NTX (incidence 20-30%). MAN is widely used to prevent CIS NTX despite low level of evidence. Herein, we took advantage of a national shortage of MAN to examine renoprotective effects of MAN in CIS treated patients. Methods: Between 2006-2012, 704 consecutive pts undergoing CIS therapy, with or without MAN, were analyzed. Pt characteristics, oncologic diagnosis, treatment, and renal function data were collected. The primary objective was to compare clinically significant NTX, as defined by > 25% reduction in glomerular filtration rate (GFR) from baseline, between the treatment groups. Cox proportional hazards regression was used to model the hazard of NTX as a function of CIS dose. Results: Of 704 pts, 442 were treated with MAN and 262 without. The median age was 58.9 years. Age (p = 0.83), gender (p = 0.77), and race (p = 0.056) were similar between groups whereas baseline GFR (MAN 91.2 ± 22; CIS 86.3 ± 24; p = 0.005) and diagnoses (p < 0.001) differed. The distribution of diagnoses was: head and neck (25.9%), genitourinary (26.0%), lung (14.3%), gastrointestinal (10.4%), lymphoma (4.5%), and other (18.9%). The mean CIS dose (mg) per cycle in MAN versus CIS only group was 126.1 ± 58 and 109.3 ± 58 respectively (p < 0.001). The CCD (mg) was higher in the MAN compared to the CIS only group (469.8 ± 295 versus 299.0 ± 241; p < 0.001). After adjusting for baseline GFR, age, gender, race, and diagnoses, the MAN group experienced lower risk of > 25% decrease in GFR at any given CCD (HR: 0.68, CI: 0.51-0.91, p = 0.01). Females (HR: 1.72, CI: 1.28-2.32; p = 0.0003), older pts (HR: 1.24, CI: 1.10-1.40; p = 0.0003), and Hispanic pts (HR: 2.39, 1.04-5.50; p = 0.04) were more likely to sustain > 25% reduction in GFR. Conclusions: MAN enhances CCD by protecting against CIS-induced NTX. Pts with MAN experienced a lower risk of clinically significant acute kidney injury (AKI) and received a higher average CIS dose per cycle and CCD. Women, older pts, and Hispanic pts had a higher risk of AKI. Future investigation is warranted to examine whether MAN-associated CCD effects translate into survival advantages.
Molecular signatures of class II HLA and p-16 status as an immune-based classification of OPSCC relying on known predictors of sensitivity to PD-1 blockade.
Authors: Saba Nabil F. , Seby Sandra , Rossi Michael R. , Magliocca Kelly R. , Griffith Christopher C , Wang Xu , Wang Dongsheng , Dwivedi Bhakti , Patel Mihir , El-Deiry Mark , Steuer Conor Ernst , Shin Dong Moon , Kowalski Jeanne , Chen Zhuo Georgia 
Published: September 2018

6052 Background: PD-1 inhibitors are known to have significant clinical activity in head and neck squamous cell cancer (SCCHN); there is, however, no selection criterion for SCCHN patients who may benefit from PD-1 inhibition. Utilizing RNA-seq analysis we explored a set of human genes encoding leukocyte antigens (HLAs) as part of a 37-gene panel predictive of response in melanoma patients to PD-1 inhibitors (Chen et al, Cancer Discov. 2016 Aug;6(8):827-37).We investigated whether this panel could define an immune-based classification of oropharyngeal squamous cell carcinoma (OPSCC). Methods: We have applied a minimal mutation and copy number content (151 genes) using an Agilent Clearseq DNA and an extensive Illumina Truseq RNA panel providing key information on gene fusions, differential gene expression, coding mutation and metagenomics on 47 SCCHN FFPE samples including 27 OPSCC. We performed an unsupervised hierarchical clustering of the samples. Two clusters with high and low expression were noted. Fisher’s exact test was performed to determine if the samples in each clusters were associated with p16 as a surrogate marker for HPV status. The same procedure was repeated on Level 3 transcriptome data from the TCGA via GDC data portal. Results: A set of fourteen immune related HLA antigen genes were identified within the 37-gene panel predictive to response to PD-1 inhibitors in p16+ versus - OPSCC (p = 0.015).We applied the same set of immune related HLA genes on the 103 patient samples from TCGA with known p16 status. When applied on all samples, there was no correlation between the HLA gene expression and p16 status (p = 0.1366); however, when restricted to OPSCC patients there was a high correlation with p16 status (p = 0.0047). Conclusions: We have identified a set of immune related HLA type II genes that are over-expressed in p16 positive OPSCC. This opens the door for further evaluation of these genes to better understand the immune related factors affecting the biology of HPV-associated OPSCC and its response to PD-1 inhibitors. (This research was supported by a grant NCI R21 CA182661-01A1to NFS and GZC).
