Mihir Patel

Racial disparities in squamous cell carcinoma of the oral tongue among women: A SEER data analysis

OBJECTIVESnThe incidence of oral tongue cancer (OTC) in the US is increasing in women. To understand this phenomenon, we examined factors influencing OTC incidence and survival.nnnMATERIALS AND METHODSnWe identified women diagnosed with OTC that were reported to the Surveillance, Epidemiology and End Results (SEER) program from 1973 to 2010. Incidence and survival rates were compared across metropolitan, urban and rural residential settings and several other demographic categories by calculating rate ratios (RRs) with the corresponding 95% confidence intervals (CIs). We examined changes in incidence of OTC across racial groups using joinpoint analyses since 1973, and assessed factors associated with survival. Patients diagnosed prior to 1988 were excluded from the survival analysis due to lack of data on treatment.nnnRESULTSnOTC incidence in white females demonstrated a significant upward trend with 0.53 annual percentage change (APC) between 1973 and 2010. The change seems to be limited to white women under the age of 50years and appears to have become pronounced in the 1990s. For African Americans (AA) on the other hand, the incidence has decreased. Incidence estimates did not differ in metropolitan, small urban and rural setting. The 1-, 5- and 10-year relative survival estimates were 86%, 63% and 54% for white women, and 76%, 46% and 33% for AA women. On multivariable analyses factors significantly associated with better survival included lower stage, younger age, married status, and receipt of surgical treatment, but not race.nnnCONCLUSIONnThe racial disparity in OTC survival is evident, but may be attributable to the differences in stage at diagnosis as well as access to and receipt of care. As the incidence of OTC is increasing in young white women, identifying the risk factors in this group may lead to a better understanding of OTC causes.

HER3 Targeting Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization: Evidence from Cell Line and Patient-Derived Xenograft Models

Purpose: Our previous work suggested that HER3 inhibition sensitizes head and neck squamous cell carcinoma (HNSCC) to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the antitumor mechanisms of EGFR/HER3 dual targeting in HNSCC. Experimental Design: We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3, and downstream signaling pathways by Western blotting and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models. Results: Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited the PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and resensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared with single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity. Conclusions: Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy. Clin Cancer Res; 23(3); 677–86. ©2016 AACR.

Deep convolutional neural networks for classifying head and neck cancer using hyperspectral imaging

Abstract. Surgical cancer resection requires an accurate and timely diagnosis of the cancer margins in order to achieve successful patient remission. Hyperspectral imaging (HSI) has emerged as a useful, noncontact technique for acquiring spectral and optical properties of tissue. A convolutional neural network (CNN) classifier is developed to classify excised, squamous-cell carcinoma, thyroid cancer, and normal head and neck tissue samples using HSI. The CNN classification was validated by the manual annotation of a pathologist specialized in head and neck cancer. The preliminary results of 50 patients indicate the potential of HSI and deep learning for automatic tissue-labeling of surgical specimens of head and neck patients.

Factors Associated With Hospital Length of Stay Following Fibular Free-Tissue Reconstruction of Head and Neck Defects: Assessment Using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Criteria

IMPORTANCEnCost containment is at the forefront of responsible health care delivery. One way to decrease costs is to decrease hospital length of stay (LOS). Data are lacking on factors contributing to LOS in patients with head and neck cancer (HNC) undergoing fibular free-tissue reconstruction (FFTR) of head and neck defects.nnnOBJECTIVEnTo identify factors contributing to increased LOS following FFTR of head and neck defects in patients with HNC using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) methodology.nnnDESIGNnRetrospective medical record review, with reference to the ACS NSQIP form, of 30 consecutive patients with HNC undergoing FFTR of head and neck defects in a single tertiary academic institution from July 2013 through June 2014. Data were collected on demographic and tumor characteristics, preoperative risk factors, operative variables, and postoperative adverse events.nnnMAIN OUTCOMES AND MEASURESnFactors associated with increased hospital LOS.nnnRESULTSnMedian LOS was 10 days (range, 8-31 days), and patients were divided into 2 groups (LOS, ≤ 10 days [n = 16]; and LOS, >10 days [n = 14]). There were no significant differences in demographics, tumor characteristics, or preoperative medical comorbidities between the 2 groups. Univariate analysis demonstrated that operative time, ventilator dependence, wound event, and altered mental status were associated with longer LOS. Multivariate analysis revealed significant association with LOS greater than 10 days for operative time of longer than 11 hours (odds ratio [OR], 7.26; 95% CI, 1.12-47.29; P =u2009.04) and ventilator dependence for more than 48 hours postoperatively (OR, 12.05; 95% CI, 1.06-137.43; P =u2009.045).nnnCONCLUSIONS AND RELEVANCEnEvaluated by the ACS NSQIP criteria, FFTR of head and neck defects in patients with HNC was associated with LOS longer than 10 days for procedures lasting longer than 11 hours and for patients who are ventilator dependent for more than 48 hours.

