Davud Sirjani, MD

All Publications

• Comorbid Depression in Patients With Head and Neck Cancer Compared With Other Cancers. JAMA otolaryngology-- head & neck surgery Martinez, M. C., Finegersh, A., Baik, F. M., Holsinger, F. C., Starmer, H. M., Orloff, L. A., Sunwoo, J. B., Sirjani, D., Divi, V., Chen, M. M. 2024

  Abstract

  Depression is more prevalent among individuals with cancer than in the general population and is correlated with increased mortality in patients with head and neck cancer (HNC) in particular.To compare the prevalence of depression between patients with HNC and patients with other cancers.This retrospective cohort study used population-level data on patients aged 18 years or older with cancer who participated in the 2019 National Health Interview Survey and had completed the Personal Health Questionnaire-8 (PHQ-8). The analysis was performed between August 7, 2023, and April 5, 2024.Any cancer diagnosis.The main outcome was prevalence and severity of depression based on the PHQ-8. The magnitude of the difference in baseline characteristics was measured between patients with HNC and those with other cancer types, and 95% CIs were used to measure the precision of these estimates. Multivariable logistic regressions were used to evaluate the association of demographic, socioeconomic, anxiety, and clinical variables with depression.From a weighted cohort of 23 496 725 adult patients with cancer, 377 080 were diagnosed with HNC (87.5% aged 51-84 years; 77.9% male). The prevalence of any depression on the PHQ-8 (mild, moderate, or severe) was 40.1% in patients with HNC vs 22.3% in patients with other cancers. Compared with patients with other cancers, patients with HNC were equally likely to screen positive for anxiety (23.6% vs 16.0%; difference, 7.6%; 95% CI, -5.9% to 21.1%), take medication for depression (10.1% vs 13.9%; difference, -3.8%; 95% CI, -11.9% to 4.4%), and state that they never feel depressed (59.7% vs 53.7%; difference, 6.0%; 95% CI, -9.1% to 21.0%). On multivariable logistic regression analysis, having HNC was associated with an increased likelihood of depression (odds ratio [OR], 2.94; 95% CI, 1.39-6.22). Other factors associated with depression were being unmarried or not living with a partner (OR, 1.94; 95% CI, 1.55-2.43) and having anxiety (OR, 23.14; 95% CI, 17.62-30.37).This cohort study found that patients with HNC were twice as likely to screen positive for depression on a validated survey than those with other cancers, despite having similar rates of self-reported depression and depression medication use. These findings suggest that self-reporting of depression may result in underreporting and undertreatment in this population and, thus, a need for further work in developing interventions to improve identification of and optimize treatment for patients with HNC and comorbid depression.

  View details for DOI 10.1001/jamaoto.2024.3233

  View details for PubMedID 39446380

• 3D Printing for the Development of Palatal Defect Prosthetics. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Calderon, C., Golzar, A., Marcott, S., Gifford, K., Napel, S., Fleischmann, D., Baik, F. M., Osborne, T. F., Finegersh, A., Sirjani, D. 2024; 41 (Suppl 2): S3-S7

  Abstract

  Three-dimensional (3D) printing has emerged as a promising new technology for the development of surgical prosthetics. Research in orthopedic surgery has demonstrated that using 3D printed customized prosthetics results in more precise implant placements and better patient outcomes. However, there has been little research on implementing customized 3D printed prosthetics in otolaryngology. The program sought to determine whether computed tomography (CT) serves as feasible templates to construct 3D printed palatal obturator prosthetics for defects in patients who have been treated for head and neck cancers.A retrospective review of patients with palatal defects was conducted and identified 1 patient with high quality CTs compatible with 3D modeling. CTs of the patient's craniofacial anatomy were used to develop a 3D model and a Formlabs 3B+ printer printed the palatal prosthetic. We successfully developed and produced an individualized prosthetic using CTs from a veteran with head and neck deformities caused by cancer treatment who was previously treated at the Veterans Affairs Palo Alto Health Care System. This project was successful in printing patient-specific implants using CT reproductions of the patient's craniofacial anatomy, particularly of the palate. The program was a proof of concept and the implant we created was not used on the patient.Customized 3D printed implants may allow otolaryngologists to enhance the performance and efficiency of surgeries and better rehabilitate and reconstruct craniofacial deformities to restore appearance and function to patients. Additional research will strive to enhance the therapeutic potential of these prosthetics to serve as low-cost, patient-specific implants.

  View details for DOI 10.12788/fp.0464

  View details for PubMedID 38813248

  View details for PubMedCentralID PMC11132111

• Suture Stenting After Sialendoscopy: A Novel Technique That Reduces Risk of Recurrent Parotitis. The Laryngoscope Finegersh, A., Chang, J., Lee, Y. J., Sirjani, D. 2023

  Abstract

  Chronic sialadenitis is associated with decreased quality of life and recurrent infections. While sialendoscopy with stenting is effective in relieving symptoms of sialadenitis, currently available stents are rigid and poorly tolerated by patients, leading to early removal and potential for adverse scarring. This study examines whether sutures can be used as a stenting material to improve patient comfort and reduce recurrence risk.This is a retrospective cohort study of a consecutive series of adult patients with chronic sialadenitis undergoing sialendoscopy with or without suture stenting. Data were collected between 2014 and 2018 with a 3-year follow-up period ending in 2021. The primary outcome measure was recurrence of sialadenitis within 3 years of surgery. Secondary outcomes were stent dislodgement and patient-reported discomfort.We included 63 patients with parotid sialadenitis of whom 28 underwent suture stenting and 35 did not receive stenting after sialendoscopy. Stents were well tolerated, with a mean duration of 34.5 days, and only 2 of 28 stents (7.1%) accidentally dislodged within the first week. Suture stenting significantly reduced symptom recurrence after sialendoscopy (OR = 0.09, 95% CI 0.02-0.45, p = 0.003; 3-year sialadenitis recurrence rate: 7.1% vs. 45.7%, p = 0.005). Cox multivariate regression for clinicodemographic variables showed an HR of 0.04 (95% CI 0.01-0.19, p < 0.001) for the risk of symptom recurrence.Suture stenting after sialendoscopy is low cost, available across all institutions, well-tolerated by patients, and highly efficacious in reducing risk of recurrent sialadenitis after sialendoscopy.3 Laryngoscope, 2023.

  View details for DOI 10.1002/lary.30828

  View details for PubMedID 37338090

• Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell phenotype. PNAS nexus Viswanathan, V., Cao, H., Saiki, J., Jiang, D., Mattingly, A., Nambiar, D., Bloomstein, J., Li, Y., Jiang, S., Chamoli, M., Sirjani, D., Kaplan, M., Holsinger, F. C., Liang, R., Von Eyben, R., Jiang, H., Guan, L., Lagory, E., Feng, Z., Nolan, G., Ye, J., Denko, N., Knox, S., Rosen, D., Le, Q. 2022; 1 (2): pgac056

  Abstract

  Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures postradiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and survival even in the absence of radiation stress. Salivary glands from Aldh3a1 -/- mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels, depletes glutathione pool, and accumulates ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

  View details for DOI 10.1093/pnasnexus/pgac056

  View details for PubMedID 35707206

• Landscape of innate lymphoid cells in human head and neck cancer reveals divergent NK cell states in the tumor microenvironment. Proceedings of the National Academy of Sciences of the United States of America Moreno-Nieves, U. Y., Tay, J. K., Saumyaa, S., Horowitz, N. B., Shin, J. H., Mohammad, I. A., Luca, B., Mundy, D. C., Gulati, G. S., Bedi, N., Chang, S., Chen, C., Kaplan, M. J., Rosenthal, E. L., Holsinger, F. C., Divi, V., Baik, F. M., Sirjani, D. B., Gentles, A. J., Newman, A. M., Freud, A. G., Sunwoo, J. B. 2021; 118 (28)

