Publications by authors named "Nishant Agrawal"

125 Publications

Doublecortin-Like Kinase 1 (DCLK1) Is a Novel NOTCH Pathway Signaling Regulator in Head and Neck Squamous Cell Carcinoma.

Front Oncol 2021 16;11:677051. Epub 2021 Jul 16.

Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, United States.

Despite recent advancements, the 5 year survival of head and neck squamous cell carcinoma (HNSCC) hovers at 60%. DCLK1 has been shown to regulate epithelial-to-mesenchymal transition as well as serving as a cancer stem cell marker in colon, pancreatic and renal cancer. Although it was reported that DCLK1 is associated with poor prognosis in oropharyngeal cancers, very little is known about the molecular characterization of DCLK1 in HNSCC. In this study, we performed a comprehensive transcriptome-based computational analysis on hundreds of HNSCC patients from TCGA and GEO databases, and found that DCLK1 expression positively correlates with NOTCH signaling pathway activation. Since NOTCH signaling has a recognized role in HNSCC tumorigenesis, we next performed a series of experiments in a collection of HNSCC cell lines to investigate the role of DCLK1 in NOTCH pathway regulation. Our analyses revealed that DCLK1 inhibition, using either a pharmacological inhibitor or siRNA, resulted in substantially decreased proliferation, invasion, migration, and colony formation. Furthermore, these effects paralleled downregulation of active NOTCH1, and its downstream effectors, HEY1, HES1 and HES5, whereas overexpression of DCLK1 in normal keratinocytes, lead to an upregulation of NOTCH signaling associated with increased proliferation. Analysis of 233 primary and 40 recurrent HNSCC cancer biopsies revealed that high DCLK1 expression was associated with poor prognosis and showed a trend towards higher active NOTCH1 expression in tumors with elevated DCLK1. Our results demonstrate the novel role of DCLK1 as a regulator of NOTCH signaling network and suggest its potential as a therapeutic target in HNSCC.
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http://dx.doi.org/10.3389/fonc.2021.677051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323482PMC
July 2021

Lip and Oral Cavity Squamous Cell Carcinoma.

Hematol Oncol Clin North Am 2021 Jul 14. Epub 2021 Jul 14.

University of Chicago, 5841 South Maryland Avenue, MC 1035, Chicago, IL 60637, USA. Electronic address:

Lip and oral cavity squamous cell carcinoma (SCC) develop from progressive dysplasia of these mucosal structures. The cancers are often preceded by premalignant lesions, and any nonhealing ulcers of the lip or oral cavity should be biopsied. Some risk factors for these 2 subsites overlap and include tobacco use, alcohol use, and an immunocompromised state. Lip and oral cavity SCC are clinically staged based on physical examination and imaging. The 5-year overall survival for early-stage lip and oral cavity SCC is around 70% to 90% but decreases to about 50% for late-stage disease.
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http://dx.doi.org/10.1016/j.hoc.2021.05.003DOI Listing
July 2021

COVIDomic: A multi-modal cloud-based platform for identification of risk factors associated with COVID-19 severity.

PLoS Comput Biol 2021 07 14;17(7):e1009183. Epub 2021 Jul 14.

Insilico Medicine Hong Kong Ltd, Pak Shek Kok, New Territories, Hong Kong.

Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in December 2019 in Wuhan, China. It was quickly established that both the symptoms and the disease severity may vary from one case to another and several strains of SARS-CoV-2 have been identified. To gain a better understanding of the wide variety of SARS-CoV-2 strains and their associated symptoms, thousands of SARS-CoV-2 genomes have been sequenced in dozens of countries. In this article, we introduce COVIDomic, a multi-omics online platform designed to facilitate the analysis and interpretation of the large amount of health data collected from patients with COVID-19. The COVIDomic platform provides a comprehensive set of bioinformatic tools for the multi-modal metatranscriptomic data analysis of COVID-19 patients to determine the origin of the coronavirus strain and the expected severity of the disease. An integrative analytical workflow, which includes microbial pathogens community analysis, COVID-19 genetic epidemiology and patient stratification, allows to analyze the presence of the most common microbial organisms, their antibiotic resistance, the severity of the infection and the set of the most probable geographical locations from which the studied strain could have originated. The online platform integrates a user friendly interface which allows easy visualization of the results. We envision this tool will not only have immediate implications for management of the ongoing COVID-19 pandemic, but will also improve our readiness to respond to other infectious outbreaks.
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http://dx.doi.org/10.1371/journal.pcbi.1009183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312936PMC
July 2021

Sensitive detection and quantification of SARS-CoV-2 in saliva.

Sci Rep 2021 06 14;11(1):12425. Epub 2021 Jun 14.

Section of Hematology and Oncology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.

