bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of tumor hypoxia on the clinical efficacy of anti-PD-1 mAb treatment in recurrent/metastatic HNSCC patients (R/M).
Authors: Zandberg Dan Paul , Velez Maria A , Menk Ashley V. , Liu Angen , Skinner Heath Devin , Duvvuri Umamaheswar , Ohr James , Chiosea Simion I. , Nilsen Marci Lee , Clump David Anthony , Ferris Robert L. , Delgoffe Greg 
Published: May 2020

6546 Background: Anti-PD-1 mAbs have changed the landscape of R/M HNSCC treatment, but physical, immunologic, and metabolic barriers present in the tumor microenvironment are likely drivers of low response rates. Hypoxia is a well-established feature of the tumor microenvironment and may act as a barrier to T cell infiltration and function. We evaluated the effect of hypoxia on the efficacy of anti-PD-1 mAb treatment in R/M HNSCC patients. Methods: We conducted a retrospective analysis of R/M patients treated with anti-PD-1 mAb that had consented to the UPMC Hillman tissue banking protocol (HCC 99-069). Pre-treatment archival FFPE samples were analyzed via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs, and the percent area (% CAIX) and mean intensity (Int) of carbonic anhydrase IX, a well-described marker of hypoxia. Tissue sections stained with PanCK, CAIX, CD8, Foxp3, and DAPI were imaged with an Olympus IX 83 microscope. ImageJ software and custom software plugins were used to determine %CAIX, Int, CD8, and Treg. PD-L1 by IHC was reported as a combined positive score (CPS) defining positive as CPS > 1. We compared non-responders (NR) i.e. PD to responders (R) i.e. PR or SD, and analyzed OS, PFS. All data were analyzed using GraphPad Prism software. Two-tailed unpaired t test was used when comparing 2 groups, 1-way ANOVA was used for multiple comparisons, and log-rank test was used for survival analysis. Results: The 36 patients included were 69% male, median age 59, 58% smokers. 61% were platinum failure. Primary site included 39% OC, 22% OPC (38% HPV positive), 17% Larynx, 17% other, 5% hypopharynx. Low %CAIX/Int, high CD8, and high CD8/Treg were all significantly associated with R. Patients with low %CAIX/Int (12 month OS Low: 75% vs. Mid: 17% vs. High:8%, p = 0.02) and high CD8/Treg had a significant increase in OS. Only high CD8 was associated with significantly higher PFS. Low %CAIX alone showed a non-significant trend towards increased R and no difference in PFS/OS. There was no difference in CD8, CD8/Treg, PD-L1 and Treg between %CAIX/Int groups. Conclusions: To our knowledge this is the first evaluation of tumor hypoxia as a predictive biomarker in anti-PD-1 mAb treated R/M HNSCC patients. Lower hypoxia by %CAIX/Int was associated with significantly increased response and OS. While further analysis in a larger dataset is needed to confirm, the lack of significant difference in CD8, Treg, PD-L1, and CD8/Treg between %CAIX/Int groups (Low, Mid, High) suggests that hypoxia may be an independent predictive marker.
CD3 and CD20 immune cell densities in primary tumors, lymph node metastasis, and recurrent disease samples of head and neck squamous cell carcinoma.