  Abstract

  Natural killer (NK) cells comprise one subset of the innate lymphoid cell (ILC) family. Despite reported antitumor functions of NK cells, their tangible contribution to tumor control in humans remains controversial. This is due to incomplete understanding of the NK cell states within the tumor microenvironment (TME). Here, we demonstrate that peripheral circulating NK cells differentiate down two divergent pathways within the TME, resulting in different end states. One resembles intraepithelial ILC1s (ieILC1) and possesses potent in vivo antitumor activity. The other expresses genes associated with immune hyporesponsiveness and has poor antitumor functional capacity. Interleukin-15 (IL-15) and direct contact between the tumor cells and NK cells are required for the differentiation into CD49a+CD103+ cells, resembling ieILC1s. These data explain the similarity between ieILC1s and tissue-resident NK cells, provide insight into the origin of ieILC1s, and identify the ieILC1-like cell state within the TME to be the NK cell phenotype with the greatest antitumor activity. Because the proportions of the different ILC states vary between tumors, these findings provide a resource for the clinical study of innate immune responses against tumors and the design of novel therapy.

  View details for DOI 10.1073/pnas.2101169118

  View details for PubMedID 34244432

• The Future of Telemedicine: Revolutionizing Health Care or Flash in the Pan? Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Losorelli, S. D., Vendra, V., Hildrew, D. M., Woodson, E. A., Brenner, M. J., Sirjani, D. B. 2021: 194599820983330

  Abstract

  The meteoric rise of telemedicine early in the COVID-19 pandemic might easily be mistaken for an ephemeral trend-one reaching its zenith in a moment of crisis. To the contrary, momentum has been mounting for telehealth over decades. The recent increase in telecare reveals its potential to deliver efficient, patient-centered, high-quality care in an increasingly technology-dependent landscape. Prior to COVID-19, surgeons lagged behind medical counterparts in embracing telemedicine; however, the pragmatic imperatives for remote care of patients and changes to Medicare removed key barriers to adoption. Otolaryngology-head and neck surgery has innovated across subspecialties, leading in COVID-19 scholarship and year-over-year publications on telemedicine. Yet, improved access to subspecialists is tempered by a digital divide that threatens to exacerbate disparities. Otolaryngology is poised to lead the transformation of procedural specialties while ensuring equitable care.

  View details for DOI 10.1177/0194599820983330

  View details for PubMedID 33399500

• Tracheostomy During the COVID-19 Pandemic: Comparison of International Perioperative Care Protocols and Practices in 26 Countries. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Bier-Laning, C., Cramer, J. D., Roy, S., Palmieri, P. A., Amin, A., Anon, J. M., Bonilla-Asalde, C. A., Bradley, P. J., Chaturvedi, P., Cognetti, D. M., Dias, F., Di Stadio, A., Fagan, J. J., Feller-Kopman, D. J., Hao, S., Kim, K. H., Koivunen, P., Loh, W. S., Mansour, J., Naunheim, M. R., Schultz, M. J., Shang, Y., Sirjani, D. B., St John, M. A., Tay, J. K., Vergez, S., Weinreich, H. M., Wong, E. W., Zenk, J., Rassekh, C. H., Brenner, M. J. 2020: 194599820961985

  Abstract

  OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has led to a global surge in critically ill patients requiring invasive mechanical ventilation, some of whom may benefit from tracheostomy. Decisions on if, when, and how to perform tracheostomy in patients with COVID-19 have major implications for patients, clinicians, and hospitals. We investigated the tracheostomy protocols and practices that institutions around the world have put into place in response to the COVID-19 pandemic.DATA SOURCES: Protocols for tracheostomy in patients with severe acute respiratory syndrome coronavirus 2 infection from individual institutions (n = 59) were obtained from the United States and 25 other countries, including data from several low- and middle-income countries, 23 published or society-endorsed protocols, and 36 institutional protocols.REVIEW METHODS: The comparative document analysis involved cross-sectional review of institutional protocols and practices. Data sources were analyzed for timing of tracheostomy, contraindications, preoperative testing, personal protective equipment (PPE), surgical technique, and postoperative management.CONCLUSIONS: Timing of tracheostomy varied from 3 to >21 days, with over 90% of protocols recommending 14 days of intubation prior to tracheostomy. Most protocols advocate delaying tracheostomy until COVID-19 testing was negative. All protocols involved use of N95 or higher PPE. Both open and percutaneous techniques were reported. Timing of tracheostomy changes ranged from 5 to >30 days postoperatively, sometimes contingent on negative COVID-19 test results.IMPLICATIONS FOR PRACTICE: Wide variation exists in tracheostomy protocols, reflecting geographical variation, different resource constraints, and limited data to drive evidence-based care standards. Findings presented herein may provide reference points and a framework for evolving care standards.

  View details for DOI 10.1177/0194599820961985

  View details for PubMedID 33138722

• Radiographic surveillance of abdominal free fat graft in complex parotid pleomorphic adenomas: A case series. Heliyon Lee, Y. J., Fischbein, N. J., Megwalu, U. n., Baik, F. M., Divi, V. n., Kaplan, M. J., Sirjani, D. B. 2020; 6 (5): e03894

  Abstract

  Free abdominal fat transfer is commonly used to restore facial volume and improve cosmesis after parotidectomy for pleomorphic adenomas. We describe the radiographic characteristics of these grafts on follow-up imaging.Medical records of four patients who underwent parotidectomy with abdominal fat graft in 2016 and had follow up imaging available were retrospectively analyzed. An otolaryngologist and neuroradiologist reviewed imaging studies, evaluated the fat grafts, and monitored for residual or recurrent disease.The abdominal fat was successfully grafted in all four patients. Post-operative baseline magnetic resonance imaging and additional surveillance imaging showed fat grafts with minimal volume loss. However, there was development of irregular enhancement consistent with fat necrosis in two of the four patients.Radiographic surveillance of free fat graft reconstruction after pleomorphic adenoma resection shows minimal contraction in size but development of fat necrosis. Recognition of expected changes should help avoid confusion with residual or recurrent disease, reassuring both patient and treating physician.

  View details for DOI 10.1016/j.heliyon.2020.e03894

  View details for PubMedID 32395660

  View details for PubMedCentralID PMC7210407

• Risks of Neoplasia and Malignancy in Surgically Resected Cystic Parotid Lesions. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Boursiquot, B. C., Fischbein, N. J., Sirjani, D., Megwalu, U. C. 2019: 194599819889699

  Abstract

  OBJECTIVES: To evaluate the risks of neoplasm and malignancy in surgically treated cystic parotid masses compared with solid or mixed lesions and to evaluate the performance of fine-needle aspiration (FNA) in parotid cysts.STUDY DESIGN: Retrospective cross-sectional study.SETTING: Single-institution academic tertiary care center.SUBJECTS AND METHODS: Patients without a history of human immunodeficiency virus or head and neck cancer who underwent parotidectomy for parotid masses and had preoperative imaging to characterize lesions as cystic, solid, or mixed (ie, partially cystic and partially solid). We assessed the risks of neoplasia and malignancy, adjusting for age, sex, race/ethnicity, facial nerve weakness, and history of malignancy. We also evaluated the sensitivity and specificity of FNA.RESULTS: We included 308 patients, 27 of whom had cystic parotid masses (5 simple and 22 complex). Cystic masses were less likely to be neoplastic compared to solid or mixed masses (44% vs 97%; odds ratio [OR], 0.03; 95% confidence interval [CI], 0.01-0.07); however, there was no difference in the risk of malignancy (22% vs 26%; OR, 0.81; 95% CI, 0.32-2.10). Cystic masses were more likely to yield nondiagnostic FNA cytology results, but for diagnostic samples, FNA was 86% sensitive and 33% specific for diagnosing neoplasia and 75% sensitive and 83% specific for diagnosing malignancy.CONCLUSION: In our population, cystic masses undergoing surgery were less likely to be neoplastic but had a similar risk of malignancy as solid masses. The risk of malignancy should be considered in the management of cystic parotid masses.