Saliva has significant advantages as a test medium for detection of SARS-CoV-2 infection in patients, such as ease of collection, minimal requirement of supplies and trained personnel, and safety. Comprehensive validation in a large cohort of prospectively collected specimens with unknown SARS-CoV-2 status should be performed to evaluate the potential and limitations of saliva-based testing. We developed a saliva-based testing pipeline for detection of SARS-CoV-2 nucleic acids using real-time reverse transcription PCR (RT-PCR) and droplet digital PCR (ddPCR) readouts, and measured samples from 137 outpatients tested at a curbside testing facility and 29 inpatients hospitalized for COVID-19. These measurements were compared to the nasal swab results for each patient performed by a certified microbiology laboratory. We found that our saliva testing positively detects 100% (RT-PCR) and 93.75% (ddPCR) of curbside patients that were identified as SARS-CoV-2 positive by the Emergency Use Authorization (EUA) certified nasal swab testing assay. Quantification of viral loads by ddPCR revealed an extremely wide range, with 1 million-fold difference between individual patients. Our results demonstrate for both community screening and hospital settings that saliva testing reliability is on par with that of the nasal swabs in detecting infected cases, and has potential for higher sensitivity when combined with ddPCR in detecting low-abundance viral loads that evade traditional testing methods.
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http://dx.doi.org/10.1038/s41598-021-91835-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203799PMC
June 2021

Generation of neoantigen-specific T cells for adoptive cell transfer for treating head and neck squamous cell carcinoma.

Oncoimmunology 2021 05 25;10(1):1929726. Epub 2021 May 25.

Cytotherapy Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; the First Affiliated Hospital, Southern University of Science and Technology), Shenzhen Guangdong, China.

Adoptive cell therapy using TCR-engineered T cells (TCR-T cells) represents a promising strategy for treating relapsed and metastatic cancers. We previously established methods to identify neoantigen-specific TCRs based on patients' PBMCs. However, in clinical practice isolation of PBMCs from advanced-stage cancer patients proves to be difficult. In this study, we substituted blood-derived T cells for tumor-infiltrating lymphocytes (TILs) and used an HLA-matched cell line of antigen-presenting cells (APCs) to replace autologous dendritic cells. Somatic mutations were determined in head and neck squamous cell carcinoma resected from two patients. HLA-A*02:01-restricted neoantigen libraries were constructed and transferred into HLA-matched APCs for stimulation of patient TILs. TCRs were isolated from reactive TIL cultures and functionality was tested using TCR- T cells and . To exemplify the screening approach, we identified the targeted neoantigen leading to recognition of the minigene construct that stimulated the strongest TIL response. Neoantigen peptides were used to load MHC-tetramers for T cell isolation and a TCR was identified targeting the KIAA1429 mutation. TCR-T cells were activated, exhibited cytotoxicity, and secreted cytokines in a dose-dependent manner, and only when stimulated with the mutant peptide. Furthermore, comparable to a neoantigen-specific TCR that was isolated from the patient's PBMCs, KIAA1429-specific TCR T cells destroyed human tumors in mice. The established protocol provides the required flexibility to methods striving to identify neoantigen-specific TCRs. By using an MHC-matched APC cell line and neoantigen-encoding minigene libraries, autologous TILs can be stimulated and screened when patient PBMCs and/or tumor material are not available anymore. Abbreviations: Head and neck squamous cell carcinoma (HNSCC); adoptive T cell therapy (ACT); T cell receptor (TCR); tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocyte (CTL); peripheral blood mononuclear cell (PBMC); dendritic cell (DC); antigen-presenting cells (APC).
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http://dx.doi.org/10.1080/2162402X.2021.1929726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158031PMC
May 2021

Radiation Therapy for Cutaneous Malignancies of the Head and Neck.

Otolaryngol Clin North Am 2021 Apr 16;54(2):307-327. Epub 2021 Feb 16.

Department of Radiation and Cellular Oncology, Duchossois Center for Advanced Medicine, University of Chicago Medicine, 5758 South Maryland Avenue, MC 9006, Chicago, IL 60637, USA.

Radiation therapy plays an integral role in the management of cutaneous malignancies of the head and neck. This article highlights the use of radiation therapy in the definitive and adjuvant setting for basal cell carcinoma, cutaneous squamous cell carcinoma, melanoma, and Merkel cell carcinoma. Themes that emerge include the overall efficacy of radiation therapy as a local therapy, the relevance of cosmesis, functional outcomes, late toxicities as secondary end points, and the multitude of treatment modalities that are used.
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http://dx.doi.org/10.1016/j.otc.2020.11.009DOI Listing
April 2021

Ultrasensitive detection of tumor-specific mutations in saliva of patients with oral cavity squamous cell carcinoma.

Cancer 2021 May 21;127(10):1576-1589. Epub 2020 Dec 21.

Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.

Background: Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck malignancy. Although the survival rate of patients with advanced-stage disease remains approximately 20% to 60%, when detected at an early stage, the survival rate approaches 80%, posing a pressing need for a well validated profiling method to assess patients who have a high risk of developing OCSCC. Tumor DNA detection in saliva may provide a robust biomarker platform that overcomes the limitations of current diagnostic tests. However, there is no routine saliva-based screening method for patients with OCSCC.

Methods: The authors designed a custom next-generation sequencing panel with unique molecular identifiers that covers coding regions of 7 frequently mutated genes in OCSCC and applied it on DNA extracted from 121 treatment-naive OCSCC tumors and matched preoperative saliva specimens.

Results: By using stringent variant-calling criteria, mutations were detected in 106 tumors, consistent with a predicted detection rate ≥88%. Moreover, mutations identified in primary malignancies were also detected in 93% of saliva samples. To ensure that variants are not errors resulting in false-positive calls, a multistep analytical validation of this approach was performed: 1) re-sequencing of 46 saliva samples confirmed 88% of somatic variants; 2) no functionally relevant mutations were detected in saliva samples from 11 healthy individuals without a history of tobacco or alcohol; and 3) using a panel of 7 synthetic loci across 8 sequencing runs, it was confirmed that the platform developed is reproducible and provides sensitivity on par with droplet digital polymerase chain reaction.

