Publications by authors named "Christine H Chung"

141 Publications

Oral secretory leukocyte protease inhibitor (SLPI): Associations with oropharyngeal cancer and treatment outcome.

PLoS One 2021 2;16(7):e0254161. Epub 2021 Jul 2.

Center for Immunization and Infection Research in Cancer, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States of America.

Background: Rates of oropharyngeal cancer (OPC) associated with alcohol & tobacco use have decreased, while human papillomavirus (HPV) associated OPC has increased among men in the US. Secretory leukocyte protease inhibitor (SLPI), detectable in a variety of secretions, has been implicated in cancers of the head and neck, associated with tumor progression and anti-viral activity. Using the recently verified oral gargle specimen, this study aimed to assess the association of salivary SLPI expression with risk of OPC and response to treatment.

Methods: A case-control study design compared levels of salivary SLPI among OPC cases to age and tobacco smoking matched healthy controls. Oral HPV DNA and SLPI was quantified from oral gargle specimens. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations of oral SLPI and risk of OPC and treatment outcomes.

Results: In crude and adjusted analyses of 96 OPC cases and 97 age- and smoking-matched controls, OPC was not significantly associated with oral gargle SLPI levels. Among cases, oral SLPI was associated with tonsillectomy (p = 0.018) and among controls oral SLPI was associated with HPV in the oral gargle (p = 0.008). Higher concentrations of SLPI was significantly associated with increased odds of incomplete treatment response (T2: OR: 12.39; 95% CI: 1.44-106.72; T3: OR: 9.86; 95% CI: 1.13-85.90) among all cases, but not among P16+ cases.

Conclusions: Salivary SLPI was not associated with OPC risk but was associated with higher odds of an incomplete treatment response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254161PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253433PMC
July 2021

Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.

J Immunother Cancer 2021 Jun;9(6)

Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.

Background: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.

Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.

Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.

Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.

Trial Registration Number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.
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http://dx.doi.org/10.1136/jitc-2021-002568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183204PMC
June 2021

TIMEx: tumor-immune microenvironment deconvolution web-portal for bulk transcriptomics using pan-cancer scRNA-seq signatures.

Bioinformatics 2021 Apr 26. Epub 2021 Apr 26.

Department of Biostatistics and Bioinformatics.

Summary: The heterogeneous cell types of the tumor-immune microenvironment (TIME) play key roles in determining cancer progression, metastasis, and response to treatment. We report the development of TIMEx, a novel tumor-immune microenvironment deconvolution method emphasizing on estimating infiltrating immune cells for bulk transcriptomics using pan-cancer single-cell RNA-seq signatures. We also implemented a comprehensive, user-friendly web-portal for users to evaluate TIMEx and other deconvolution methods with bulk transcriptomic profiles.

Availability: TIMEx web portal is freely accessible at http://timex.moffitt.org.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab244DOI Listing
April 2021

Concurrent Cetuximab and Nivolumab as a Second-Line or beyond Treatment of Patients with Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results of Phase I/II Study.

Cancers (Basel) 2021 Mar 9;13(5). Epub 2021 Mar 9.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.

We hypothesized the combination of cetuximab and nivolumab would improve survival in recurrent and/or metastatic (R/M) HNSCC by providing synergy in cancer control and evaluated toxicities and efficacy of the combination. Effects of sequential administration of cetuximab and anti-Programmed Cell Death-1 checkpoint inhibitors (CPI) were also explored. Patients who failed at least one line of palliative treatment for incurable HNSCC were treated with cetuximab 500 mg/m IV on Day (D)-14 as a lead-in followed by cetuximab 500 mg/m IV and nivolumab 240 mg/m IV on D1 and D15 every 28-D cycle. Electronic health record-derived real-world data (RWD) were used to explore sequential treatment effects of CPI and cetuximab. A total of 45 evaluable patients were analyzed, and 31/45 (69%) patients had prior exposure to either CPI or cetuximab. The only grade 4 treatment-related adverse event was cetuximab infusion reaction in one patient. The 1-year progression-free survival (PFS) and overall survival (OS) rates were 19% and 44%, respectively. Although patients with no prior CPI (23/45, 51%) showed a trend for more favorable PFS relative to patients with prior CPI (22/45, 49%), the improvement in the 1-year OS did not reach the statistical threshold. For evaluation of sequential CPI and cetuximab treatment effects, we selected RWD-cetuximab cohort with 173 patients and RWD-CPI cohort with 658 patients from 6862 R/M HNSCC. Our result suggested patients treated with RWD-cetuximab after RWD-CPI had worse OS compared to no prior RWD-CPI (HR 1.81, 95% CI 1.02-3.16). Our data suggest the combination of cetuximab and nivolumab is well tolerated. Optimal sequencing of cetuximab and CPI may have an impact in prognosis and requires further evaluation.
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http://dx.doi.org/10.3390/cancers13051180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967147PMC
March 2021

Survival outcomes of patients with subglottic squamous cell carcinoma : a study of the National Cancer Database.

Eur Arch Otorhinolaryngol 2021 Mar 1. Epub 2021 Mar 1.

Department of Head and Neck-Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Background: Subglottic squamous cell carcinoma (SCC) represents less than 5% of all laryngeal cancers. Our objective was to better characterize survival using the National Cancer Database (NCDB) registry from 2004 to 2015.