  View details for DOI 10.1177/0194599819889699

  View details for PubMedID 31791199

• Regionalization of head and neck cancer surgery may fragment care and impact overall survival LARYNGOSCOPE Chen, M. M., Megwalu, U. C., Liew, J., Sirjani, D., Rosenthal, E. L., Divi, V. 2019; 129 (6): 1413–19

  View details for DOI 10.1002/lary.27440

  View details for Web of Science ID 000468091400035

• Retrograde parotidectomy under local anesthesia for benign, malignant, and inflammatory lesions AMERICAN JOURNAL OF OTOLARYNGOLOGY Chang, M., Coughran, A., Lee, Y., Collins, J., Sirjani, D. 2019; 40 (2): 152–55

  View details for DOI 10.1016/j.amjoto.2019.01.002

  View details for Web of Science ID 000460493900005

• Retrograde parotidectomy under local anesthesia for benign, malignant, and inflammatory lesions. American journal of otolaryngology Chang, M., Coughran, A., Lee, Y., Collins, J., Sirjani, D. 2019

  Abstract

  OBJECTIVE: To report the patient selection, surgical technique, and outcomes of parotidectomy using local anesthesia under monitored anesthesia care (MAC).METHODS: A retrospective chart review was performed for patients undergoing parotidectomy under local anesthesia at an academic head and neck surgery center.RESULTS: Six patients deemed high risk for general anesthesia (GA) due to medical comorbidities or with a strong preference to avoid GA underwent parotidectomy using local anesthesia and MAC. Parotidectomy was performed for several indications, including benign tumors, malignant tumors, and chronic sialadenitis. Mean age of patients was 78.0 ± 7.9 years, and all had an American Society of Anesthesia score ≥ 2 and Charlson comorbidity index ≥4. Mean operative time was 102.8 ± 38.3 min, comparable to that of parotidectomy under general anesthesia. No major complications occurred. Minor complications included three cases of temporary postoperative facial nerve weakness limited to 1-2 lower division branches. At most recent follow up (10 to 48 months), all patients were medically stable and disease free.CONCLUSION: In carefully selected patients, parotidectomy under local anesthesia is a viable treatment alternative that can be offered to patients. Successful outcomes require preoperative counseling, meticulous technique, and close collaboration with anesthesia colleagues.

  View details for PubMedID 30691973

• Saliva: an all-rounder of our body. European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V Roblegg, E. n., Coughran, A. n., Sirjani, D. n. 2019

  Abstract

  Saliva is a multifaceted bodily fluid that is often taken for granted but is indispensable for oral health and overall well-being in humans. Although mainly comprised of water (99.5%), proteins, ions and enzymes turn saliva into a viscoelastic solution that performs a variety of vital tasks. This review article gives a brief overview of the salivary gland system, as well as the composition, output and functions of saliva. It also addresses the current applications of saliva for diagnostic purposes, the clinical relevance of saliva in oral diseases as well as current treatment options.

  View details for DOI 10.1016/j.ejpb.2019.06.016

  View details for PubMedID 31220573

• Utility of videolaryngoscopy for diagnostic and therapeutic interventions in head and neck surgery. American journal of otolaryngology Shenson, J. A., Marcott, S. n., Dewan, K. n., Lee, Y. J., Mariano, E. R., Sirjani, D. B. 2019: 102284

  Abstract

  Videolaryngoscopy is commonly used by anesthesiologists to manage difficult airways. Recently otolaryngologists have reported use in select procedures; to date there is limited evaluation in head and neck surgery.Patients who underwent direct laryngoscopy (DL) with use of GlideScope videolaryngoscopy (GVL) were retrospectively identified from a tertiary care Veterans Affairs hospital. GVL was used to assist or replace traditional laryngoscopes for diagnostic and therapeutic procedures.Nineteen patients (48-83 years old) underwent 21 procedures. Difficult endotracheal intubation was reported in 53% of patients. GVL replaced traditional DL in 76% of cases, assisted evaluation prior to traditional DL in 10%, and rescued failed traditional DL in 14%. No complications occurred. Three indications for GVL were identified.GVL was safe in our experience and provides unique benefits in selected scenarios in head and neck surgery. Otolaryngologists can consider videolaryngoscopy as a complement to traditional DL.

  View details for DOI 10.1016/j.amjoto.2019.102284

  View details for PubMedID 32505434

• Jaw Opening Decreases Window to the Deep Parotid Lobe OTOLARYNGOLOGY-HEAD AND NECK SURGERY Lee, Y., Megwalu, U., Melara, E., Divi, V., Fernandes, V. T., Sirjani, D. 2018; 159 (3): 439–41

  View details for DOI 10.1177/0194599818766317

  View details for Web of Science ID 000443735400005

• Regionalization of Head and Neck Cancer Surgery May Fragment Care and Impact Overall Survival. The Laryngoscope Chen, M. M., Megwalu, U. C., Liew, J., Sirjani, D., Rosenthal, E. L., Divi, V. 2018

  Abstract

  OBJECTIVE: While surgical treatment concentrates in tertiary care centers, an increasing number of patients request postoperative radiation therapy (PORT) at a separate center closer to home. Our goal was to determine whether fragmentation of surgery and PORT were associated with poorer oncologic outcomes.METHODS: We conducted a retrospective cohort study of 32,813 head and neck cancer patients treated with surgery and PORT in the National Cancer Data Base. Our main outcome was overall survival (OS). Statistical analysis included chi2 , t tests, Kaplan-Meier, and Cox regression analysis.RESULTS: Fragmented care was independently associated with increased risk of mortality (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03-1.13), whereas distance to surgical center>30 miles (HR, 0.92; 95% CI, 0.87-0.97) was associated with improved OS. On subgroup analysis, fragmented care was associated with decreased OS only among patients who had surgery at an academic center (HR, 1.10; 95% CI, 1.04-1.17). Within academic centers, greater distance from the surgical center was associated with improved survival only in patients who received PORT at the same facility (HR, 0.85; 95% CI, 0.78-0.93), but this effect was negated among patients who had fragmented care (HR, 0.97; 95% CI, 0.85-1.11).CONCLUSION: When cancer care is fragmented, there is no longer a survival benefit for patients to travel for surgical care at academic medical centers. Fragmented care is independently associated with worse survival, and further research is needed to evaluate the causes of this difference in survival to determine if improving care coordination can mitigate this survival difference.LEVEL OF EVIDENCE: NA. Laryngoscope, 2018.