Conclusions: The current data highlight the feasibility of somatic mutation identification in driver genes in saliva collected at the time of OCSCC diagnosis.
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http://dx.doi.org/10.1002/cncr.33393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084899PMC
May 2021

Sensitive detection and quantification of SARS-CoV-2 in saliva.

medRxiv 2020 Dec 7. Epub 2020 Dec 7.

Saliva has significant advantages as a test medium for detection of SARS-CoV-2 infection in patients, such as ease of collection, minimal requirement of supplies and trained personnel, and safety. Comprehensive validation in a large cohort of prospectively collected specimens with unknown SARS-CoV-2 status should be performed to evaluate the potential and limitations of saliva-based testing. We developed a saliva-based testing pipeline for detection of SARS-CoV-2 nucleic acids using real-time reverse transcription PCR (RT-PCR) and droplet digital PCR (ddPCR) readouts, and measured samples from 137 outpatients tested at a curbside testing facility and 29 inpatients hospitalized for COVID-19. These measurements were compared to the nasal swab results for each patient performed by a certified microbiology laboratory. We found that our saliva testing positively detects 100% (RT-PCR) and 93.75% (ddPCR) of curbside patients that were identified as SARS-CoV-2 positive by the Emergency Use Authorization (EUA) certified nasal swab testing assay. Quantification of viral loads by ddPCR revealed an extremely wide range, with 1 million-fold difference between individual patients. Our results demonstrate for both community screening and hospital settings that saliva testing reliability is on par with that of the nasal swabs in detecting infected cases, and has potential for higher sensitivity when combined with ddPCR in detecting low-abundance viral loads that evade traditional testing methods.
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http://dx.doi.org/10.1101/2020.12.04.20241059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743089PMC
December 2020

Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Mod Pathol 2021 05 10;34(5):862-874. Epub 2020 Dec 10.

Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAF mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor's expression profile resembles a BRAF or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P < 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R = 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAF-mutant PTC-EFG had BRAF-like predicted BRS (mean -0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean -0.17), and NIFTP had RAS-like BRS (mean 0.35; P < 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.
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http://dx.doi.org/10.1038/s41379-020-00724-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064913PMC
May 2021

Genetic Mutations in Young Nonsmoking Patients With Oral Cavity Cancer: A Systematic Review.

OTO Open 2020 Oct-Dec;4(4):2473974X20970181. Epub 2020 Nov 3.

Department of Otolaryngology-Head and Neck Surgery, University of Washington, Seattle, Washington, USA.

Objective: This investigation aims to review the known genetic mutations associated with oral cavity squamous cell carcinoma (OCSCC) in young adults with limited environmental risk factors (YLERs).

Data Sources: A comprehensive search strategy was designed to identify studies in MEDLINE (Ovid), Embase (Ovid), and Scopus from database inception to May 2017 that included adults ≤50 years of age with OCSCC and minimal tobacco use history (≤10 pack-years) who had their tumors genetically sequenced or mutational profiles analyzed.

Review Methods: Identified articles were screened by 2 reviewers. Quality of evidence was graded by the MINORS criteria for case-control studies; other studies were graded by assigning a level of evidence for gene mutation literature.

Results: Thirteen studies met our inclusion criteria, and 130 patients met our criteria for age and tobacco history. was the most commonly evaluated gene (10 of 13 studies) and the most frequently observed mutation. One study reported that nonsmokers had significantly fewer mutations, while 9 studies found no difference in the prevalence of mutations. No other mutations were found specific to this cohort.

Conclusions: mutations may occur at a similar rate in YLERs with OCSCC as compared with older patients or those with risk factors. However, few studies have aimed to characterize the genetic landscape of oral cavity tumors in this population, often with small sample sizes. Future studies are needed to explore unidentified genetic alterations leading to tumor susceptibility or alternative mechanisms of carcinogenesis.
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http://dx.doi.org/10.1177/2473974X20970181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643225PMC
November 2020

The mutational landscape of early- and typical-onset oral tongue squamous cell carcinoma.

Cancer 2021 Feb 4;127(4):544-553. Epub 2020 Nov 4.

Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: The incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing among younger birth cohorts. The etiology of early-onset OTSCC (diagnosed before the age of 50 years) and cancer driver genes remain largely unknown.

Methods: The Sequencing Consortium of Oral Tongue Cancer was established through the pooling of somatic mutation data of oral tongue cancer specimens (n = 227 [107 early-onset cases]) from 7 studies and The Cancer Genome Atlas. Somatic mutations at microsatellite loci and Catalog of Somatic Mutations in Cancer mutation signatures were identified. Cancer driver genes were identified with the MutSigCV and WITER algorithms. Mutation comparisons between early- and typical-onset OTSCC were evaluated via linear regression with adjustments for patient-related factors.