IDO1 as a mechanism of adaptive immune resistance to anti-PD1 monotherapy in HNSCC.
Authors: Wirth Lori J , Burtness Barbara , Mehra Ranee , Bauman Jessica Ruth , Lee Jina , Smith Nicole Marie Stauffer , Lefranc-Torres Armida , Westra William H. , Bishop Justin A. , Faquin William C , Lin Derrick T. , Pai Sara I. 
Published: September 2018

6053 Background: Patients with recurrent/metastatic human papillomavirus-associated head and neck squamous cell carcinoma (HPV-HNSCC) demonstrate improved response rates to anti-PD-1 blockade, which may be attributed to the inherent inflammation associated with the local expression of foreign, highly immunogenic viral antigens. However, these response rates are at best 25%, suggesting there may be immune resistance networks that are limiting clinical responses to anti-PD-1 therapy. To address this question, we investigated other potential immune checkpoint pathways that may be upregulated in PD-L1 expressing HPV-HNSCCs. Methods: Using a custom microarray of 59 immune-related genes, we compared the gene expression profile of laser-captured micro-dissected PD-L1 (+) and (-) immune fronts in HPV-HNSCCs. Gene expression was validated using quantitative PCR (qPCR) and protein expression geographically localized using quantitative multiplex biomarker imaging in a separate cohort of HPV-HNSCCs. Furthermore, we assayed pre- and post-treatment biopsies from anti-PD-1 treated patients and correlated gene expression with clinical responses. Results: Of the immune-related genes, IDO1 was increased 65-fold in 10 PD-L1(+) as compared to 5 PD-L1(-) HPV-HNSCCs (p = 0.004). qPCR confirmed upregulated expression of IDO1 and quantitative immunofluorescence demonstrated that PD-L1 and IDO1 geographically co-localized within the tumor microenvironment in a validation cohort of 25 HPV-HNSCC patients. In anti-PD1 treated patients, IDO1 expression increased up to two-fold and correlated with disease progression in HNSCC patients. Conclusions: IDO1 is an immune checkpoint molecule that modulates T cell activity through the depletion of L-tryptophan. We propose that IDO1 is an adaptive immune resistance pathway to anti-PD-1 monotherapy. The results provide rationale for combinatorial therapies targeting the IDO1 and PD-1:PD-L1 networks in HNSCC patients.
Poor-prognosis nasopharyngeal carcinoma as defined by a molecularly distinct subgroup and prediction by a miRNA expression signature.