  View details for PubMedID 30152007

• Outcomes in Head and Neck Resections That Require Multiple-Flap Reconstructions A Systematic Review JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Gao, R. W., Nuyen, B. A., Divi, V., Sirjani, D., Rosenthal, E. L. 2018; 144 (8): 746–52

  View details for DOI 10.1001/jamaoto.2018.0835

  View details for Web of Science ID 000441939900018

• Oropharyngeal Squamous Cell Carcinoma Incidence and Mortality Trends in the United States, 1973-2013 LARYNGOSCOPE Megwalu, U. C., Sirjani, D., Devine, E. E. 2018; 128 (7): 1582–88

  View details for DOI 10.1002/lary.26972

  View details for Web of Science ID 000440007000029

• Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Saiki, J. P., Cao, H., Van Wassenhove, L. D., Viswanathan, V., Bloomstein, J., Nambiar, D. K., Mattingly, A. J., Jiang, D., Chen, C., Stevens, M. C., Simmons, A. L., Park, H., von Eyben, R., Kool, E. T., Sirjani, D., Knox, S. M., Quynh Thu Le, Mochly-Rosen, D. 2018; 115 (24): 6279–84

  View details for DOI 10.1073/pnas.1802184115

  View details for Web of Science ID 000434933400059

• Association of Time between Surgery and Adjuvant Therapy with Survival in Oral Cavity Cancer. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Chen, M. M., Harris, J. P., Orosco, R. K., Sirjani, D., Hara, W., Divi, V. 2018; 158 (6): 1051–56

  Abstract

  Objective The National Cancer Center Network recommends starting radiation therapy within 6 weeks after surgery for oral cavity squamous cell carcinoma (OCSCC), but there is limited evidence of the importance of the total time from surgery to completion of radiation therapy (package time). We set out to determine if there was an association between package time and survival in OCSCC and to evaluate the impact of treatment location on outcomes. Study Design Retrospective cohort study. Setting Tertiary academic medical center. Subjects and Methods We reviewed the records of patients with OCSCC who completed postoperative radiation therapy at an academic medical center from 2008 to 2016. The primary endpoints were overall survival and recurrence-free survival. Statistical analysis included chi2 tests and Cox proportional hazards regressions. Results We identified 132 patients with an average package time of 12.6 weeks. On multivariate analysis, package time >11 weeks was independently associated with decreased overall survival (hazard ratio, 6.68; 95% CI, 1.42-31.44) and recurrence-free survival (hazard ratio, 2.94; 95% CI, 1.20-7.18). Patients who received radiation therapy at outside facilities were more likely to have treatment delays (90.2% vs 62.9%, P = .001). Conclusions Prolonged package times are associated with decreased overall and recurrence-free survival among patients with OCSCC. Patients who received radiation therapy at outside facilities are more likely to have prolonged package times.

  View details for PubMedID 29313448

• Association of Time between Surgery and Adjuvant Therapy with Survival in Oral Cavity Cancer OTOLARYNGOLOGY-HEAD AND NECK SURGERY Chen, M. M., Harris, J. P., Orosco, R. K., Sirjani, D., Hara, W., Divi, V. 2018; 158 (6): 1051–56

  View details for DOI 10.1177/0194599817751679

  View details for Web of Science ID 000434026700021

• Aldehyde dehydrogenase 3A1 activation prevents radiation-induced xerostomia by protecting salivary stem cells from toxic aldehydes. Proceedings of the National Academy of Sciences of the United States of America Saiki, J. P., Cao, H., Van Wassenhove, L. D., Viswanathan, V., Bloomstein, J., Nambiar, D. K., Mattingly, A. J., Jiang, D., Chen, C., Stevens, M. C., Simmons, A. L., Park, H. S., von Eyben, R., Kool, E. T., Sirjani, D., Knox, S. M., Le, Q. T., Mochly-Rosen, D. 2018

  Abstract

  Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1-/- adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy.

  View details for PubMedID 29794221

• Association of Survival With Shorter Time to Radiation Therapy After Surgery for US Patients With Head and Neck Cancer JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Harris, J. P., Chen, M. M., Orosco, R. K., Sirjani, D., Divi, V., Hara, W. 2018; 144 (4): 349–59

  Abstract

  Shortening the time from surgery to the start of radiation (TS-RT) is a consideration for physicians and patients. Although the National Comprehensive Cancer Network recommends radiation to start within 6 weeks, a survival benefit with this metric remains controversial.To determine the association of delayed TS-RT with overall survival (OS) using a large cancer registry.In this observational cohort study, 25 216 patients with nonmetastatic stages III to IV head and neck cancer were identified from the National Cancer Database (NCDB).Patients received definitive surgery followed by adjuvant radiation therapy, with an interval duration defined as TS-RT.Overall survival as a function of TS-RT and the effect of clinicopathologic risk factors and accelerated fractionation.We identified 25 216 patients with nonmetastatic squamous cell carcinoma of the head and neck. There were 18 968 (75%) men and 6248 (25%) women and the mean (SD) age of the cohort was 59 (10.9) years. Of the 25 216 patients, 9765 (39%) had a 42-days or less TS-RT and 4735 (19%) had a 43- to 49-day TS-RT. Median OS was 10.5 years (95% CI, 10.0-11.1 years) for patients with a 42-days or less TS-RT, 8.2 years (95% CI, 7.4-8.6 years; absolute difference, -2.4 years, 95% CI, -1.5 to -3.2 years) for patients with a 43- to 49-day TS-RT, and 6.5 years (95% CI, 6.1-6.8 years; absolute difference, -4.1 years, 95% CI, -3.4 to -4.7 years) for those with a 50-days or more TS-RT. Multivariable analysis found that compared with a 42-days or less TS-RT, there was not a significant increase in mortality with a 43- to 49-day TS-RT (HR, 0.98; 95% CI, 0.93-1.04), although there was for a TS-RT of 50 days or more (HR, 1.07; 95% CI, 1.02-1.12). A significant interaction was identified between TS-RT and disease site. Subgroup effect modeling found that a delayed TS-RT of 7 days resulted in significantly worse OS for patients with tonsil tumors (HR, 1.22; 95% CI, 1.05-1.43) though not other tumor subtypes. Accelerated fractionation of 5.2 fractions or more per week was associated with improved survival (HR, 0.93; 95% CI, 0.87-0.99) compared with standard fractionation.Delayed TS-RT of 50 days or more was associated with worse overall survival. The multidisciplinary care team should focus on shortening TS-RT to improve survival. Unavoidable delays may be an indication for accelerated fractionation or other dose intensification strategies.

  View details for PubMedID 29522072

  View details for PubMedCentralID PMC5876822

• Jaw Opening Decreases Window to the Deep Parotid Lobe. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Lee, Y., Megwalu, U., Melara, E., Divi, V., Fernandes, V. T., Sirjani, D. 2018: 194599818766317

  Abstract

  To describe the relationship between jaw opening and access to the deep parotid window, we identified the following distances in 10 human skulls: symphysis to angle of mandible, mastoid tip to angle of mandible, angle of mandible to condylar process, and mastoid tip to condylar process. With the jaw closed and open, these distances were measured with 1 to 3 wooden blocks, each measuring 1 cm, between the upper and lower incisors. The triangular deep parotid area formed by the last 3 distances was calculated. A repeated measures analysis of variance showed a significant decrease in the deep parotid area with increasing interincisal distance ( P < .01). A generalized estimating equation model demonstrated a statistically significant decreasing area of the deep parotid window with increasing interincisal distance. These results suggest that nasal intubation may improve access to the parotid window.