Results: Two novel driver genes (ATXN1 and CDC42EP1) and 5 previously reported driver genes (TP53, CDKN2A, CASP8, NOTCH1, and FAT1) were identified. Six recurrent mutations were identified, with 4 occurring in TP53. Early-onset OTSCC had significantly fewer nonsilent mutations even after adjustments for tobacco use. No associations of microsatellite locus mutations and mutation signatures with the age of OTSCC onset were observed.

Conclusions: This international, multicenter consortium is the largest study to characterize the somatic mutational landscape of OTSCC and the first to suggest differences by age of onset. This study validates multiple previously identified OTSCC driver genes and proposes 2 novel cancer driver genes. In analyses by age, early-onset OTSCC had a significantly smaller somatic mutational burden that was not explained by differences in tobacco use.

Lay Summary: This study identifies 7 specific areas in the human genetic code that could be responsible for promoting the development of tongue cancer. Tongue cancer in young patients (under the age of 50 years) has fewer overall changes to the genetic code in comparison with tongue cancer in older patients, but the authors do not think that this is due to differences in smoking rates between the 2 groups. The cause of increasing cases of tongue cancer in young patients remains unclear.
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http://dx.doi.org/10.1002/cncr.33309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891879PMC
February 2021

Adjuvant treatment for high-risk salivary gland malignancies and prognostic stratification based on a 20-year single institution experience.

Health Sci Rep 2020 Dec 7;3(4):e195. Epub 2020 Oct 7.

Department of Radiation and Cellular Oncology University of Chicago Chicago Illinois.

Background And Aim: Retrospective analysis of the utility of adjuvant radiation (RT) or chemoradiation (CRT) and identify prognostic features for patients with high-risk head and neck salivary gland cancers.

Methods: From 1/1997 to 12/2017, 108 patients underwent surgery, and RT (n = 50) or CRT (n = 58) for positive lymph node(s), extracapsular extension, perineural invasion, lymphovascular space invasion, positive/close margin, and/or grade 3 disease. Outcomes were estimated with the Kaplan-Meier method. Significant predictors identified through regression analyses were incorporated into multivariable regression (MVA). Toxicities were compared using chi-square.

Results: The median follow-up was 52 months (range: 3-226). The number of risk factors (RFs) between RT and CRT groups were: 0 to 1 (44% vs 7%), 2 to 3 (48% vs 41%), or 4 to 6 (8% vs 52%), respectively ( < .01). On MVA, stage 3 or 4 disease predicted worse outcomes including overall survival (HR 4.55, = .01). Increasing number of RFs predicted worse disease-free survival, distant metastasis-free survival, and overall survival (2-3 RFs: HR 3.38, = .03; 4-6 RFs: HR 5.78,  < .01), but not locoregional control ( = .54). So, adjuvant CRT may have provided comparable locoregional control for patients with more adverse features, but the CRT did not translate into improved distant control. There was no difference in acute or late grade 3+ toxicities, or parenteral nutrition ( = .98, = .85, and = .83), respectively.

Conclusions: Adjuvant CRT provides adequate locoregional control in patients with more adverse RFs. The absolute number of RFs serves prognostic significance and should be considered in future prospective trials.
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http://dx.doi.org/10.1002/hsr2.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539565PMC
December 2020

TMPRSS2, a SARS-CoV-2 internalization protease is downregulated in head and neck cancer patients.

J Exp Clin Cancer Res 2020 Sep 23;39(1):200. Epub 2020 Sep 23.

UOSD Clinical Trial Center, Biostatistics and Bioinformatics, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: SARS-coronavirus-2 enters host cells through binding of the Spike protein to ACE2 receptor and subsequent S priming by the TMPRSS2 protease. We aim to assess differences in both ACE2 and TMPRSS2 expression in normal tissues from oral cavity, pharynx, larynx and lung tissues as well as neoplastic tissues from the same areas.

Methods: The study has been conducted using the TCGA and the Regina Elena Institute databases and validated by experimental model in HNSCC cells. We also included data from one COVID19 patient who went under surgery for HNSCC.

Results: TMPRSS2 expression in HNSCC was significantly reduced compared to the normal tissues. It was more evident in women than in men, in TP53 mutated versus wild TP53 tumors, in HPV negative patients compared to HPV positive counterparts. Functionally, we modeled the multivariate effect of TP53, HPV, and other inherent variables on TMPRSS2. All variables had a statistically significant independent effect on TMPRSS2. In particular, in tumor tissues, HPV negative, TP53 mutated status and elevated TP53-dependent Myc-target genes were associated with low TMPRSS2 expression. The further analysis of both TCGA and our institutional HNSCC datasets identified a signature anti-correlated to TMPRSS2. As proof-of-principle we also validated the anti-correlation between microRNAs and TMPRSS2 expression in a SARS-CoV-2 positive HNSCC patient tissues Finally, we did not find TMPRSS2 promoter methylation.

Conclusions: Collectively, these findings suggest that tumoral tissues, herein exemplified by HNSCC and lung cancers might be more resistant to SARS-CoV-2 infection due to reduced expression of TMPRSS2. These observations may help to better assess the frailty of SARS-CoV-2 positive cancer patients.
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http://dx.doi.org/10.1186/s13046-020-01708-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510014PMC
September 2020

Discordance of COVID-19 guidelines for patients with cancer: A systematic review.

J Surg Oncol 2020 Jul 15. Epub 2020 Jul 15.