Results: 403 patients met inclusion criteria. 63.8% presented with advanced-stage disease. Treatment regimens were as follows: 15.9% underwent surgery alone, 16.9% underwent surgery followed by adjuvant therapy, and 67.2% underwent primary chemo/radiation (C/RT). Five-year overall survival (OS) was 58.6% for Stage I and II patients, 49.1% for Stage III, and 36.3% for stage IV. Adjusted OS for all-stage patients was worse with C/RT compared to upfront surgery (40.6% vs. 58.4%; HR 1.83 [95%CI 1.29-2.61] p < 0.001) and adjusted OS for stage 4 disease was significantly worse with C/RT compared to surgery (26.0% vs. 45.2%, HR 1.79 [95%CI 1.17-2.73] p = 0.007).

Conclusion: Majority of patients were treated with primary C/RT. Adjusted survival favors upfront surgery versus C/RT, especially in patients with Stage IV disease.
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http://dx.doi.org/10.1007/s00405-021-06712-wDOI Listing
March 2021

Utilizing a large-scale biobanking registry to assess patient priorities and preferences for cancer research and education.

PLoS One 2021 5;16(2):e0246686. Epub 2021 Feb 5.

Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.

Patients consented to biobanking studies typically do not specify research conducted on their samples and data. Our objective was to gauge cancer biobanking participant preferences on research topics. Patient-participants of a biobanking study at a comprehensive cancer center who had an appointment within the last 5 years, had a valid email address, and with a last known vital status of alive, were emailed a newsletter containing a link to a survey about preferences and priorities for research. The survey assessed demographics and research interest in three domains: cancer site, cancer-related topics, and issues faced by cancer patients. 37,384 participants were contacted through email to participate in the survey. 16,158 participants (43.2%) opened the email, 1,626 (4.3% overall, 10% of those who opened the email) completed the survey, and 1,291 (79.4% of those who completed the survey) selected at least one research priority. Among those who selected at least one research priorities for cancer-relevant topics, the most commonly selected were cancer treatment (66%), clinical trials (54%), and cancer prevention (53%). Similarly, the most selected priorities for cancer-related issues faced by patients were physical side effects of cancer (57%), talking to the oncologist (53%), and emotional challenges due to cancer (47%). Differences by gender were observed, with females reporting more interest in research generally. Cancer patients participating in a biobanking protocol prioritized research on treatments, prevention and side effects, which varied by gender.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246686PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864448PMC
February 2021

Reduced-Dose Radiation Therapy for HPV-Associated Oropharyngeal Carcinoma (NRG Oncology HN002).

J Clin Oncol 2021 Mar 28;39(9):956-965. Epub 2021 Jan 28.

Stanford University, Stanford, CA.

Purpose: Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.

Patients And Methods: In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).

Results: Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( = .04). For IMRT, 2-year PFS was 87.6% ( = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% 52.4%; < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( = .56).

Conclusion: The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.
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http://dx.doi.org/10.1200/JCO.20.03128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078254PMC
March 2021

Recent Advances and Future Directions in Clinical Management of Head and Neck Squamous Cell Carcinoma.

Cancers (Basel) 2021 Jan 18;13(2). Epub 2021 Jan 18.

Moffitt Cancer Center, Department of Head and Neck-Endocrine Oncology, Tampa, FL 33612, USA.

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence of HPV-related HNSCC is increasing in the United States and Western Europe, which led to a shift in understanding of the pathophysiology, treatment, and prognosis of this disease. The outcomes for non-metastatic HNSCC remains very encouraging and continues to improve. Advances in radiation technology and techniques, better organ preserving surgical options, and multidisciplinary treatment modalities have improved cure rates for locally advanced HNSCC patients. The treatment of metastatic disease, however, remains an area of need. The advancement of immune checkpoint inhibitors has provided significantly better outcomes, but only a small proportion of patients obtain benefits. Most recurrent and/or metastatic HNSCC patients continue to have poor survival. This has led to the vigorous investigation of new biomarkers and biomarker-based therapies. Novel therapeutic options including adaptive cellular therapy and therapeutic vaccines are also on the horizon. In this review, we highlight the latest advances in the field of HNSCC and the future direction of research.
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http://dx.doi.org/10.3390/cancers13020338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831487PMC
January 2021

Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma.

Mol Carcinog 2021 02 30;60(2):138-150. Epub 2020 Dec 30.

Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

Prognosis for patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains poor. Development of more effective and less toxic targeted therapies is necessary for HNSCC patients. Checkpoint kinase 1 (CHK1) plays a vital role in cell cycle regulation and is a promising therapeutic target in HNSCC. Prexasertib, a CHK1 inhibitor, induces DNA damage and cell death, however, its effect on the tumor immune microenvironment (TIME) is largely unknown. Therefore, we evaluated a short-term and long-term effects of prexasertib in HNSCC and its TIME. Prexasertib caused increased DNA damage and cell death in vitro and significant tumor regression and improved survival in vivo. The gene expression and multiplex immunohistochemistry (mIHC) analyses of the in vivo tumors demonstrated increased expression of genes that are related to T-cell activation and increased immune cell trafficking, and decreased expression of genes that related to immunosuppression. However, increased expression of genes related to immunosuppression emerged over time suggesting evasion of immune surveillances. These findings in gene expression analyses were confirmed using mIHC which showed differential modulation of TIME in the tumor margins and as well as cores over time. These results suggest that evasion of immune surveillance, at least in part, may contribute to the acquired resistance to prexasertib in HNSCC.
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http://dx.doi.org/10.1002/mc.23275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856233PMC
February 2021

A Transparent Approach to Calculate Detection Rate and Residual Risk for Carrier Screening.