Authors: Laban Simon , Remark Romain , Idel Christian , Ribbat-Idel Julika , Schröck Andreas , Ezić Jasmin , Döscher Johannes , Theodoraki Marie-Nicole , Krupar Rosemarie , Sikora Andrew G. , Kristiansen Glen , Bootz Friedrich , Akturk Guray , Ettrich Thomas Jens , El-Osta Hazem Edmond , Schuler Patrick J , Brunner Cornelia , Hoffmann Thomas K , Perner Sven , Gnjatic Sacha 
Published: May 2020

6551 Background: Immune cell (IC) infiltrates in primary tumors (PT) have been identified as prognostic markers in head and neck squamous cell carcinoma (HNSCC). IC densities may differ among PT, lymph node metastasis (LNM) and recurrent disease (RD) and by primary disease site (oral cavity- OC, oropharynx- OP, hypopharynx- HP, larynx- L). Here, we compare CD3 and CD20 IC densities in PT, LNM and RD in paired samples from different disease sites and determine the prognostic impact of IC infiltrates. Methods: Tissue microarrays with 425 PT, 198 LNM and 46 RD samples--each in triplicate--were stained immunohistochemically for CD3 and CD20 in the same slide. Immune cell densities per mm2 were determined using a digital image analysis software (QuPath). Individual means were calculated from triplicates of each sample. IC infiltrates from different sample types (PT, LNM, RD) and primary tumor sites were compared using Kruskal-Wallis and Mann-Whitney-U tests. Paired samples were compared using Wilcoxon signed rank test. IC densities were classified as CD3 high/low and CD20 high/low for each primary tumor site using the individual median as a cut-off. Overall survival (OS) was calculated using the Kaplan-Meier method. P-values for each hypothesis were corrected using a false discovery rate of 5%. Results: CD3 and CD20 IC densities differed significantly by sample type (both p<0.0001) and primary site (CD3: p=0.012, CD20: p=0.0017). CD3 and CD20 densities were significantly lower in PT compared to LNM or in RD compared to PT and LNM. Paired samples (n=172) revealed a significantly higher CD3 and CD20 density (both p<0.0005) in LNM compared to PT, but no significant differences between PT and RD (n=28, p>0.05). CD3 densities were significantly higher than CD20 densities in all sample types. CD3high patients had the best prognosis in all sites except for OC (q<0.05) independent of CD20 status. In OC, CD3 density was not prognostic, but CD3low/CD20high patients had the worst OS compared to CD3low/CD20low and CD3high/CD20high or even CD3high/CD20low patients (p=0.018) who had the best prognosis. Conclusions: IC densities of CD3 and CD20 vary by sample type and primary site. Except for OC, in all sites the prognostic impact is determined by CD3high, whereas in OSCC only the combination of CD3 and CD20 IC densities achieves a good prognostic value. Interestingly, CD3low/CD20high patients have the worst overall survival in OC patients. Further work is needed to understand the interaction of B- and T cell infiltrates in the tumor, especially in OC.
HPV ctDNA analysis in unresectable recurrent/metastatic oropharyngeal cancer.
Authors: Haring Catherine T , Brummel Collin , Jewell Brittany , Heft Neal Molly , Bellile Emily , Spector Matthew E , Mierzwa Michelle , Worden Francis P. , Tewari Muneesh , Brenner Chad , Swiecicki Paul 
Published: May 2020

6554 Background: There is an increasing incidence of human papillomavirus associated (HPV+) oropharyngeal cancer (OPC). While HPV + portents improved prognosis, survival for patients with unresectable recurrent/metastatic (R/M) OPC remains poor. Extant data suggest that HPV ctDNA levels correlate with disease burden and treatment outcomes in patients with HPV + OPC in the primary setting but scant data exists in the metastatic setting. Objective: To develop a highly precise droplet digital (ddPCR) assay for quantification of plasma HPV ctDNA and to evaluate whether HPV ctDNA predicts treatment response in patients with HPV+ R/M OPC. Methods: Patients with HPV + R/M OPC starting systemic therapy were enrolled in a biorepository in which blood was collected prior to each cycle of therapy. PCR probes were created for the most common high-risk HPV subtypes, 16 and 18. HPV ctDNA was extracted from plasma and quantified with ddPCR. Percent change in HPV ctDNA was calculated after 1 and 2 cycles of treatment. Treatment response was assessed per standard of care or study protocol after 2-3 cycles of treatment. ROC curve analyses were performed. Results: A precise ddPCR assay was developed to identify plasma HPV ctDNA in 10 patients who underwent 16 distinct treatment courses. On ROC curve analysis, percent change in HPV ctDNA after 2 cycles of treatment was predictive of radiographic response (AUC 0.82, p = 0.03). The optimal cutoff point to optimize sensitive and specificity was identified as 30% change in HPV ctDNA (Table). Changes in HPV ctDNA after 1 cycle of treatment were also predictive of radiographic response (AUC 0.82, p = 0.05). Conclusions: Changes in HPV ctDNA may be predictive of treatment response in patients with R/M HPV + OPC. Furthermore, HPV ctDNA predicts response earlier than conventional imaging. While validation is needed, this assay shows promise in identifying poor responders who can be directed early towards clinical trials or alternative therapies. [Table: see text]
Molecular correlates of response to preoperative olaparib alone or with cisplatin or with durvalumab in head and neck squamous cell carcinoma (HNSCC): A Hellenic Cooperative Oncology Group study.