Department of Thoracic Surgery, Roswell Park Cancer Institute, Buffalo, New York.

This review was aimed to systematically evaluate the available literature on the impact of COVID-19 on cancer care and to critically analyze the diagnostic and therapeutic strategies suggested by various healthcare providers, societies, and institutions. Majority guidelines for various types of cancers favored a delay in treatment or a nonsurgical approach wherever feasible. These guidelines are based on a low level of evidence and have significant discordance for the role and timing of surgery, especially in early tumors.
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http://dx.doi.org/10.1002/jso.26110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405271PMC
July 2020

Quantifying the annual incidence and underestimation of seasonal influenza: A modelling approach.

Theor Biol Med Model 2020 07 10;17(1):11. Epub 2020 Jul 10.

Department of Mathematics and Statistics, York University, Toronto, M3J 1P3, Canada.

Background: Seasonal influenza poses a significant public health and economic burden, associated with the outcome of infection and resulting complications. The true burden of the disease is difficult to capture due to the wide range of presentation, from asymptomatic cases to non-respiratory complications such as cardiovascular events, and its seasonal variability. An understanding of the magnitude of the true annual incidence of influenza is important to support prevention and control policy development and to evaluate the impact of preventative measures such as vaccination.

Methods: We use a dynamic disease transmission model, laboratory-confirmed influenza surveillance data, and randomized-controlled trial (RCT) data to quantify the underestimation factor, expansion factor, and symptomatic influenza illnesses in the US and Canada during the 2011-2012 and 2012-2013 influenza seasons.

Results: Based on 2 case definitions, we estimate between 0.42-3.2% and 0.33-1.2% of symptomatic influenza illnesses were laboratory-confirmed in Canada during the 2011-2012 and 2012-2013 seasons, respectively. In the US, we estimate between 0.08-0.61% and 0.07-0.33% of symptomatic influenza illnesses were laboratory-confirmed in the 2011-2012 and 2012-2013 seasons, respectively. We estimated the symptomatic influenza illnesses in Canada to be 0.32-2.4 million in 2011-2012 and 1.8-8.2 million in 2012-2013. In the US, we estimate the number of symptomatic influenza illnesses to be 4.4-34 million in 2011-2012 and 23-102 million in 2012-2013.

Conclusions: We illustrate that monitoring a representative group within a population may aid in effectively modelling the transmission of infectious diseases such as influenza. In particular, the utilization of RCTs in models may enhance the accuracy of epidemiological parameter estimation.
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http://dx.doi.org/10.1186/s12976-020-00129-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347407PMC
July 2020

Status and strategies for the management of head and neck cancer during COVID-19 pandemic: Indian scenario.

Head Neck 2020 Jul 13;42(7):1460-1465. Epub 2020 May 13.

Department of Otorhinolaryngology, Head and Neck Surgery, The Chinese University of Hong Kong, Hong Kong SAR.

In India, oral cancer is the most common head and neck cancer (HNC) in men, mainly caused by the consumption of smoked and smokeless tobacco. During the current pandemic, delaying surgery for even 1 or 2 months may lead to more extensive surgery or inoperability, where only supportive care can be provided. Being semi-emergent in nature, treatment for these patients is currently on hold or delayed in most centers across the country. This study was conducted to assess the impact of COVID-19 pandemic and inability of the health system to treat HNC in a timely fashion and how surgeons are coping to this emergent situation. This article highlights the situation in India, a country burdened with one of the highest incidence rates of HNC.
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http://dx.doi.org/10.1002/hed.26227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267542PMC
July 2020

A Surgical Safety Checklist for Performing Tracheotomy in Patients with Coronavirus Disease 19.

Otolaryngol Head Neck Surg 2020 07 28;163(1):42-46. Epub 2020 Apr 28.

Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, The University of Chicago Medicine, Chicago, Illinois, USA.

Performance of tracheotomy is a potential necessary step in the patient with coronavirus disease 19 (COVID-19) and prolonged mechanical ventilation. Due to viral aerosolization, tracheotomy carries a high risk of transmission of COVID-19 to the health care team performing the procedure. We share our institution's surgical safety checklist for performing tracheotomy in patients with COVID-19, including key modifications intended to mitigate risk to the surgical team.
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http://dx.doi.org/10.1177/0194599820922981DOI Listing
July 2020

Dose and Volume De-Escalation for Human Papillomavirus-Positive Oropharyngeal Cancer is Associated with Favorable Posttreatment Functional Outcomes.

Int J Radiat Oncol Biol Phys 2020 07 18;107(4):662-671. Epub 2020 Apr 18.

Department of Radiation and Cellular Oncology, University of Chicago Medicine, Chicago, Illinois. Electronic address:

Purpose: To report functional outcomes for patients with human papillomavirus-positive oropharyngeal cancer treated on a phase 2 protocol of risk- and induction chemotherapy response-adapted dose and volume de-escalated radiation therapy (RT)/chemoradiation (CRT).

Methods And Materials: Patients were stratified as low risk (LR) or high risk (HR) according to T/N-stage and smoking history. Induction chemotherapy was followed by radiographic response assessment. LR patients with ≥50% response received 50 Gy RT (RT50), whereas LR patients with 30% to 50% response or HR patients with ≥50% response received 45 Gy CRT (CRT45). All other patients received 75 Gy CRT (CRT75) with RT limited to the first echelon of uninvolved nodes. Pre- and post-RT/CRT modified barium swallow studies were performed. Percutaneous endoscopic gastrostomy (PEG) tube placement, body mass index (BMI), and narcotic use were recorded. Statistical comparisons used linear or logistic regression, the Mann-Whitney U test, the χ test, or Fisher's exact test as appropriate.