J Mol Diagn 2021 01;23(1):91-102

Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. Electronic address:

Carrier screening involves detection of carrier status for genes associated with recessive conditions. A negative carrier screening test result bears a nonzero residual risk (RR) for the individual to have an affected child. The RR depends on the prevalence of specific conditions and the detection rate (DR) of the test itself. Herein, we provide a detailed approach for calculating DR and RR. DR was calculated on the basis of the sum of disease allele frequencies (DAFs) of pathogenic variants found in published literature. As a proof of concept, DAF data for cystic fibrosis were compared with society guidelines. The DAF data calculated by this method were consistent with the published cystic fibrosis guideline. In addition, we compared DAF for four genes (ABCC8, ASPA, GAA, and MMUT) across three laboratories, and outlined the likely reasons for discrepancies between these laboratories. The utility of carrier screening is to support couples with information while making reproductive choices. Accurate development of DR and RR is therefore critical. The method described herein provides an unbiased and transparent process to collect, calculate, and report these data.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.009DOI Listing
January 2021

Histoecology: Applying Ecological Principles and Approaches to Describe and Predict Tumor Ecosystem Dynamics Across Space and Time.

Cancer Control 2020 Jul-Aug;27(3):1073274820946804

Integrated Mathematical Oncology Department, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Cancer cells exist within a complex spatially structured ecosystem composed of resources and different cell types. As the selective pressures imposed by this environment determine the fate of cancer cells, an improved understanding of how this ecosystem evolves will better elucidate how tumors grow and respond to therapy. State of the art imaging methods can now provide highly resolved descriptions of the microenvironment, yielding the data required for a thorough study of its role in tumor growth and treatment resistance. The field of landscape ecology has been studying such species-environment relationship for decades, and offers many tools and perspectives that cancer researchers could greatly benefit from. Here, we discuss one such tool, species distribution modeling (SDM), that has the potential to, among other things, identify critical environmental factors that drive tumor evolution and predict response to therapy. SDMs only scratch the surface of how ecological theory and methods can be applied to cancer, and we believe further integration will take cancer research in exciting new and productive directions. Here we describe how species distribution modeling can be used to quantitatively describe the complex relationship between tumor cells and their microenvironment. Such a description facilitates a deeper understanding of cancers eco-evolutionary dynamics, which in turn sheds light on the factors that drive tumor growth and response to treatment.
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http://dx.doi.org/10.1177/1073274820946804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710396PMC
April 2021

Molecular Determinants of Thyroid Nodules with Indeterminate Cytology and Mutations.

Thyroid 2021 01 25;31(1):36-49. Epub 2020 Aug 25.

Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida, USA.

gene family mutations are the most prevalent in thyroid nodules with indeterminate cytology and are present in a wide spectrum of histological diagnoses. We evaluated differentially expressed genes and signaling pathways across the histological/clinical spectrum of -mutant nodules to determine key molecular determinants associated with a high risk of malignancy. Sixty-one thyroid nodules with mutations were identified. Based on the histological diagnosis and biological behavior, the nodules were grouped into five categories indicating their degree of malignancy: non-neoplastic appearance, benign neoplasm, indeterminate malignant potential, low-risk cancer, or high-risk cancer. Gene expression profiles of these nodules were determined using the NanoString PanCancer Pathways and IO 360 Panels, and Angiopoietin-2 level was determined by immunohistochemical staining. The analysis of differentially expressed genes using the five categories as supervising parameters unearthed a significant correlation between the degree of malignancy and genes involved in cell cycle and apoptosis (, , , , , , , , and ), pathway (, , , , , and ), and stromal factors ( and ). The expression of Angiopoietin-2 by immunohistochemistry also showed the same trend of increasing expression from non-neoplastic appearance to high-risk cancer ( < 0.0001). The gene expression analysis of -mutant thyroid nodules suggests increasing upregulation of key oncogenic pathways depending on their degree of malignancy and supports the concept of a stepwise progression. The utility of expression as a potential diagnostic biomarker warrants further evaluation.
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http://dx.doi.org/10.1089/thy.2019.0650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864115PMC
January 2021

Real-Time In-Organism NMR Metabolomics Reveals Different Roles of AMP-Activated Protein Kinase Catalytic Subunits.

Anal Chem 2020 06 11;92(11):7382-7387. Epub 2020 May 11.

Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul 08826, Korea.