Authors: Psyrri Amanda , Papaxoinis George , Gavrielatou Niki , Gkotzamanidou Maria , Economopoulou Panagiota , Kotsantis Ioannis , Spathis Aris , Anastasiou Maria , Gkolfinopoulos Stavros , Nifora Martha , Fountzilas George , Foukas Periklis 
Published: May 2020

6556 Background: Poly(ADP-ribose) polymerase (PARP) inhibitors drive increased DNA damage and tumor cell death, particularly in tumors with existing defects in DNA repair. Furthermore,they promote immune priming, through a range of molecular mechanisms. Foremost, among candidate intracellular pathways is STING (stimulator of interferon genes), an innate immune response activated by cytosolic DNA (perhaps a consequence of DNA damage) that can lead to enhanced interferon (IFN) production. PARP inhibitor-induced DNA damage also leads to adaptive upregulation of programmed death ligand 1 (PD-L1) expression. To this end, there is increasing rationale for testing PARP inhibitors alone or in combination with chemotherapy or PD1 checkpoint inhibitors in HNSCC. Methods: 39 patients were enrolled in OPHELIA phase II trial in which pts were randomized 3:3:3:1 to Cisplatin (C) 60 mg/m2 on d1 followed by Olaparib (O) 75mg d 1-5 (Arm A), O 300 mg bid for 21-28 days (Arm B), no treatment (ARM C) orD 1500 mg on d1 followed by O 600 mg daily for 21-28 days (Arm D). Response was defined as tumor reduction noted on exam, imaging or pathology. Pretreatment biopsies were subjected to 310 gene OncoDNA NGS panel. Double Stranded Brakes/Repair (DSB/R) was measured by evaluating phosphorylation of histone H2AX by immunochistochemistry (IHC). In addition, IHC for PD-L1 (CPS) and STING was performed in paired pre- and post-treatment biopsies. Results: 17/36 pts in (O) treatment arms (6/11 evaluable pts Arm A, 9/11 evaluable pts Arm B, 2/11evaluable\ pts arm D) developed a response. One patient in D+O arm developed path CR. Low γH2AX staining at pretreatment biopsies was associated with progression (p=0.029). Higher PD-L1 expression (CPS≥1) was associated with disease progression (p=0.014). CPS PD-L1 was upregulated following (O) treatment. STING expression was not significantly upregulated post treatment in (O) treatment arms. Alterations in genes that have been previously reported to be associated with (O) sensitivity, namely DNA damage Response/Repair (DDR) genes and genes involved in chromatin remodeling ( CHK2, KMT2D, KMT2C, ARID2 and AJUBA), were identified in responders. Conclusions: This window study demonstrated promising signs of activity of (O) in HNSCC, particularly in tumors with high expression of γH2AX and alterations in DDR or chromatin remodeling genes. Clinical trial information: NCT02882308 .
Computational discovery of non-mutational tumor-restricted antigens reveals evidence of immunoediting in head and neck squamous cell carcinoma.
Authors: Kemnade Jan Ole , Wheeler Thomas M. , Cardenas Maria , Sikora Andrew G. , Frederick Mitchell 
Published: May 2020

6564 Background: We previously identified 107 expression-based tumor antigens (EbTAgs) defined as genes with negligible expression in healthy tissue and overexpression in cancer. EbTAgs present novel targets for the adaptive anti-tumor immune response and exhibit evidence of immunoediting in highly immune infiltrated oral cavity tumors. To detail the landscape of EbTAgs in head and neck squamous cell carcinoma (HNSC) and further elucidate EbTAg immunoediting, we compared the expression EbTAgs in the context of tumor immune infiltration among four HNSCC subtypes: oral cavity (OC), HPV+ oropharyngeal (HPV+OP), HPV- oropharyngeal (HPV-OP), and laryngeal/hypopharyngeal (LH). Methods: Upper quartile FPKM gene expression values of all protein coding genes were calculated for all HNSC samples using RNAseq data from The Cancer Genome Atlas (TCGA). TCGA HNSC tumors were divided into subtypes and analyzed for EbTAg expression. Individual tumor sample immune infiltrate was determined using unsupervised clustering of 14 immune cell signature ssGSEA scores for the HNSC dataset as a whole and for each subtype. Results: LH tumors expressed significantly more EbTAgs than other subtypes (p=0.0014), specifically HPV+OP (p=0.0008, Tukey’s test). Immune clustering analysis showed that LH tumors were significantly more likely to be in the low than the high immune cluster whereas the reverse was true for HPV+OP tumors (p<0.0001). Hypothesizing that EbTAg expression was a function of tumor immune infiltration rather than HNSC subtype, we compared EbTAg expression between tumors in low and high immune clusters of the entire HNSC dataset as well as of each HNSC subtype. Significantly more EbTAgs were expressed in low immune tumors compared to high immune tumors of the HNSC dataset (p<0.0001). Similarly, significantly more EbTAgs were expressed in low immune tumors compared to high immune tumors of the OC, OP-all tumors, and HPV+OP datasets (p=0.0003, p<0.0001, p=0.0006) with a trend of more EbTAgs in the immune low versus high tumors in the HPV-OP and LH datasets (p=0.12, p=0.095). Conclusions: EbTAg expression in TCGA HNSC samples correlates with tumor immune infiltration resulting in lower expression under greater immunological pressure. These results reinforce the hypothesis that EbTAgs undergo immunoediting and are immunologically relevant. Exploration of EbTAgs as antigenic targets of modular vaccines or adoptive T-cell therapy as well as biomarkers of immune checkpoint inhibition therapy response is warranted.