Results: Twenty-eight LR and 34 HR patients were enrolled; 49 completed RT50/CRT45 and 11 completed CRT75. PEG-tube dependency at the end of RT/CRT and 3 months post-RT/CRT significantly differed according to risk and treatment groups (all P < .05). Treatment intensity was independently associated with 3-month PEG status while adjusting for risk group (P = .002). The CRT75 group had a median -8.42% change from baseline BMI at 1 year post-RT/CRT versus -2.54% for the RT50/CRT45 group (P = .01). At the end of RT/CRT, CRT75 patients were less likely to tolerate a normal diet, more likely to have swallowing performance status scale scores ≥4, more likely to have Rosenbek's penetration-aspiration scores ≥7, more likely to have developed trismus, and more likely to require narcotics >2 months (all P < .05).

Conclusions: Induction chemotherapy followed by risk- and response-adapted dose and volume de-escalated RT/CRT is associated with clinically meaningful functional outcomes including (1) improved swallowing function, (2) higher BMI, and (3) shorter narcotic use for patients receiving de-escalation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.04.014DOI Listing
July 2020

Medically Necessary, Time-Sensitive Procedures: Scoring System to Ethically and Efficiently Manage Resource Scarcity and Provider Risk During the COVID-19 Pandemic.

J Am Coll Surg 2020 Aug 9;231(2):281-288. Epub 2020 Apr 9.

Department of Surgery, University of Chicago Medicine and Biological Sciences, Chicago, IL.

Hospitals have severely curtailed the performance of nonurgent surgical procedures in anticipation of the need to redeploy healthcare resources to meet the projected massive medical needs of patients with coronavirus disease 2019 (COVID-19). Surgical treatment of non-COVID-19 related disease during this period, however, still remains necessary. The decision to proceed with medically necessary, time-sensitive (MeNTS) procedures in the setting of the COVID-19 pandemic requires incorporation of factors (resource limitations, COVID-19 transmission risk to providers and patients) heretofore not overtly considered by surgeons in the already complicated processes of clinical judgment and shared decision-making. We describe a scoring system that systematically integrates these factors to facilitate decision-making and triage for MeNTS procedures, and appropriately weighs individual patient risks with the ethical necessity of optimizing public health concerns. This approach is applicable across a broad range of hospital settings (academic and community, urban and rural) in the midst of the pandemic and may be able to inform case triage as operating room capacity resumes once the acute phase of the pandemic subsides.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195575PMC
August 2020

Novel Strategies to Effectively De-escalate Curative-Intent Therapy for Patients With HPV-Associated Oropharyngeal Cancer: Current and Future Directions.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-13

Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago, Chicago, IL.

The treatment of patients with HPV-associated oropharyngeal cancer (HPV-OPC) is rapidly evolving and challenging the standard of care of definitive radiotherapy with concurrent cisplatin. There are numerous promising de-escalation strategies under investigation, including deintensified definitive chemoradiotherapy, transoral surgery followed by de-escalated adjuvant therapy, and induction chemotherapy followed by de-escalated locoregional therapy. Definitive radiotherapy alone or with cetuximab is not recommended for curative-intent treatment of patients with locally advanced HPV-OPC. The results of ongoing phase III studies are awaited to help answer key questions and address ongoing controversies to transform the treatment of patients with HPV-OPC. Strategies for de-escalation under investigation include the incorporation of immunotherapy and the use of novel biomarkers for patient selection for de-escalation.
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http://dx.doi.org/10.1200/EDBK_280687DOI Listing
March 2020

Molecular biology of oral cavity squamous cell carcinoma.

Oral Oncol 2020 03 7;102:104552. Epub 2020 Jan 7.

Section of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of Chicago Medicine, Chicago, IL 60637, USA. Electronic address:

Oral cavity squamous cell carcinoma (OCSCC) is a heterogeneous and complex disease that arises due to dysfunction of multiple molecular signaling pathways. Recent advances in high-throughput genetic sequencing technologies coupled with innovative analytical techniques have begun to characterize the molecular determinants driving OCSCC. An understanding of the key molecular signaling networks underlying the initiation and progression of is essential for informing treatment of the disease. In this chapter, we discuss recent findings of key genes altered in OCSCC and potential treatments targeting these genes.
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http://dx.doi.org/10.1016/j.oraloncology.2019.104552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659372PMC
March 2020

Somatic mitochondrial mutation discovery using ultra-deep sequencing of the mitochondrial genome reveals spatial tumor heterogeneity in head and neck squamous cell carcinoma.

Cancer Lett 2020 02 10;471:49-60. Epub 2019 Dec 10.

Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA. Electronic address:

Mutations in mitochondrial DNA (mtDNA) have been linked to risk, progression, and treatment response of head and neck squamous cell carcinoma (HNSCC). Due to their clonal nature and high copy number, mitochondrial mutations could serve as powerful molecular markers for detection of cancer cells in bodily fluids, surgical margins, biopsies and lymph node (LN) metastasis, especially at sites where tumor involvement is not histologically apparent. Despite a pressing need for high-throughput, cost-effective mtDNA mutation profiling system, current methods for library preparation are still imperfect for detection of low prevalence heteroplasmic mutations. To this end, we have designed an ultra-deep amplicon-based sequencing library preparation approach that covers the entire mitochondrial genome. We sequenced mtDNA in 28 HNSCCs, matched LNs, surgical margins and bodily fluids, and applied multiregional sequencing approach on 14 primary tumors. Our results demonstrate that this quick, sensitive and cost-efficient method allows obtaining a snapshot on the mitochondrial heterogeneity, and can be used for detection of low frequency tumor-associated mtDNA mutations in LNs, sputum and serum specimens. These findings provide the foundation for using mitochondrial sequencing for risk assessment, early detection, and tumor surveillance.
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http://dx.doi.org/10.1016/j.canlet.2019.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980748PMC
February 2020

Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma.

J Clin Invest 2019 10;129(10):4276-4289

Head and Neck Service, Department of Surgery, and.

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.METHODSAn integrated genomic analysis of 1,045 ACCs (177 primary, 868 R/M) was performed to identify alterations associated with advanced and metastatic tumors. Intratumoral genetic heterogeneity, germline mutations, and therapeutic actionability were assessed.RESULTSCompared with primary tumors, R/M tumors were enriched for alterations in key Notch (NOTCH1, 26.3% vs. 8.5%; NOTCH2, 4.6% vs. 2.3%; NOTCH3, 5.7% vs. 2.3%; NOTCH4, 3.6% vs. 0.6%) and chromatin-remodeling (KDM6A, 15.2% vs. 3.4%; KMT2C/MLL3, 14.3% vs. 4.0%; ARID1B, 14.1% vs. 4.0%) genes. TERT promoter mutations (13.1% of R/M cases) were mutually exclusive with both NOTCH1 mutations (q = 3.3 × 10-4) and MYB/MYBL1 fusions (q = 5.6 × 10-3), suggesting discrete, alternative mechanisms of tumorigenesis. This network of alterations defined 4 distinct ACC subgroups: MYB+NOTCH1+, MYB+/other, MYBWTNOTCH1+, and MYBWTTERT+. Despite low mutational load, we identified numerous samples with marked intratumoral genetic heterogeneity, including branching evolution across multiregion sequencing.CONCLUSIONThese observations collectively redefine the molecular underpinnings of ACC progression and identify further targets for precision therapies.FUNDINGAdenoid Cystic Carcinoma Research Foundation, Pershing Square Sohn Cancer Research grant, the PaineWebber Chair, Stand Up 2 Cancer, NIH R01 CA205426, the STARR Cancer Consortium, NCI R35 CA232097, the Frederick Adler Chair, Cycle for Survival, the Jayme Flowers Fund, The Sebastian Nativo Fund, NIH K08 DE024774 and R01 DE027738, and MSKCC through NIH/NCI Cancer Center Support Grant (P30 CA008748).
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http://dx.doi.org/10.1172/JCI128227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763222PMC
October 2019

Immune profiles in primary squamous cell carcinoma of the head and neck.

Oral Oncol 2019 09 12;96:77-88. Epub 2019 Jul 12.

Department of Medicine, University of Chicago, IL, United States. Electronic address:

Objectives: In this study we describe the tumor microenvironment, the signaling pathways and genetic alterations associated with the presence or absence of CD8+ T-cell infiltration in primary squamous cell carcinoma of the head and neck (SCCHN) tumors.

Materials And Methods: Two SCCHN multi-analyte cohorts were utilized, the Cancer Genome Atlas (TCGA) and the Chicago Head and Neck Genomics (CHGC) cohort. A well-established chemokine signature classified SCCHN tumors into high and low CD8+ T-cell inflamed phenotypes (TCIP-H, TCIP-L respectively). Gene set enrichment and iPANDA analyses were conducted to dissect differences in signaling pathways, somatic mutations and copy number aberrations for TCIP-H versus TCIP-L tumors, stratified by HPV status.

Results: TCIP-H SCCHN tumors were enriched in multiple immune checkpoints irrespective of HPV-status. HPV-positive tumors were enriched in markers of T-regulatory cells (Tregs) and HPV-negative tumors in protumorigenic M2 macrophages. TCIP-L SCCHN tumors were enriched for the β-catenin/WNT and Hedgehog signaling pathways, had frequent mutations in NSD1, amplifications in EGFR and YAP1, as well as CDKN2A deletions. TCIP-H SCCHN tumors were associated with the MAPK/ERK, JAK/STAT and mTOR/AKT signaling pathways, and were enriched in CASP8, EP300, EPHA2, HRAS mutations, CD274, PDCD1LG2, JAK2 amplifications.

Conclusions: Our findings support that combinatorial immune checkpoint blockade and depletion strategies targeting Tregs in HPV-positive and M2 macrophages in HPV-negative tumors may lead to improved antitumor immune responses in patients with TCIP-H SCCHN. We highlight novel pathways and genetic events that may serve as candidate biomarkers and novel targeted therapies to enhance the efficacy of immunotherapy in SCCHN patients.
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http://dx.doi.org/10.1016/j.oraloncology.2019.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893610PMC
September 2019

Tonsil Cancer.