AMP-activated protein kinase (AMPK in human and AAK in ) is a master regulator of metabolism. It has many isotypes, but its isotype-dependent functions are largely unknown. By developing real-time in-organism NMR metabolomics for , we were able to study different roles of the isotypic catalytic subunits of AAK/AMPK, AAK-1, and AAK-2 in live worms at the whole organism level. The knockout animals exhibited enhanced glucose production under starvation, strikingly opposite to knockout animals. Unusually high compensatory expression of the reciprocal isotypes in each KO strain and the results for the double KO animals suggested an unconventional phenotype-genotype relationship and the dominance of in glucose production. The gene expression patterns showed that the differential phenotypes of KO strain are due to reduced TCA and glycolysis and enhanced gluconeogenesis compared to the KO strain. Subsequent C-isotope incorporation experiment showed that the glucose production in KO occurs through the activation of fatty acid oxidation and glyoxylate shunt. Revealing differential roles of the isotypes of AAK/AMPK, our convenient approach is readily applicable to many models for human metabolic diseases.
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http://dx.doi.org/10.1021/acs.analchem.9b05670DOI Listing
June 2020

Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial.

J Clin Oncol 2020 08 23;38(22):2476-2487. Epub 2020 Apr 23.

University of Washington, Seattle Cancer Care Alliance, Seattle, WA.

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC.

Methods: In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies.

Results: Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation.

Conclusion: Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.
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http://dx.doi.org/10.1200/JCO.20.00201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392746PMC
August 2020

Long noncoding RNA, , as a prognostic biomarker in head and neck squamous cell carcinoma (HNSCC).

Am J Transl Res 2020 15;12(2):684-696. Epub 2020 Feb 15.

Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center Tampa, FL, USA.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy characterized by frequent mutations and metastasis. Long noncoding RNAs (lncRNAs) have been implicated in tumorigenesis and serve as novel prognostic biomarkers in different cancers. To enhance our understanding of lncRNAs that may have biological significance in HNSCC and may serve as prognostic biomarkers, we globally profiled lncRNAs in HNSCC by analyzing the RNA-seq data from The Atlas of Noncoding RNAs in Cancer (TANRIC) database. Of 3576 lncRNAs, we identified 926 (higher-688, lower-238) lncRNAs with a 2-fold abundance difference among the forty HNSCC and paired adjacent normal tissue. We investigated differential abundance of lncRNAs based on mutation and p16 status. We found 133 lncRNAs to have differential abundance by 2-fold among the mutant vs wild-type samples, whereas among p16-negative vs positive samples, we identified 710 lncRNAs with the same criteria. Meanwhile, analysis of the 15 most abundant lncRNAs in the tumor samples identified five lncRNAs whose higher abundance was associated with poor overall patient survival. Among these five, higher abundance of associated with poor patient survival in an independent cohort of 82 HNSCC patients. To further evaluate the potential function of , we performed lncRNA-mRNAs co-expression analysis and found that higher abundance of associated with cancer-related biological pathways including EMT and other inflammatory response pathways. In summary, we report is more abundant in tumors compared to adjacent normal tissue and that it may serve as a potential prognostic biomarker in HNSCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061833PMC
February 2020

Effects of Tobacco Smoking on the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma.

Clin Cancer Res 2020 03 17;26(6):1474-1485. Epub 2019 Dec 17.

Department of Head and Neck-Endocrine Oncology, Moffitt Cancer Center, Tampa, Florida.

Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) who actively smoke during treatment have worse survival compared with never-smokers and former-smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response. We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers.

Experimental Design: Tumor specimens were subjected to analysis of CD3, CD8, FOXP3, PD-1, PD-L1, and pancytokeratin by multiplex immunofluorescence, whole-exome sequencing, and RNA sequencing. Immune markers were measured in tumor core, tumor margin, and stroma.

Results: Our data indicate that current smokers have significantly lower numbers of CD8 cytotoxic T cells and PD-L1 cells in the TIM compared with never- and former-smokers. While tumor mutation burden and mutant allele tumor heterogeneity score do not associate with smoking status, gene-set enrichment analyses reveal significant suppression of IFNα and IFNγ response pathways in current smokers. Gene expression of canonical IFN response chemokines, , , and , are lower in current smokers than in former smokers, suggesting a mechanism for the decreased immune cell migration to tumor sites.

Conclusions: These results suggest active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T cells, likely as a result of suppression of IFN response pathways. Our study highlights the importance of understanding the interaction between smoking and TIM in light of emerging immune modulators for cancer management.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073297PMC
March 2020

Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.

Lancet Oncol 2020 02 11;21(2):261-270. Epub 2019 Dec 11.

Ignyta, San Diego, CA, USA.

Background: Recurrent gene fusions, such as ROS1 fusions, are oncogenic drivers of various cancers, including non-small-cell lung cancer (NSCLC). Up to 36% of patients with ROS1 fusion-positive NSCLC have brain metastases at the diagnosis of advanced disease. Entrectinib is a ROS1 inhibitor that has been designed to effectively penetrate and remain in the CNS. We explored the use of entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive NSCLC.

Methods: We did an integrated analysis of three ongoing phase 1 or 2 trials of entrectinib (ALKA-372-001, STARTRK-1, and STARTRK-2). The efficacy-evaluable population included adult patients (aged ≥18 years) with locally advanced or metastatic ROS1 fusion-positive NSCLC who received entrectinib at a dose of at least 600 mg orally once per day, with at least 12 months' follow-up. All patients had an Eastern Cooperative Oncology Group performance status of 0-2, and previous cancer treatment (except for ROS1 inhibitors) was allowed. The primary endpoints were the proportion of patients with an objective response (complete or partial response according to Response Evaluation Criteria in Solid Tumors version 1.1) and duration of response, and were evaluated by blinded independent central review. The safety-evaluable population for the safety analysis included all patients with ROS1 fusion-positive NSCLC in the three trials who received at least one dose of entrectinib (irrespective of dose or duration of follow-up). These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).