DURTRERAD: A phase II open-label study evaluating feasibility and efficacy of durvalumab (D) and durvalumab and tremelimumab (DT) in combination with radiotherapy (RT) in non-resectable locally advanced HPV-negative HNSCC—Results of the preplanned feasibility interim analysis.
Authors: Klinghammer Konrad Friedrich , Gauler Thomas Christoph , Stromberger Carmen , Kofla Grzegorz , de Wit Maike , Gollrad Johannes , Rauer Izabella , Martus Peter , Tinhofer Inge , Budach Volker , Keilholz Ulrich , Burock Susen 
Published: May 2020

6574 Background: DURTRERAD is a randomized phase II study evaluating feasibility and efficacy of durvalumab (anti-PD-L1) vs. durvalumab and tremelimumab (anti-CTLA-4) in combination with radiotherapy as primary treatment for locally advanced HPV negative HNSCC. (NCT03624231). Concurrent chemo-RT with a platinum-based regimen is considered the standard treatment, although efficacy and long-term toxicity are not satisfactory. Combining immunotherapy with RT might result in improved efficacy with limited long-term toxicity. Methods: The phase II study planned to enroll 120 pts, 60 pts (1:1) in each treatment arm. Treatment with DT (1500mg/75 mg, arm DT),or D (1500mg, arm D) both in combination with RT (70Gy) was considered to be feasible if less than 10% of the patients treated will discontinue treatment due to on-treatment toxicities. A first interim analysis for feasibility and efficacy was planned after randomisation of 20 patients. Results: So far 23 patients have been screened, 16 patients have been randomised and started their allocated treatment, 10 in arm D and 6 in arm DT. Of 10 patients in arm D 1 patient stopped infusional treatment due to immune related toxicity. Out of 6 patients in the DT arm, however, 5 patients stopped treatment due to treatment related AEs, 2 pts due to immune related toxicity with one Grade 5 AE. Three patients stopped due to non-immune related AE. The grade 5 AE prompted the interim analysis, which revealed non-feasibility as well as safety-issues of the DT+radiotherapy combination . As a result, the DT arm was prematurely terminated. Conclusions: Even though in the recurrent/metastatic setting DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of advanced HPV negative unresectable HNSCC, warranting early disclosure of these results. No increase in toxicity was observed in the D monotherapy arm, and the trial continued with D monotherapy in combination with RT. Clinical trial information: NCT03624231 .
Single-cell multiplexed proteomics to identify novel polyfunctional CD8+ T cell signatures induced by nivolumab in head and neck cancer patients after salvage surgery.