N Engl J Med 2019 Jul;381(4):e8

University of Chicago, Chicago, IL

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http://dx.doi.org/10.1056/NEJMicm1814882DOI Listing
July 2019

Identification of Novel RAS Signaling Therapeutic Vulnerabilities in Diffuse Intrinsic Pontine Gliomas.

Cancer Res 2019 08 14;79(16):4026-4041. Epub 2019 Jun 14.

John G. Rangos Sr. Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania.

Diffuse intrinsic pontine gliomas (DIPG) are incurable brain tumors with an aggressive onset. Apart from irradiation, there are currently no effective therapies available for patients with DIPG, who have a median survival time of less than one year. Most DIPG cells harbor mutations in genes encoding histone H3 (H3K27M) proteins, resulting in a global reduction of H3K27 trimethylation and activation of oncogenic signaling pathways. Here we show that the H3K27M mutations contribute to RAS pathway signaling, which is augmented by additional RAS activators including PDGFRA. H3K27M mutation led to increased expression of receptor tyrosine kinases (RTK). A RAS pathway functional screen identified ERK5, but not ERK1/2, as a RAS pathway effector important for DIPG growth. Suppression of ERK5 decreased DIPG cell proliferation and induced apoptosis and . In addition, depletion or inhibition of ERK5 significantly increased survival of mice intracranially engrafted with DIPG cells. Mechanistically, ERK5 directly stabilized the proto-oncogene MYC at the protein level. Collectively, our data demonstrate an underappreciated role of H3K27M in RAS activation and reveal novel therapeutic targets for treating DIPG tumors. SIGNIFICANCE: These findings identify the H3K27M mutation as an enhancer of RAS activation in DIPG and ERK5 as a novel, immediately actionable molecular target. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4026/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3521DOI Listing
August 2019

Identification of neoantigen-specific T cells and their targets: implications for immunotherapy of head and neck squamous cell carcinoma.

Oncoimmunology 2019;8(4):e1568813. Epub 2019 Feb 6.

Department of Medicine, The University of Chicago, Chicago, IL, USA.

To develop a practically applicable method for T-cell receptor (TCR)-engineered T cell immunotherapy targeting neoantigens, we have been attempting to identify neoantigen-specific T cell receptors (TCRs) and establish TCR-engineered T cells in a 3-4-month period. In this study, we report the characterization of T cell repertoires in tumor microenvironment (TME) and identification of neoantigen-specific TCRs after stimulation of patient-derived T cells. We screened 15 potential neoantigen peptides and successfully identified two CD8HLA-dextramer T cells, which recognized MAGOHB and ZCCHC14. All three dominant TCR clonotypes from MAGOHB-HLA dextramer-sorted CD8 T cells were also found in T cells in TME, while none of dominant TCR clonotypes from ZCCHC14-HLA dextramer-sorted CD8 T cells was found in the corresponding TME. The most dominant TCRA/TCRB pairs for these two neoantigens were cloned into HLA-matched healthy donors' T lymphocytes to generate TCR-engineered T cells. The functional assay showed MAGOHB TCR-engineered T cells could be significantly activated in a mutation-specific, HLA-restricted and peptide-dose-dependent manner while ZCCHC14 TCR-engineered T cells could not. Our data showed neoantigen-reactive T cell clonotypes that were identified in the patient's peripheral blood could be present in the corresponding TME and might be good TCRs targeting neoantigens.
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http://dx.doi.org/10.1080/2162402X.2019.1568813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422382PMC
February 2019

Genomic analysis identifies frequent deletions of Dystrophin in olfactory neuroblastoma.

Nat Commun 2018 12 21;9(1):5410. Epub 2018 Dec 21.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Olfactory neuroblastoma (ONB) is a rare malignant neoplasm arising in the upper portion of the sinonasal cavity. To better understand the genetic bases for ONB, here we perform whole exome and whole genome sequencing as well as single nucleotide polymorphism array analyses in a series of ONB patient samples. Deletions involving the dystrophin (DMD) locus are found in 12 of 14 (86%) tumors. Interestingly, one of the remaining tumors has a deletion in LAMA2, bringing the number of ONBs with deletions of genes involved in the development of muscular dystrophies to 13 or 93%. This high prevalence implicates an unexpected functional role for genes causing hereditary muscular dystrophies in ONB.
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http://dx.doi.org/10.1038/s41467-018-07578-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303314PMC
December 2018

Head and Neck Masses.

Med Clin North Am 2018 Nov 20;102(6):1013-1025. Epub 2018 Sep 20.

Section of Otolaryngology, Department of Surgery, University of Chicago Medicine, Chicago, IL, USA. Electronic address:

Head and neck cancers comprise 4% of the cancer burden in the United States each year. Many types of head and neck cancers present as an asymptomatic, nontender neck mass or nonspecific symptoms, such as hoarseness, sore throat, and pain. Head and neck cancers are frequently diagnosed incidentally by the primary care physician or dentist. This review summarizes the epidemiology, clinical manifestations, diagnosis, and treatment of several common head and neck cancers in order to provide an increased awareness for the internist to facilitate early detection of these diseases.
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http://dx.doi.org/10.1016/j.mcna.2018.06.012DOI Listing
November 2018
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