Findings: Patients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018), 41 (77%; 95% CI 64-88) of 53 patients in the efficacy-evaluable population had an objective response. Median follow-up was 15·5 monhts (IQR 13·4-20·2). Median duration of response was 24·6 months (95% CI 11·4-34·8). In the safety-evaluable population, 79 (59%) of 134 patients had grade 1 or 2 treatment-related adverse events. 46 (34%) of 134 patients had grade 3 or 4 treatment-related adverse events, with the most common being weight increase (ten [8%]) and neutropenia (five [4%]). 15 (11%) patients had serious treatment-related adverse events, the most common of which were nervous system disorders (four [3%]) and cardiac disorders (three [2%]). No treatment-related deaths occurred.

Interpretation: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients. These data highlight the need to routinely test for ROS1 fusions to broaden therapeutic options for patients with ROS1 fusion-positive NSCLC.

Funding: Ignyta/F Hoffmann-La Roche.
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http://dx.doi.org/10.1016/S1470-2045(19)30690-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811790PMC
February 2020

A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors.

J Immunother Cancer 2019 12 4;7(1):342. Epub 2019 Dec 4.

Sanford Research, Sioux Falls, SD, USA.

Background: Expressed on activated T and natural killer cells, 4-1BB/CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs).

Methods: Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks.

Results: No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis.

Conclusions: The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity.

Trial Registration: ClinicalTrials.gov identifier: NCT02444793.
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http://dx.doi.org/10.1186/s40425-019-0815-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894203PMC
December 2019

Estimation of immune cell content in tumor using single-cell RNA-seq reference data.

BMC Cancer 2019 Jul 19;19(1):715. Epub 2019 Jul 19.

Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Background: The rapid development of single-cell RNA sequencing (scRNA-seq) provides unprecedented opportunities to study the tumor ecosystem that involves a heterogeneous mixture of cell types. However, the majority of previous and current studies related to translational and molecular oncology have only focused on the bulk tumor and there is a wealth of gene expression data accumulated with matched clinical outcomes.

Results: In this paper, we introduce a scheme for characterizing cell compositions from bulk tumor gene expression by integrating signatures learned from scRNA-seq data. We derived the reference expression matrix to each cell type based on cell subpopulations identified in head and neck cancer dataset. Our results suggest that scRNA-Seq-derived reference matrix outperforms the existing gene panel and reference matrix with respect to distinguishing immune cell subtypes.

Conclusions: Findings and resources created from this study enable future and secondary analysis of tumor RNA mixtures in head and neck cancer for a more accurate cellular deconvolution, and can facilitate the profiling of the immune infiltration in other solid tumors due to the expression homogeneity observed in immune cells.
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http://dx.doi.org/10.1186/s12885-019-5927-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642583PMC
July 2019

Methylation of HPV 16 and EPB41L3 in oral gargles: Associations with oropharyngeal cancer detection and tumor characteristics.

Int J Cancer 2020 02 26;146(4):1018-1030. Epub 2019 Jul 26.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL.

Oropharyngeal cancer (OPC) incidence is increasing significantly among men and often requires intensive therapy causing significant morbidity. Early detection of OPC is needed, when monotherapy can be safely delivered with less treatment-associated morbidity, while maintaining high cure rates. We conducted a study of 101 pretreatment male OPC cases matched 1:1 to 101 disease-free controls for age and smoking history. Oral gargles were collected from cases and controls with additional biopsies or aspirates from cases. The HPV SPF -LiPA PCR assay was utilized for HPV genotyping. Methylation of three CpG sites (438, 427 and 425) in the EPB41L3 gene and methylation status of the L1 (6,367, 6,389), L2 (4,257, 4,262, 4,266, 4,269, 4,275, 4,282) and E2 (3,412, 3,415, 3,417, 3,433, 3,436) CpG sites of HPV 16 positive specimens was assessed by pyrosequencing. Significant correlations were observed between tumor and oral specimens for all methylation biomarkers (p < 0.01). EPB41L3 and HPV 16 L1, L2 and E2 methylation were significantly (p < 0.0001) higher among cases than controls, regardless of early vs. late disease. When HPV 16 genes and EPB41L3 methylation status were combined in a logistic regression analysis, a sensitivity of 70.3% and a specificity of 90.9% were observed for the detection of OPC from an oral gargle. Our data suggest that methylation biomarkers measured in oral gargles may have utility in identifying OPC early. Future studies are needed to replicate these findings and to inform additional biomarkers that can maximize specificity and sensitivity for early OPC detection.
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http://dx.doi.org/10.1002/ijc.32570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787351PMC
February 2020

Ultrasound characterization for thyroid nodules with indeterminate cytology: inter-observer agreement and impact of combining pattern-based and scoring-based classifications in risk stratification.

Endocrine 2019 11 12;66(2):278-287. Epub 2019 Jul 12.