Authors: Zhao Lan , Gao Feng , Wei Wang , Duan Xin , Zhang Yuchen , Zhu Lina , Wang Xin 
Published: September 2018

6056 Background: Nasopharyngeal carcinoma (NPC) is a highly invasive and metastatic cancer, with diverse molecular characteristics and clinical outcomes. Our aim in this study is to dissect the molecular heterogeneity of NPC, followed by construction of a prognostic model for prediction of distant metastasis. Methods: For molecular subtyping of NPC using miRNA expression data, we selected 86 stage II (AJCC 7th Edition) NPC patients from GSE32960 as training cohort. The remaining 226 NPC patients from GSE32960 and 246 NPC patients from GSE70970 were used as two validation cohorts. Consensus clustering was employed for unsupervised classification of the training cohort. Classifier was built using support vector machine (SVM), and was validated in the two validation cohorts. Univariate and multivariate Cox regression analyses were employed for feature selection and constructing a prognostic model for predicting high-risk distant metastasis, respectively. Results: We identified three NPC subtypes (NPC1, 2, and 3) that are molecularly distinct and clinically relevant. NPC1 (~45%) is enriched for cell cycle related pathways, and patients classified to NPC1 have an intermediate survival; NPC3 (~19%) is enriched for immune related pathways, and has good clinical outcomes. More importantly, NPC2 (~36%) is associated with poor prognosis, and is characterized by upregulation of epithelial-mesenchymal transition (EMT). Out of the total 25 differentially expressed miRNAs in NPC2, miR-142, miR-26a, miR-141 and let-7i have significant prognostic power (p < 0.05), as determined by univariate Cox regression analysis. For identification of high-risk distant metastasis, we built a multivariate Cox regression model using the selected 4 miRNAs. Our model can robustly stratify NPC patients into high- and low- risk groups both in GSE32960 (HR 3.1, 95% CI 1.8-5.4, p = 1.2e-05) and GSE70970 (HR 2.2, 95% CI 1.1-4.5, p = 0.022) cohorts. Conclusions: We proposed for the first time that NPC can be stratified into three subtypes. Using a panel of 4 miRNAs, we established a prognostic model that can robustly stratify NPC patients into high- and low- risk groups of distant metastasis.
CDKN2A copy number loss in HPV- and HPV+ head and neck cancer to indicate poor prognosis: An integrated genomic and clinical TCGA analysis.
Authors: Chen William S. , Bindra Ranjit , Mo Allen , Hayman Thomas , Husain Zain , Contessa Joseph N. , Gaffney Stephen G. , Townsend Jeffrey P. , Yu James B. 
Published: September 2018

6060 Background: HPV infection is associated with high p16 expression and relatively good prognosis in head and neck cancers. Analysis of CDKN2A, the gene that encodes the p16 tumor suppressor protein, may further elucidate the association between HPV status and prognosis in head and neck squamous cell carcinomas (HNSCCs). We aimed to identify whether CDKN2A copy number loss was associated with poor survival in HNSCCs stratified by HPV status. Methods: We analyzed The Cancer Genome Atlas (TCGA) head and neck cancer data, integrating genomic measurements with clinical metadata. Patients 85 years old or younger with a primary tumor in the oral cavity, oropharynx, hypopharynx, or larynx were included. Defining CDKN2A copy number loss as a relative log2 copy number ratio < −0.6, CDKN2A mRNA and p16 protein expression levels were compared to confirm significant differences in gene transcription and translation between the copy number loss and non-copy number loss patient groups. Overall survival (OS) and disease-free survival (DFS) were evaluated to characterize prognostic differences between genomic groups. Results: 397 patients negative for HPV (HPV−) and 91 patients positive for HPV (HPV+) HNSCC were identified. 139 HPV− patients and 9 HPV+ patients demonstrated CDKN2A copy number loss. The CDKN2A copy number loss group expressed significantly lower levels of CDKN2A mRNA and p16 protein than did the non-copy number loss group in both HPV+ and HPV− disease. Median OS for HPV− patients with and without CDKN2A copy number loss was 21.8 months and 46.0 months (P = 0.02). Median DFS was 12.0 and 19.4 months respectively (P < 0.05). Median OS for HPV+ patients with and without CDKN2A copy number loss was 12.7 months and 57.4 months (P = 0.004) and median DFS was 7.0 and 36.6 months respectively (P = 0.02). Conclusions: CDKN2A copy number loss was associated with low CDKN2A mRNA and p16 protein expression, with poor prognosis in terms of disease-free and overall survival.