Detection of Head and Neck Cancer in Surgical Specimens Using Quantitative Hyperspectral Imaging

Purpose: This study intends to investigate the feasibility of using hyperspectral imaging (HSI) to detect and delineate cancers in fresh, surgical specimens of patients with head and neck cancers. Experimental Design: A clinical study was conducted in order to collect and image fresh, surgical specimens from patients (N = 36) with head and neck cancers undergoing surgical resection. A set of machine-learning tools were developed to quantify hyperspectral images of the resected tissue in order to detect and delineate cancerous regions which were validated by histopathologic diagnosis. More than two million reflectance spectral signatures were obtained by HSI and analyzed using machine-learning methods. The detection results of HSI were compared with autofluorescence imaging and fluorescence imaging of two vital-dyes of the same specimens. Results: Quantitative HSI differentiated cancerous tissue from normal tissue in ex vivo surgical specimens with a sensitivity and specificity of 91% and 91%, respectively, and which was more accurate than autofluorescence imaging (P < 0.05) or fluorescence imaging of 2-NBDG (P < 0.05) and proflavine (P < 0.05). The proposed quantification tools also generated cancer probability maps with the tumor border demarcated and which could provide real-time guidance for surgeons regarding optimal tumor resection. Conclusions: This study highlights the feasibility of using quantitative HSI as a diagnostic tool to delineate the cancer boundaries in surgical specimens, and which could be translated into the clinic application with the hope of improving clinical outcomes in the future. Clin Cancer Res; 23(18); 5426–36. ©2017 AACR.

Transoral Robotic Surgery–Assisted Endoscopy With Primary Site Detection and Treatment in Occult Mucosal Primaries

Importance Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment. Objective To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy. Design, Setting, and Participants In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy. Main Outcomes and Measures Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy. Results Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy. Conclusions and Relevance Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.

A Correlative Analysis of PD-L1, PD-1, PD-L2, EGFR, HER2, and HER3 Expression in Oropharyngeal Squamous Cell Carcinoma

We explored potential associations of the PD-1/PD-L1/PD-L2 pathway with clinical characteristics, outcome, and expression of EGFR, HER2, HER3 in oropharyngeal squamous cell carcinoma (OPSCC) using an institutional database. Protein expression was assessed by IHC on tissue microarray sections (EGFR, HER2, HER3) or whole tissue sections (PD-1/PD-L1/PD-L2). Expression of EGFR, HER2, HER3, PD-L1, and PD-L2 was quantified on tumor cells. Maximum density of PD-1 positive lymphocytes was measured on a scale of 0 to 4 within the tumor mass and peritumoral stroma. Associations between biomarkers and patient outcomes were tested using descriptive and inferential statistics, logistic regression, and Cox proportional hazards models. We analyzed tissue samples from 97 OPSCC cases: median age 59 years, p16+ (71%), male (83.5%), never smokers (18%), stage 3 to 4 disease (77%). Twenty-five percent of cases were PD-L1 positive. The proportion of PD-L1+ tumors was higher in p16+ (29%) than p16− OPSCC (11%, P = 0.047). There was no correlation between PD-L1, PD-L2, PD-1, EGFR, HER2, or HER3 expression. Positive PD-L1 status correlated with advanced nodal disease on multivariate analysis (OR 5.53; 95% CI, 1.06–28.77; P = 0.042). Negative PD-L2 expression was associated with worse survival (HR 3.99; 95% CI, 1.37–11.58; P = 0.011) in p16− OPSCC. Lower density of PD-1 positive lymphocytes in peritumoral stroma was associated with significantly increased risk of death on multivariate analysis (HR 3.17; 95% CI, 1.03–9.78; P = 0.045) after controlling for prognostic factors such as stage and p16 status. PD-L1 expression on tumor cells correlates with p16 status and advanced nodal status in OPSCC. PD-1 positive lymphocytes in peritumoral stroma serve as an independent prognostic factor for overall survival. Mol Cancer Ther; 17(3); 710–6. ©2018 AACR.