  View details for PubMedID 29609515

• Outcomes in Head and Neck Resections That Require Multiple-Flap Reconstructions: A Systematic Review. JAMA otolaryngology-- head & neck surgery Gao, R. W., Nuyen, B. A., Divi, V. n., Sirjani, D. n., Rosenthal, E. L. 2018

  Abstract

  Complex head and neck cancer defects that require multiflap reconstructions are technically feasible, but the morbidity and patient outcomes of such large-scale head and neck operations have yet to be systematically reviewed.To systematically review existing literature to characterize the outcomes of large-scale head and neck resections that require multiple-flap reconstructions (defined as defects that require >1 flap [free, pedicled, or combinations thereof]).Two authors independently searched PubMed, Embase, and the Cochrane Review databases for English-only texts published on any date. Included studies examined patients who underwent complex head and neck surgical resections that required multiple simultaneous flaps for reconstruction. Included studies reported results on at least one of the following outcomes: functional and aesthetic, patient survival, or cost (estimated by operating room time, length of stay, and/or complications). Methodological Index for Non-Randomized Studies (MINORS) criteria for bias and modified Oxford Centre for Evidence-Based Medicine recommendations were used to assess study quality.Twenty-four studies published from November 1, 1992, through September 1, 2016, met the final inclusion criteria, with a total of 487 patients (370 male [79.4%]; mean [SD] weighted age, 55.1 [4.1] years). Sixty-two of 250 patients (24.8%) were partially or fully dependent on feeding tubes at follow-up. Twenty-two of 75 patients (29.3%) had poor postoperative oral competence, causing moderate to severe drooling. Nineteen of 108 patients (17.6%) had unintelligible speech. Nine of 64 patients (14.1%) were unsatisfied with their aesthetic outcome. The mean (SD) reported survival was 2.36 (1.39) years. The mean (SD) length of stay was 24.5 (12.2) days in 219 patients. Eighty-eight minor complications (eg, partial flap necrosis, donor site complications) and 185 major complications (eg, surgical reexplorations, flap loss, or cardiopulmonary complications) were reported in 380 patients. Mean (SD) MINORS scores were 16.0 (3.2) for comparison studies and 11.4 (1.8) for noncomparison studies.Because of limited patient life expectancies, modest functional and aesthetic outcomes, and significant associated costs, surgeons should weigh the curative potential and palliative benefits for individual patients with a comprehensive view of the overall outcomes of extensive head and neck resections and reconstructions. Realistic expectations should be emphasized during preoperative discussions with patients.

  View details for PubMedID 29978196

• Oropharyngeal squamous cell carcinoma incidence and mortality trends in the United States, 1973-2013. The Laryngoscope Megwalu, U. C., Sirjani, D., Devine, E. E. 2017

  Abstract

  OBJECTIVE: To analyze oropharyngeal squamous cell carcinoma incidence and mortality trends in the United States for the years 1973 through 2013.STUDY DESIGN: Cross-sectional study using a large population-based cancer database.METHODS: Data on incidence and mortality rates were extracted from the Surveillance, Epidemiology, and End Results (SEER) 9 Database. Annual percentage change in rates was calculated using Joinpoint regression analysis (National Cancer Institute, Bethesda, MD).RESULTS: Incidence rates increased (annual percent change [APC]; 1.52, 95% confidence interval [CI] 0.17 to 2.88) from 1973 to 1983, remained stable (APC -0.52, 95% CI -1.30 to 0.26) from 1983 to 1997, and increased (APC 1.32, 95% CI 0.83 to 1.81) from 1997 to 2013. Overall, incidence rates increased for males (APC 0.73, 95% CI 0.22 to 1.25) but not females (APC -0.77, 95% CI -0.68 to 0.82). Incidence rates increased in the white population (APC 0.79, 95% CI 0.33 to 1.25) but decreased in the black population (APC -0.72, 95% CI -1.41 to -0.02). The incidence rates increased for tongue-base tumors (APC 1.17, 95% CI 0.42 to 1.92) and tonsil tumors (APC 0.47, 95% CI 1.10 to 4.96) but decreased for other sites. Incidence-based mortality decreased (APC -0.78, 95% CI -1.13 to -0.42) from 1993 to 2013.CONCLUSION: Oropharyngeal squamous cell carcinoma incidence rates increased in a nonlinear fashion from 1973 to 2013, whereas mortality rates declined. This, along with variation in trends by demographic and tumor factors, suggest that human papilloma virus is the main driver of the recent rise in incidence.LEVEL OF EVIDENCE: 2b. Laryngoscope, 2017.

  View details for PubMedID 29086431

• Retrograde Parotidectomy and facial nerve outcomes: A case series of 44 patients AMERICAN JOURNAL OF OTOLARYNGOLOGY Kligerman, M. P., Song, Y., Schoppy, D., Divi, V., Megwalu, U. C., Haughey, B. H., Sirjani, D. 2017; 38 (5): 533–36

  Abstract

  The most common surgical method to remove benign parotid tumors remains the prograde approach. We examined if a retrograde surgical technique offers better outcomes than historical prograde controls.A retrospective chart review at Stanford Hospital was conducted to identify retrograde parotidectomies between February 2012 and October 2014 that were staffed by the senior author (DS) with resident involvement. Facial nerve (FN) outcomes and other post-surgical parameters were recorded.We identified 44 consecutive cases and found that 18.2% (n=8) of patients experienced temporary paresis and 2.3% (n=1) experienced minor (HB 2) permanent paresis limited to one branch. The average hospital length of stay was 0.64 days and complication rate was 6.8%.The retrograde technique has complication rates comparable to historical rates for the prograde technique and is amenable to minimally invasive outpatient superficial parotidectomy.

  View details for PubMedID 28647300

• Node-positive cutaneous squamous cell carcinoma of the head and neck: Survival, high-risk features, and adjuvant chemoradiotherapy outcomes. Head & neck Amoils, M., Lee, C. S., Sunwoo, J., Aasi, S. Z., Hara, W., Kim, J., Sirjani, D., Colevas, A. D., Chang, A. L., Divi, V. 2017

  Abstract

  Data lacks to guide treatment of regionally metastatic cutaneous head and neck squamous cell carcinoma (HNSCC).We conducted a retrospective review of 80 patients treated for regionally metastatic cutaneous HNSCC. The effect of various clinicopathologic variables on overall survival (OS) was investigated, in addition to outcomes by treatment modality.On multivariate regression, cutaneous primary >2 cm (p = .03) and extracapsular spread (ECS; p = .01) were significantly associated with decreased OS. Location of regional metastasis (neck vs parotid vs both) had no effect on OS (p = .2), nor did the presence of a cutaneous primary at the time of presentation (p = .9). The 3-year survival was 43%, 52%, and 49% for surgery alone, adjuvant radiation, and adjuvant chemoradiation, respectively. Fifty-one percent of patients had a recurrence of their disease.Regionally metastatic cutaneous HNSCC is an aggressive disease associated with high recurrence rates. Patients with tumors >2 cm and ECS have poorer OS despite adjuvant therapy. © 2017 Wiley Periodicals, Inc. Head Neck 39: 881-885, 2017.

  View details for DOI 10.1002/hed.24692

  View details for PubMedID 28252823

• Risk of Nodal Metastasis in Major Salivary Gland Adenoid Cystic Carcinoma. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery Megwalu, U. C., Sirjani, D. 2017: 194599817690138-?

  Abstract

  Objective To determine the risk of nodal metastasis, examine risk factors for nodal metastasis, and evaluate the impact of nodal metastasis on survival in patients with major salivary gland adenoid cystic carcinoma. Study Design Retrospective cohort study from a large population- based cancer database. Methods Data were extracted from the SEER 18 database (Surveillance, Epidemiology, and End Results) of the National Cancer Institute. The study cohort included 720 patients diagnosed with major salivary gland adenoid cystic carcinoma between 1988 and 2013. Results The overall rate of lymph node metastasis was 17%. T3 disease (odds ratio, 4.74) and T4 disease (odds ratio, 9.24) were associated with increased risk of nodal metastasis. Age, sex, and site were not associated with nodal metastasis. Nodal metastasis was associated with worse overall survival (hazard ratio, 2.56) and disease-specific survival (hazard ratio, 3.27), after adjusting for T stage, presence of distant metastasis, site, surgical resection, radiotherapy, neck dissection, age, sex, race, marital status, and year of diagnosis. Conclusion Major salivary gland adenoid cystic carcinoma carries significant risk of nodal metastasis. Advanced T stage is associated with increased risk of nodal metastasis. Nodal metastasis is associated with worse survival.