Department of Head and Neck-Endocrine Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.

Background: The American Thyroid Association (ATA) sonographic patterns stratify the risk of malignancy of cytologically indeterminate thyroid nodules (ITNs). This study aimed to (1) assess inter-observer agreement for sonographic features and patterns; (2) identify potential sources of disagreement; and (3) evaluate whether the number of suspicious features risk-stratifies non-ATA and high-suspicion patterns.

Methods: Three observers independently reviewed the ultrasound images of 463 ITNs with histological follow-up consecutively evaluated between October 2008 and June 2015 at an academic cancer center. Each observer evaluated individual sonographic features. ATA sonographic patterns were derived from the interpretation of sonographic features. Nodules not fitting into any of the proposed patterns were clustered into a non-ATA pattern.

Results: The inter-observer agreement for ATA sonographic patterns and echogenicity was fair, moderate for margins, good for composition and echogenic foci, and very good for extrathyroidal extension and lymph node metastasis. The interpretation of each sonographic feature was significantly different between observers, and there was complete disagreement in at least one of the features in 104 (22%) nodules. A total of 169 nodules (37%) were classified into the non-ATA pattern. The number of suspicious features allowed risk stratifying nodules with non-ATA and high-suspicion sonographic patterns. Most Non-invasive Follicular Thyroid Neoplasms with Papillary-like Nuclear Features had 0-1 suspicious features and none had >2.

Conclusions: Echogenicity interpretation was the greatest source of disagreement. The number of suspicious features risk-stratifies ITNs with non-ATA or high-suspicion patterns. Future studies attempting to objectivize the interpretation of echogenicity and heterogeneity are needed.
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http://dx.doi.org/10.1007/s12020-019-02000-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771547PMC
November 2019

Targeting the Hedgehog Pathway Using Itraconazole to Prevent Progression of Barrett's Esophagus to Invasive Esophageal Adenocarcinoma.

Ann Surg 2021 06;273(6):e206-e213

Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: The aim of the study was to investigate whether inhibition of Sonic Hedgehog (SHH) pathway would prevent progression of Barrett's Esophagus (BE) to esophageal adenocarcinoma.

Background: The hedgehog signaling pathway is a leading candidate as a molecular mediator of BE and esophageal adenocarcinoma (EAC). Repurposed use of existing off-patent, safe and tolerable drugs that can inhibit hedgehog, such as itraconazole, could prevent progression of BE to EAC.

Methods: The efficacy of itraconazole was investigated using a surgical rat reflux model of Barrett's Metaplasia (BM). Weekly intraperitoneal injections of saline (control group) or itraconazole (treatment group; 200 mg/kg) were started at 24 weeks postsurgery. Esophageal tissue was harvested at 40 weeks. The role of the Hh pathway was also evaluated clinically. Esophageal tissue was harvested after 40 weeks for pathological examination and evaluation of the SHH pathway by immunohistochemistry.

Results: BM was present in control animals 29 of 31 (93%) versus itraconazole 22 of 24 (91%). EAC was significantly lower in itraconazole 2 of 24 (8%) versus control 10 of 31 (32%), respectively (P = 0.033). Esophageal SHH levels were lower in itraconazole vs control (P = 0.12). In esophageal tissue from humans with recurrent or persistent dysplastic BE within 24 months of ablative treatment, strong SHH and Indian Hedgehog expression occurred in distal BE versus proximal squamous epithelium, odds ratio = 6.1 (95% confidence interval: 1.6, 23.4) and odds ratio = 6.4 (95% confidence interval: 1.2, 32.8), respectively.

Conclusion: Itraconazole significantly decreases EAC development and SHH expression in a preclinical animal model of BM. In humans, BE tissue expresses higher SHH, Indian Hedgehog, and bone morphogenic protein levels than normal squamous esophageal epithelium.
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http://dx.doi.org/10.1097/SLA.0000000000003455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147663PMC
June 2021

lncDIFF: a novel quasi-likelihood method for differential expression analysis of non-coding RNA.

BMC Genomics 2019 Jul 2;20(1):539. Epub 2019 Jul 2.

Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, 33612, USA.

Background: Long non-coding RNA (lncRNA) expression data have been increasingly used in finding diagnostic and prognostic biomarkers in cancer studies. Existing differential analysis tools for RNA sequencing do not effectively accommodate low abundant genes, as commonly observed in lncRNAs.

Results: We investigated the statistical distribution of normalized counts for low expression genes in lncRNAs and mRNAs, and proposed a new tool lncDIFF based on the underlying distribution pattern to detect differentially expressed (DE) lncRNAs. lncDIFF adopts the generalized linear model with zero-inflated Exponential quasi-likelihood to estimate group effect on normalized counts, and employs the likelihood ratio test to detect differential expressed genes. The proposed method and tool are applicable to data processed with standard RNA-Seq preprocessing and normalization pipelines. Simulation results showed that lncDIFF was able to detect DE genes with more power and lower false discovery rate regardless of the data pattern, compared to DESeq2, edgeR, limma, zinbwave, DEsingle, and ShrinkBayes. In the analysis of a head and neck squamous cell carcinomas data, lncDIFF also appeared to have higher sensitivity in identifying novel lncRNA genes with relatively large fold change and prognostic value.