Label-free reflectance hyperspectral imaging for tumor margin assessment: a pilot study on surgical specimens of cancer patients

Abstract. A label-free, hyperspectral imaging (HSI) approach has been proposed for tumor margin assessment. HSI data, i.e., hypercube (x,y,λ), consist of a series of high-resolution images of the same field of view that are acquired at different wavelengths. Every pixel on an HSI image has an optical spectrum. In this pilot clinical study, a pipeline of a machine-learning-based quantification method for HSI data was implemented and evaluated in patient specimens. Spectral features from HSI data were used for the classification of cancer and normal tissue. Surgical tissue specimens were collected from 16 human patients who underwent head and neck (H&N) cancer surgery. HSI, autofluorescence images, and fluorescence images with 2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose (2-NBDG) and proflavine were acquired from each specimen. Digitized histologic slides were examined by an H&N pathologist. The HSI and classification method were able to distinguish between cancer and normal tissue from the oral cavity with an average accuracy of 90%±8%, sensitivity of 89%±9%, and specificity of 91%±6%. For tissue specimens from the thyroid, the method achieved an average accuracy of 94%±6%, sensitivity of 94%±6%, and specificity of 95%±6%. HSI outperformed autofluorescence imaging or fluorescence imaging with vital dye (2-NBDG or proflavine). This study demonstrated the feasibility of label-free, HSI for tumor margin assessment in surgical tissue specimens of H&N cancer patients. Further development of the HSI technology is warranted for its application in image-guided surgery.

Honokiol Radiosensitizes Squamous Cell Carcinoma of the Head and Neck by Downregulation of Survivin

Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues (n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo. Results: Overexpression of survivin was significantly associated with lymph nodes metastatic status (P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT (n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN (n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions: Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. Clin Cancer Res; 24(4); 858–69. ©2017 AACR.

Development of Late Toxicities in Patients with Oral Tongue Cancer Treated with Surgical Resection and Adjuvant Radiation Therapy

Objectives The late effects of RT are not well reported in patients with oral tongue cancer (OTC). This study reports the incidence of late effects and factors associated with the development of late effects in OTC patients. Methods Patients with OTC treated in our institution from 2003 to 2013 were evaluated. The association between RT doses, including mandible maximum and minimum doses and total 3D maximum dose, and late toxicity, defined as development of osteoradionecrosis (ORN), percutaneous endoscopic gastrostomy (PEG) tube dependence for >6u2009months after treatment, and narcotic dependency >6u2009months posttreatment were assessed using both univariate and multivariable (MV) analysis. Results Seventy-six patients with OTC (45% males and 55% females) were treated with definitive surgical resection followed by adjuvant RT. The median follow-up was 4.3u2009years. Combined late toxicities were reported in 38% of patients. Thirty-four percent of the patients had narcotic dependency and, 3.9% of the patients had ORN of the mandible. Thirteen percent of patients developed PEG tube dependency that was significantly associated with a higher 3D maximum radiation dose on univariate analysis (pu2009<u20090.01). On MV analysis, 3D maximum dose remained significantly associated with long-term PEG tube dependency (pu2009=u20090.05). Conclusion Patients with OTC treated with adjuvant RT are at significant risk for development of late toxicities. Increasing maximum dose is associated with long-term PEG tube dependence, and care should be taken to reduce the “hot spot” within radiation treatment plans as much as possible.