  View details for DOI 10.1177/0194599817690138

  View details for PubMedID 28168897

• Association of Postoperative Radiotherapy With Survival in Patients With N1 Oral Cavity and Oropharyngeal Squamous Cell Carcinoma JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY Chen, M. M., Harris, J. P., Hara, W., Sirjani, D., Divi, V. 2016; 142 (12): 1224-1230

  Abstract

  The guidelines for head and neck cancer recommend consideration of adjuvant postoperative radiotherapy (PORT) for patients with pT1N1 or pT2N1 disease in the absence of other adverse features. This recommendation was recently changed for oropharyngeal (OP) squamous cell carcinoma (SCC).To examine the use and outcomes of PORT for N1 OP SCC and oral cavity (OC) SCC.This retrospective cohort study identified 1467 adult patients with OC SCC and 790 patients with OP SCC with pT1N1 or pT2N1 disease in the absence of other adverse features from the National Cancer Database from January 1, 2004, to December 31, 2013. Patients who received adjuvant chemotherapy or palliative radiotherapy or who had adverse pathologic features were excluded. Statistical analysis included χ2 tests and Cox proportional hazards regression analysis. Data were analyzed from November 10, 2015, to June 30, 2016.Overall survival.Of the 1467 patients with OC SCC (842 men [57.4%]; 625 women [42.6%]; mean [SD] age, 61.3 [13.8] years), 740 (50.4%) received PORT. Of the 790 patients with OP SCC (584 men [73.9%]; 206 women [26.1%]; mean [SD] age, 58.2 [10.3] years), 449 (56.8%) received PORT. After controlling for patient demographics, pathologic characteristics, and hospital-level variables, PORT was associated with improved overall survival for patients with OC SCC (hazard ratio [HR], 0.76; 95% CI, 0.63-0.92) and OP SCC (HR, 0.62; 95% CI, 0.41-0.92) with pN1 disease without adverse features. On stratified analysis, this association persisted for patients younger than 70 years (OC SCC HR, 0.77; 95% CI, 0.61-0.97; OP SCC HR, 0.48; 95% CI, 0.31-0.75) and those with pT2 disease (OC SCC HR, 0.64; 95% CI, 0.43-0.96; OP SCC HR, 0.56; 95% CI, 0.32-0.95), but there was no association with overall survival among patients 70 years or older (OC SCC HR, 0.78; 95% CI, 0.58-1.06; OP SCC HR, 1.55; 95% CI, 0.63-3.82) and those with pT1 disease (OC SCC HR, 0.80; 95% CI, 0.60-1.07; OP SCC HR, 0.66; 95% CI, 0.35-1.24).PORT may be associated with improved survival in patients with pN1 OC and OP SCC, especially in those younger than 70 years or those with pT2 disease.

  View details for DOI 10.1001/jamaoto.2016.3519

  View details for PubMedID 27832255

• Lymph Node Count From Neck Dissection Predicts Mortality in Head and Neck Cancer JOURNAL OF CLINICAL ONCOLOGY Divi, V., Chen, M. M., Nussenbaum, B., Rhoads, K. F., Sirjani, D. B., Holsinger, F. C., Shah, J. L., Hara, W. 2016; 34 (32): 3892-?

  Abstract

  Multiple smaller studies have demonstrated an association between overall survival and lymph node (LN) count from neck dissection in patients with head and neck cancer. This is a large cohort study to examine these associations by using a national cancer database.The National Cancer Database was used to identify patients who underwent upfront nodal dissection for mucosal head and neck squamous cell carcinoma between 2004 and 2013. Patients were stratified by LN count into those with < 18 nodes and those with ≥ 18 nodes on the basis of prior work. A multivariable Cox proportional hazards regression model was constructed to predict hazard of mortality. Stratified models predicted hazard of mortality both for patients who were both node negative and node positive.There were 45,113 patients with ≥ 18 LNs and 18,865 patients with < 18 LNs examined. The < 18 LN group, compared with the ≥ 18 LN group, had more favorable tumor characteristics, with a lower proportion of T3 and T4 lesions (27.9% v 39.8%), fewer patients with positive nodes (46.6% v 60.5%), and lower rates of extracapsular extension (9.3% v 15.1%). Risk-adjusted Cox models predicting hazard of mortality by LN count showed an 18% increased hazard of death for patients with < 18 nodes examined (hazard ratio [HR] 1.18; 95% CI, 1.13 to 1.22). When stratified by clinical nodal stage, there was an increased hazard of death in both groups (node negative: HR, 1.24; 95% CI, 1.17 to 1.32; node positive: HR, 1.12; 95% CI, 1.05 to 1.19).The results of our study demonstrate a significant overall survival advantage in both patients who are clinically node negative and node positive when ≥ 18 LNs are examined after neck dissection, which suggests that LN count is a potential quality metric for neck dissection.

  View details for DOI 10.1200/JCO.2016.67.3863

  View details for PubMedID 27480149

• Contemporary mandibular reconstruction. Current opinion in otolaryngology & head and neck surgery Divi, V., Schoppy, D. W., Williams, R. A., Sirjani, D. B. 2016; 24 (5): 433-439

  Abstract

  Multiple disease processes, including neoplasia, trauma, and medication side-effects, necessitate segmental resection and subsequent reconstruction of the mandible. As surgical techniques have advanced, several technologies have been developed with the potential to significantly transform a surgeon's approach to the restoration of mandibular continuity. The purpose of this review is to highlight many of these relatively newer tools and discuss their evolving role in mandibular reconstruction.Several contemporary studies have documented the application of different approaches and modifications to mandibular reconstruction - including computer-aided design or computer-aided modeling, contemporary plating systems, osseointegrated implants, and various modifications to existing osseocutaneous free tissue transfer options - and have reported relatively high success rates.In discussing these reports, we present a survey of current and developing technologies in the field of mandibular reconstruction and aim to provide sufficient context for the gradual integration of these techniques into practice.

  View details for DOI 10.1097/MOO.0000000000000284

  View details for PubMedID 27348352

• Faster Triage of Veterans With Head and Neck Cancer. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Kligerman, M., Asaly, A., Kwan, M., Kaplan, M., Fee, W. E., Yuan, A., Benedam-Lenrow, E., Song, Y., Pham, R., Sirjani, D. 2016; 33 (Suppl 5): 24S–29S

  Abstract

  High-risk patients with a growing mass require proper assessment, including a thorough history, physical examination, and fine-needle aspiration for diagnosis.

  View details for PubMedID 30766220

• Ameloblastoma: a clinical review and trends in management EUROPEAN ARCHIVES OF OTO-RHINO-LARYNGOLOGY McClary, A. C., West, R. B., McClary, A. C., Pollack, J. R., Fischbein, N. J., Holsinger, C. F., Sunwoo, J., Colevas, A. D., Sirjani, D. 2016; 273 (7): 1649-1661

  Abstract

  Ameloblastoma is a rare odontogenic neoplasm of the mandible and maxilla, with multiple histologic variants, and high recurrence rates if improperly treated. The current mainstay of treatment is wide local excision with appropriate margins and immediate reconstruction. Here we review the ameloblastoma literature, using the available evidence to highlight the change in management over the past several decades. In addition, we explore the recent molecular characterization of these tumors which may point towards new potential avenues of personalized treatment.