Authors: Gulati Shuchi , Haque Sulsal , Palackdharry Sarah , Steele Aubrey , Allen Casey , Takiar Vinita , Riaz Muhammad Kashif , Lehn Maria , Jandarov Roman , Zender Chad , Patil Yash , Tang Alice L , Cervenka Brian , Sukari Ammar , Nagasaka Misako , Wise-Draper Trisha Michel 
Published: May 2020

6576 Background: Immune checkpoint inhibitors (ICIs) are FDA approved for use in head and neck squamous cell cancer (HNSCC), however, only ~20% patients achieve a response. Identification of biomarkers of response or toxicity remains a challenge. Polyfunctional T-cells, or T-cells producing multiple cytokines, have been recognized as contributors to durable immunity against various cancers. However, their role has not been studied prospectively in HNSCC patients receiving ICIs. To look for an early predictor of response, we used single-cell functional proteomic profiling (IsoPlexis) on blood samples pre- and post- first dose of nivolumab (nivo) in patients on our phase-II study of locally recurrent HNSCC (NCT03355560). Methods: HNSCC patients who failed definitive radiation +/-chemotherapy and were subsequently treated with curative intent salvage resection were enrolled to receive 6 months of nivo beginning 4 to 11 weeks after surgery. Blood samples were collected before and after the first dose of nivo. Peripheral blood mononuclear cells were isolated, enriched for CD8+ T cells and using the 32-plex IsoCode technology, single-cell cytokine signals were captured and polyfunctional strength of CD8+ T cells was evaluated across four groups (effector, stimulatory, regulatory, inflammatory). A comparison analysis was performed between pre- and post- nivo treatment and between patients who relapsed (non-responders) vs those who did not (responders). Results: Thirty-three of 39 planned patients have been enrolled, of which 28 are evaluable and 5/28 (18%) developed recurrence. Median age is 68 years (range 51-85), 9/28 (32%) patients are female, 26/28 (93%) are white, disease sites include oropharyngeal 6/28 (21%), oral cavity 11/28 (39%) and larynx 11/28 (39%). Samples were evaluated at a median follow up of 5.9 months from enrollment. Single-cell analysis demonstrated a strong upregulation of polyfunctional human CD8+ T cell subsets in responders. Polyfunctional Strength Index (PSI) was enhanced in CD8+ T cells across the responders’ samples, composed largely of effector cytokines (granzyme-β, IFN-γ, MIP-1α, perforin, TNF-α). Conclusions: Single-cell functional proteomic analysis revealed significantly upregulated polyfunctional profiles and an increase in effector cytokines in patients who responded to nivo. This data provides important insights into PD-1 inhibitor triggered T-cell activity and may be used to predict response to ICIs in HNSCC patients using a blood test. Clinical trial information: NCT03355560 .
Risk of chronic opioid use after radiation for head and neck cancer: A systematic review and meta-analysis.
Authors: Zayed Sondos , Lin Cindy , Boldt Gabriel , Read Nancy , Mendez Lucas , Venkatesan Varagur , Sathya Jinka , Moulin Dwight , Palma David A. 
Published: May 2020

6579 Background: Opioid overuse is a major international public health concern. The prevalence and risk factors for chronic opioid use (COU) in radiation-induced head and neck pain are poorly understood. The aim of this study was to estimate the rates of COU and to identify risk factors for COU in head and neck cancer (HNC) patients undergoing curative-intent radiotherapy (RT) or chemoradiotherapy (CRT). Methods: We performed a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, using the PubMed (Medline), EMBASE, and Cochrane library databases, queried from dates of inception until present. COU was defined as persistent opioid use ≥3 months after treatment completion. Studies in the English language that reported on COU in HNC patients who received RT/CRT were included. Meta-analyses were performed using random effects models. Heterogeneity was assessed using the I2 value. Results: A total of 134 studies were identified, with 7 retrospective studies (reporting on 1841 patients) meeting inclusion criteria. Median age was 59.4 years (range 56.0-62.0) with 1343 (72.9%) men and 498 (27.1%) women. Primary tumour locations included oropharynx (891, 48.4%), oral cavity (533, 29.0%), larynx (93, 5.1%), hypopharynx (32, 1.7%), and nasopharynx (29, 1.6%). 846 (46.0%) patients had stage I/II disease and 926 (50.3%) had stage III-IV disease. 301 (16.3%) patients had RT alone, 738 (40.1%) received CRT, and 594 (32.3%) underwent surgery followed by adjuvant RT/CRT. The proportion of HNC patients who received radiotherapy and developed COU was 40.7% at 3 months (95% CI 22.6%-61.7%, I2= 97.1%), 15.5% at 6 months (95% CI 7.3%-29.7%, I2= 94.3%) and 7.0% at 1 year. There were significant differences in COU based on primary tumor sites (P < 0.0001), with the highest rate (46.6%) in oropharyngeal malignancies. Other factors associated with COU included history of psychiatric disorder (61.7%), former/current alcohol abuse (53.9%), and start of opioids prior to radiation treatment (51.6%). There was no significant difference in the proportion of COU by gender (P = 0.683), disease stage (I/II vs III/IV; P = 0.443), or treatment received (RT, CRT, or adjuvant RT/CRT; P = 0.711). Conclusions: A significant proportion of patients who undergo radiotherapy for head and neck cancer suffer from COU. High-risk factors for COU include an oropharyngeal primary tumour, history of psychiatric disorder, former/current alcohol abuse, and pre-treatment opioid use. New strategies to mitigate opioid use are needed.