Conclusions: lncDIFF is a powerful differential analysis tool for low abundance non-coding RNA expression data. This method is compatible with various existing RNA-Seq quantification and normalization tools. lncDIFF is implemented in an R package available at https://github.com/qianli10000/lncDIFF .
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http://dx.doi.org/10.1186/s12864-019-5926-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604377PMC
July 2019

Locally advanced high-risk HPV related oropharyngeal squamous cell carcinoma (OPSCC); have we forgotten it is a different disease?

Cancers Head Neck 2018 3;3. Epub 2018 Oct 3.

6Head and Neck and Endocrine Oncology, Moffitt Cancer Center, Tampa, USA.

HPV related OPSCC has a distinct behavior and improved outcome. As immunotherapy has recently evolved into a new standard for advanced (SCCHN), trials for high-risk SCCHN have trended to encompass both HPV related and unrelated diseases. In this invited editorial, we question the wisdom of this approach and argue for the design of trials focused specifically on HPV related locally advanced oropharyngeal squamous cell carcinoma as a unique disease entity.
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http://dx.doi.org/10.1186/s41199-018-0035-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460663PMC
October 2018

Oral gargle-tumor biopsy human papillomavirus (HPV) agreement and associated factors among oropharyngeal squamous cell carcinoma (OPSCC) cases.

Oral Oncol 2019 05 3;92:85-91. Epub 2019 Apr 3.

Center for Immunization and Infection Research in Cancer, Moffitt Cancer Center, United States. Electronic address:

Objective: Assess oral gargle-tumor human papillomavirus (HPV) agreement among oropharyngeal squamous cell carcinoma (OPSCC) cases by several disease characteristics.

Materials And Methods: 171 treatment naïve OPSCC were enrolled 2014-2017. Tumors were categorized as early or late disease with early disease defined as T1-2 with no nodal involvement or at most a single ipsilateral positive node <3 cm. Oral gargle samples were obtained via a 30-second rinse and gargle. The RHA Kit HPV SP-LiPA was utilized for HPV genotyping of tumor (FFPE) and oral gargle specimens. Sensitivity, specificity, positive and negative predictive value, percent agreement, and 95% exact binomial confidence intervals were estimated. Multivariable logistic regression models were fit to predict agreement.

Results: 83.0% and 93.0% of oral gargle and tumor specimens were HPV positive. Oral gargle-tumor agreement for any oncogenic HPV type and HPV 16 was 73.7%. High oncogenic HPV oral gargle-tumor agreement was observed for late disease presentation, p16 positive cases, and tumors at the tonsils (74.5-80.8%). Similar trends were observed for HPV 16. Agreement for any oncogenic HPV and HPV 16 was significantly higher for late vs. early disease (77.9% vs 57.1%, p = 0.01). Oral gargle-tumor oncogenic HPV and HPV 16 agreement was independently associated with age ≥50 years and late disease presentation.

Conclusion: Overall, oral-tumor HPV agreement among OPSCC was relatively high. However, oral-tumor HPV agreement was significantly lower among younger cases and those diagnosed with earlier disease. Additional biomarkers are needed to improve oral HPV test characteristics to identify OPSCC early.
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http://dx.doi.org/10.1016/j.oraloncology.2019.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736648PMC
May 2019

CancerInSilico: An R/Bioconductor package for combining mathematical and statistical modeling to simulate time course bulk and single cell gene expression data in cancer.

PLoS Comput Biol 2018 06 19;14(4):e1006935. Epub 2019 Apr 19.

Department of Oncology, Division of Biostatistics and Bioinformatics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD United States of America.

Bioinformatics techniques to analyze time course bulk and single cell omics data are advancing. The absence of a known ground truth of the dynamics of molecular changes challenges benchmarking their performance on real data. Realistic simulated time-course datasets are essential to assess the performance of time course bioinformatics algorithms. We develop an R/Bioconductor package, CancerInSilico, to simulate bulk and single cell transcriptional data from a known ground truth obtained from mathematical models of cellular systems. This package contains a general R infrastructure for running cell-based models and simulating gene expression data based on the model states. We show how to use this package to simulate a gene expression data set and consequently benchmark analysis methods on this data set with a known ground truth. The package is freely available via Bioconductor: http://bioconductor.org/packages/CancerInSilico/.
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http://dx.doi.org/10.1371/journal.pcbi.1006935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504085PMC
June 2018

PTEN loss is associated with resistance to cetuximab in patients with head and neck squamous cell carcinoma.

Oral Oncol 2019 04 4;91:69-78. Epub 2019 Mar 4.

Department of Medicine, Yale University School of Medicine and Yale Cancer Center, United States. Electronic address:

Introduction: Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab.

Methods: Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing.

Results: For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008).

Conclusion: Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.
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http://dx.doi.org/10.1016/j.oraloncology.2019.02.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855599PMC
April 2019

Human Papillomavirus Genotype Detection in Oral Gargle Samples Among Men With Newly Diagnosed Oropharyngeal Squamous Cell Carcinoma.

JAMA Otolaryngol Head Neck Surg 2019 05;145(5):460-466

Center for Immunization and Infection Research in Cancer, Tampa, Florida.