  View details for DOI 10.1007/s00405-015-3631-8

  View details for PubMedID 25926124

• Consultation via telemedicine and access to operative care for patients with head and neck cancer in a Veterans Health Administration population HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Beswick, D. M., Vashi, A., Song, Y., Pham, R., Holsinger, F. C., Rayl, J. D., Walker, B., Chardos, J., Yuan, A., Benadam-Lenrow, E., Davis, D., Sung, C. K., Divi, V., Sirjani, D. B. 2016; 38 (6): 925-929

  Abstract

  The purpose of this study was to evaluate a telemedicine model that utilizes an audiovisual teleconference as a preoperative visit.Veterans Health Administration (VHA) patients with head and neck cancer at 2 remote locations were provided access to the Palo Alto Veterans Affairs (PAVA) Health Care System otolaryngology department via the telemedicine protocol: tissue diagnosis and imaging at the patient site; data review at PAVA; and a preoperative teleconference connecting the patient to PAVA. Operative care occurred at PAVA. Follow-up care was provided remotely via teleconference.Fifteen patients were evaluated. Eleven underwent surgery, 4 with high-grade neoplasms (carcinoma). Average time from referral to operation was 28 days (range, 17-36 days) and 72 (range, 31-108 days), respectively, for high-grade and low-grade groups. The average patient was spared 28 hours traveling time and $900/patient was saved on travel-related costs.A telemedicine model enables timely access to surgical care and permits considerable savings among select VHA patients with head and neck cancer. © 2016 Wiley Periodicals, Inc. Head Neck 38: 925-929, 2016.

  View details for DOI 10.1002/hed.24386

  View details for PubMedID 26899939

• Oral Squamous Cell Carcinoma Mimicking Peri-Implantitis CLINICAL ADVANCES IN PERIODONTICS Chainani-Wu, N., Chang, C., Sim, C., Wu, T. C., Cox, D., Sirjani, D., Silverman, S. 2016; 6 (2): 83–88

  View details for DOI 10.1902/cap.2015.150041

  View details for Web of Science ID 000381742800005

• Oral Squamous Cell Carcinoma Mimicking Peri-Implantitis. Clinical advances in periodontics Chainani-Wu, N., Chang, C., Sim, C., Wu, T. C., Cox, D., Sirjani, D., Silverman, S. 2016; 6 (2): 83-88

  Abstract

  Peri-implantitis is inflammation and alveolar bone loss around a dental implant. Published case reports have described squamous cell carcinoma (SCC) development around dental implants.A 60-year-old female presented with two small fistulas on the alveolar ridge of missing tooth #18. The mucosa around the fistulas appeared normal otherwise, with no hyperplasia, erythema, or keratotic changes. The patient had a 14-year history of recurrent erythroleukoplakia (with microscopic dysplasia) on the left tongue that had been managed by surgical removal (scalpel and carbon dioxide laser), biopsies, and close follow-up. She had no other medical conditions. She reported that she had an implant placed to replace tooth #18 4 years ago that had been removed without flap reflection, curettage, or biopsy 1 year previously as a result of peri-implantitis. Periapical radiographs showed that the peri-implant radiolucency in the region of tooth #18 was unchanged in dimensions from the time of implant removal 1 year ago. Curettage and biopsy of the area were performed and showed the presence of a well-differentiated SCC.This is a case of peri-implant SCC development in a patient at high risk for oral SCC. The carcinoma was present within the alveolar defect in the area of a failed implant that had been removed 1 year previously. The overlying surface mucosa did not show the clinical changes typically seen in carcinoma. This case and others demonstrate the importance of periodic oral and radiographic examination after implant placement. Although rare, neoplasia must be considered in the evaluation of peri-implant pathology.

  View details for DOI 10.1902/cap.2015.150041

  View details for PubMedID 31535489

• Botulinum Toxin Confers Radioprotection in Murine Salivary Glands INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Zeidan, Y. H., Xiao, N., Cao, H., Kong, C., Le, Q., Sirjani, D. 2016; 94 (5): 1190-1197

  Abstract

  Xerostomia is a common radiation sequela, which has a negative impact on the quality of life of patients with head and neck cancer. Current treatment strategies offer only partial relief. Botulinum toxins (BTX) have been successfully used in treating a variety of radiation sequelae such as cystitis, proctitis, fibrosis, and facial pain. The purpose of this study was to evaluate the effect of BTX on radiation-induced salivary gland damage.We used a previously established model for murine salivary gland irradiation (IR). The submandibular glands (SMGs) of C5BL/6 mice (n=6/group) were injected with saline or BTX 72 hours before receiving 15 Gy of focal irradiation. Saliva flow was measured 3, 7, and 28 days after treatment. The SMGs were collected for immunohistochemistry, confocal microscopy, and Western blotting. A cytokine array consisting of 40 different mouse cytokines was used to evaluate cytokine profiles after radiation treatment.Irradiated mice showed a 50% reduction in saliva flow after 3 days, whereas mice preinjected with BTX had 25% reduction in saliva flow (P<.05). Cell death detected by TUNEL staining was similar in SMG sections of both groups. However, neutrophil infiltrate, detected by myeloperoxidase staining, was 3-fold lower for the BTX treated mice. A cytokine array showed a 2-fold upregulation of LPS-induced chemokine (LIX/CXCL5) 3 days after IR. BTX pretreatment reduced LIX levels by 40%. At 4 weeks after IR, the saline (control) group showed a 40% reduction in basal SMG weight, compared with 20% in the BTX group. Histologically, BTX-pretreated glands showed relative preservation of acinar structures after radiation.These data suggest that BTX pretreatment ameliorates radiation-induced saliva dysfunction. Moreover, we demonstrate a novel role for CXCL5 in the acute phase of salivary gland damage after radiation. These results carry important clinical implications for the treatment of xerostomia in patients with head and neck cancer.

  View details for DOI 10.1016/j.ijrobp.2015.12.371

  View details for Web of Science ID 000372564800026

  View details for PubMedCentralID PMC4839970

• Anterolateral approach to the upper cervical spine: Case report and operative technique HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Song, Y., Tharin, S., Divi, V., Prolo, L. M., Sirjani, D. B. 2015; 37 (9): E115-E119

  Abstract

  Transcervical approaches to the upper cervical spine are challenging because several upper anterior neurovascular structures need to be displaced to provide access. Although various techniques have been described, the anterolateral approach is one of the safest and most effective methods available to access the anterior C2-C3 disc space. Despite the approach's efficacy, however, it can cause postoperative complications because of, at least partly, the inter-surgeon differences in the methods by which the larynx and hypopharynx are displaced medially.We present a case report of a patient treated with a modified anterolateral approach to C2-C3. The approach provided excellent visualization while protecting vital structures. The patient recovered without any postoperative dysphagia or other surgical complications.The anterolateral approach to C2-C3 described herein safely protects the contents of the submandibular triangle while providing a wide exposure for direct access to the C2-C3 disc space. © 2015 Wiley Periodicals, Inc. Head Neck 37: E115-E119, 2015.

  View details for DOI 10.1002/hed.23951

  View details for Web of Science ID 000359605700004

  View details for PubMedID 25522016

• CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget Murillo-Sauca, O., Chung, M. K., Shin, J. H., Karamboulas, C., Kwok, S., Jung, Y. H., Oakley, R., Tysome, J. R., Farnebo, L. O., Kaplan, M. J., Sirjani, D., Divi, V., Holsinger, F. C., Tomeh, C., Nichols, A., Le, Q. T., Colevas, A. D., Kong, C. S., Uppaluri, R., Lewis, J. S., Ailles, L. E., Sunwoo, J. B. 2014; 5 (16): 6854-6866

  Abstract

  Tumor-initiating cells (TICs) in squamous cell carcinoma of the head and neck (SCCHN) are best characterized by their surface expression of CD44. Although there is great interest in identifying strategies to target this population, no marker of these cells has been found to be functionally active. Here, we examined the expression of the purported marker of normal human oral epithelial stem cells, CD271. We show that CD271 expression is restricted to a subset of the CD44+ cells. Using xenograft assays, we show that the CD44+CD271+ subpopulation contains the most tumorigenic cells. Loss of CD271 function results in a block in the G2-M phase of the cell cycle and a profound negative impact on the capacity of these cells to initiate tumor formation in vivo. Incubation with recombinant NGF results in enhanced phosphorylation of Erk, providing additional evidence that CD271 is functionally active. Finally, incubation of SCCHN cells with antibody to CD271 results in decreased Erk phosphorylation and decreased tumor formation in vivo. Thus, our data are the first to demonstrate that CD271 more specifically identifies the TIC subpopulation within the CD44+ compartment in SCCHN and that this receptor is a functionally active and targetable molecule.

  View details for PubMedID 25149537

• Neurotrophic factor GDNF promotes survival of salivary stem cells. journal of clinical investigation Xiao, N., Lin, Y., Cao, H., Sirjani, D., Giaccia, A. J., Koong, A. C., Kong, C. S., Diehn, M., Le, Q. 2014; 124 (8): 3364-3377

  Abstract

  Stem cell-based regenerative therapy is a promising treatment for head and neck cancer patients that suffer from chronic dry mouth (xerostomia) due to salivary gland injury from radiation therapy. Current xerostomia therapies only provide temporary symptom relief, while permanent restoration of salivary function is not currently feasible. Here, we identified and characterized a stem cell population from adult murine submandibular glands. Of the different cells isolated from the submandibular gland, this specific population, Lin-CD24+c-Kit+Sca1+, possessed the highest capacity for proliferation, self renewal, and differentiation during serial passage in vitro. Serial transplantations of this stem cell population into the submandibular gland of irradiated mice successfully restored saliva secretion and increased the number of functional acini. Gene-expression analysis revealed that glial cell line-derived neurotrophic factor (Gdnf) is highly expressed in Lin-CD24+c-Kit+Sca1+ stem cells. Furthermore, GDNF expression was upregulated upon radiation therapy in submandibular glands of both mice and humans. Administration of GDNF improved saliva production and enriched the number of functional acini in submandibular glands of irradiated animals and enhanced salisphere formation in cultured salivary stem cells, but did not accelerate growth of head and neck cancer cells. These data indicate that modulation of the GDNF pathway may have potential therapeutic benefit for management of radiation-induced xerostomia.

  View details for DOI 10.1172/JCI74096

  View details for PubMedID 25036711

  View details for PubMedCentralID PMC4109543

• A Novel Aldehyde Dehydrogenase-3 Activator (Alda-89) Protects Submandibular Gland Function from Irradiation without Accelerating Tumor Growth. Clinical cancer research Xiao, N., Cao, H., Chen, C., Kong, C. S., Ali, R., Chan, C., Sirjani, D., Graves, E., Koong, A., Giaccia, A., Mochly-Rosen, D., Le, Q. 2013; 19 (16): 4455-4464

  Abstract

  To determine the effect of Alda-89 (an ALDH3 activitor) on (i) the function of irradiated (radiotherapy) submandibular gland (SMG) in mice, (ii) its toxicity profile, and (iii) its effect on the growth of head and neck cancer (HNC) in vitro and in vivo.Adult mice were infused with Alda-89 or vehicle before, during, and after radiotherapy. Saliva secretion was monitored weekly. Hematology, metabolic profile, and postmortem evaluation for toxicity were examined at the time of sacrifice. Alda-89 or vehicle was applied to HNC cell lines in vitro, and severe combined immunodeficient (SCID) mice transplanted with HNC in vivo with or without radiation; HNC growth was monitored. The ALDH3A1 and ALDH3A2 protein expression was evaluated in 89 patients with HNC and correlated to freedom from relapse (FFR) and overall survival (OS).Alda-89 infusion significantly resulted in more whole saliva production and a higher percentage of preserved acini after radiotherapy compared with vehicle control. There was no difference in the complete blood count, metabolic profile, and major organ morphology between the Alda-89 and vehicle groups. Compared with vehicle control, Alda-89 treatment neither accelerated HNC cell proliferation in vitro, nor did it affect tumor growth in vivo with or without radiotherapy. Higher expression of ALDH3A1 or ALDH3A2 was not significantly associated with worse FFR or OS in either human papillomavirus (HPV)-positive or HPV-negative group.Alda-89 preserves salivary function after radiotherapy without affecting HNC growth or causing measurable toxicity in mice. It is a promising candidate to mitigate radiotherapy-related xerostomia.

  View details for DOI 10.1158/1078-0432.CCR-13-0127

  View details for PubMedID 23812668

• Cost-effectiveness landscape analysis of treatments addressing xerostomia in patients receiving head and neck radiation therapy. Oral surgery, oral medicine, oral pathology and oral radiology Sasportas, L. S., Hosford, D. N., Sodini, M. A., Waters, D. J., Zambricki, E. A., Barral, J. K., Graves, E. E., Brinton, T. J., Yock, P. G., Le, Q., Sirjani, D. 2013; 116 (1): e37-51

  Abstract

  Head and neck (H&N) radiation therapy (RT) can induce irreversible damage to the salivary glands thereby causing long-term xerostomia or dry mouth in 68%-85% of the patients. Not only does xerostomia significantly impair patients' quality-of-life (QOL) but it also has important medical sequelae, incurring high medical and dental costs. In this article, we review various measures to assess xerostomia and evaluate current and emerging solutions to address this condition in H&N cancer patients. These solutions typically seek to accomplish 1 of the 4 objectives: (1) to protect the salivary glands during RT, (2) to stimulate the remaining gland function, (3) to treat the symptoms of xerostomia, or (4) to regenerate the salivary glands. For each treatment, we assess its mechanisms of action, efficacy, safety, clinical utilization, and cost. We conclude that intensity-modulated radiation therapy is both the most widely used prevention approach and the most cost-effective existing solution and we highlight novel and promising techniques on the cost-effectiveness landscape.

  View details for DOI 10.1016/j.oooo.2013.02.017

  View details for PubMedID 23643579

• Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence CANCER Ho, A. S., Tsao, G. J., Chen, F. W., Shen, T., Kaplan, M. J., Colevas, A. D., Fischbein, N. J., Quon, A., Quynh-Thu Le, Q. T., Pinto, H. A., Fee, W. E., Sunwoo, J. B., Sirjani, D., Hara, W., Yao, M. 2013; 119 (7): 1349-1356

  Abstract

  In head and neck cancer (HNC), 3-month post-treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post-treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.A 10-year retrospective analysis of HNC patients was carried out with long-term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3-month scans, 175 had 3- and 12-month scans, and 77 had 3-, 12-, and 24-month scans.PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT-detected and clinically detected recurrences, with similar 3-year disease-free survival (41% vs 46%, P = .91) and 3-year overall survival (60% vs 54%, P = .70) rates. Compared with 3-month PET/CT, 12-month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.HNC patients with negative 3-month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT-detected and clinically detected recurrences, although larger prospective studies are needed for further investigation.

  View details for DOI 10.1002/cncr.27892

  View details for Web of Science ID 000316811900010

• A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272

  Abstract

  To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

  View details for DOI 10.1158/1078-0432.CCR-11-0179

  View details for PubMedID 21998334

• Lefort I Osteotomy access to the Anterior Skull Base Operative Techniques in Otolaryngology Sirjani DB, Futran N. 2010; 21 (1): 22-25