Importance: The most common cause of oropharyngeal squamous cell carcinoma is human papillomavirus (HPV) infection, and currently the standard of care to determine the HPV infection status in this type of carcinoma is to use p16 immunohistochemistry as a surrogate marker of high-risk HPV infection. Although p16 immunohistochemistry is limited by the inability to determine the specific HPV genotypes, oral gargle samples may be a readily available source of HPV DNA for genotyping.

Objective: To determine the specific HPV genotypes present in both oral gargle samples and tumor specimens.

Design, Setting, And Participants: This prospective, biomarker cohort study conducted at a single specialized cancer hospital in Florida screened approximately 800 potentially eligible participants from May 2014 through October 2017. To be eligible for participation, patients had to meet all of the following criteria: 18 years of age or older, male sex, newly diagnosed as having stage I to IV cancer of the oropharynx, a squamous cell carcinoma diagnosis, treatment naive or at least 4 weeks after chemoradiation or surgical treatment of other diseases, fully understand the study procedures and risks involved, and voluntarily agree to participate by signing an informed consent statement.

Main Outcomes And Measures: Detection rate of HPV infection and HPV genotypes in oral gargle samples and tumor specimens.

Results: A cohort of 204 male participants with newly diagnosed oropharyngeal squamous cell carcinoma was assessed in this prospective collection of comprehensive clinical data and oral gargle samples. Most study participants (190 [93.1%]) were white and ever smokers (114, 55.9%), with a median age of 61 years (range, 35-87 years). The HPV infection status could be assessed in 203 of 204 participants (99.5%) using oral gargle samples: 35 samples (17.2%) were negative for HPV infection, whereas 168 samples (82.8%) were positive for HPV infection. The detection rate of HPV genotypes was 93.0% in tumor specimens (160 specimens) and 82.8% (168 samples) in oral gargle samples. The oral gargle samples frequently had low-risk HPV genotypes that were not detected in tumors, but these low-risk genotypes were always a coinfection with high-risk genotypes.

Conclusions And Relevance: Oral gargle samples can be used to detect the majority of clinically relevant HPV genotypes found in oropharyngeal squamous cell carcinoma, but the interpretation of HPV detected in these samples should be assessed with caution for general cancer risk assessment given that sensitive assays can concomitantly detect low-risk genotypes.
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http://dx.doi.org/10.1001/jamaoto.2019.0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537790PMC
May 2019

Evolving role of human papillomavirus as a clinically significant biomarker in head and neck squamous cell carcinoma.

Expert Rev Mol Diagn 2019 01 21;19(1):63-70. Epub 2018 Dec 21.

b Department of Anatomic Pathology , Moffitt Cancer Center , Tampa , FL , USA.

: The majority of squamous cell carcinoma (SCC) of the oropharynx, one of the sites within the head and neck region, is now associated with high-risk human papillomavirus (HPV) in North America. Several modalities are available to determine the HPV status, however, the understanding of each assay in its application and limitations is essential for accurate interpretation and appropriate utilization of results in management of these patients. : This expert review will cover the role of HPV in head and neck squamous cell carcinoma (HNSCC), indications for HPV testing, HPV detection methods in tumors, saliva and serum, and exploiting HPV status as a prognostic biomarker of clinical outcome in HNSCC. : The HPV status is the most significant diagnostic and prognostic biomarker in HNSCC, specifically in the oropharynx. Research underway is currently delineating the role of HPV and p16 testing in non-oropharyngeal sites. While the feasibility of non-invasive serum and saliva testing for HPV detection has been established, the clinical application of these assays is still evolving.
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http://dx.doi.org/10.1080/14737159.2019.1559056DOI Listing
January 2019

Patient choice for high-volume center radiation impacts head and neck cancer outcome.

Cancer Med 2018 10 2;7(10):4964-4979. Epub 2018 Sep 2.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Studies suggest treatment outcomes may vary between high (HVC)- and low-volume centers (LVC). Radiation therapy (RT) for head and neck cancer (HNC) requires weeks of treatment, the inconvenience of which may influence a patient's choice for treatment location. We hypothesized that receipt of RT for HNC at a HVC would influence outcomes compared to patients evaluated at a HVC, but who chose to receive RT at a LVC.

Methods: From 1998 to 2011, 1930 HNC patients were evaluated at a HVC and then treated with RT at either a HVC or LVC. Time-to-event outcomes and treatment factors were compared.

Results: Median follow-up was 34 months. RT was delivered at a HVC for 1368 (71%) patients and at a LVC in 562 (29%). Patients were more likely to choose HVC-RT if they resided in the HVC's county or required definitive RT (all P < 0.001). HVC-RT was associated with a significant improvement in 3-year LRC (84% vs 68%), DFS (68% vs 48%), and OS (72% vs 57%) (all P < 0.001). On multivariate analysis (MVA), HVC-RT independently predicted for improved LRC, DFS, and OS (all P < 0.05).

Conclusions: In patients evaluated at a HVC, the choice of RT location was primarily influenced by their residing distance from the HVC. HVC-RT was associated with improvements in LRC, DFS, and OS in HNC. As treatment planning and delivery are technically demanding in HNC, the choice to undergo treatment at a HVC may result in more optimal delivered dose, RT duration, and outcome.
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http://dx.doi.org/10.1002/cam4.1756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198196PMC
October 2018
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