Andrey Finegersh, MD, PhD

All Publications

• Toll-like Receptor Agonists Are Unlikely to Provide Benefits in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Cancers Maddineni, S., Chen, M., Baik, F., Divi, V., Sunwoo, J. B., Finegersh, A. 2023; 15 (17)

  Abstract

  Recurrent and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has poor survival rates. Immunotherapy is the standard of care for R/M HNSCC, but objective responses occur in a minority of patients. Toll-like receptor (TLR) agonists promote antitumor immune responses and have been explored in clinical trials.A search for clinical trials using TLR agonists in HNSCC was performed under PRISMA guidelines. Data on patient characteristics, safety, and efficacy were collected and analyzed.Three phase 1b trials with 40 patients and three phase 2 trials with 352 patients studying TLR8 and TLR9 agonists in combination with other treatment regimens for HNSCC were included. In phase 2 trials, there was no significant change in the objective response rate (RR = 1.13, CI 0.80-1.60) or association with increased grade 3+ adverse events (RR = 0.91, CI 0.76-1.11) associated with TLR agonist use.TLR agonists do not appear to provide additional clinical benefits or increase adverse events in the treatment of HNSCC. Given these results across multiple clinical trials and drug regimens, it is unlikely that additional trials of TLR agonists will demonstrate clinical benefits in HNSCC.

  View details for DOI 10.3390/cancers15174386

  View details for PubMedID 37686661

• 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

• Transoral Surgery in HPV-Positive Oropharyngeal Carcinoma: Oncologic Outcomes in the Veterans Affairs System. The Laryngoscope Faraji, F., Kumar, A., Voora, R., Soliman, S. I., Cherry, D., Courtney, P. T., Finegersh, A., Guo, T., Cohen, E., Califano, J. A., Mell, L., Rose, B., Orosco, R. K. 2023

  Abstract

  OBJECTIVES: Most transoral robotic surgery (TORS) literature for HPV-positive oropharyngeal squamous cell carcinoma (HPV-OPC) derives from high-volume tertiary-care centers. This study aims to describe long-term recurrence and survival outcomes among Veterans Health Administration patients.MATERIALS AND METHODS: Using the US Veterans Affairs database, we identified patients with HPV-OPC treated with TORS between January 2010 and December 2016. Patients were stratified in risk categories: low (0-1 metastatic nodes, negative margins), intermediate (close margins, 2-4 metastatic nodes, lymphovascular or perineural invasion, pT3-pT4 tumor), or high (positive margins, extranodal extension (ENE), and/or ≥5 metastatic nodes). Primary outcomes included overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS).RESULTS: The cohort included 161 patients of which 29 (18%) were low-risk, 45 (28%) intermediate-risk, and 87 (54%) high-risk. ENE was present in 41% of node-positive cases and 24% had positive margins. Median follow-up was 5.6years (95% CI, 3.0-9.3). The 5-year DSS for low, intermediate, and high-risk groups were: 100%, 90.0% (95% CI, 75.4-96.1%), and 88.7% (95% CI, 78.3-94.2%). Pathologic features associated with poor DSS on univariable analysis included pT3-T4 tumors (HR 3.81, 95% CI, 1.31-11; p=0.01), ≥5 metastatic nodes (HR 3.41, 95% CI, 1.20-11; p=0.02), and ENE (HR 3.53, 95% CI, 1.06-12; p=0.04). Higher 5-year cumulative incidences of recurrence were observed in more advanced tumors (pT3-T4, 33% [95% CI, 14-54%] versus pT1-T2, 13% [95% CI, 8-19%]; p=0.01).CONCLUSIONS: In this nationwide study, patients with HPV-OPC treated with TORS followed by adjuvant therapy at Veterans Affairs Medical Centers demonstrated favorable survival outcomes comparable to those reported in high-volume academic centers and clinical trials.LEVEL OF EVIDENCE: 4 Laryngoscope, 2023.

  View details for DOI 10.1002/lary.30784

  View details for PubMedID 37255050

• Local Tumor Behavior Associated With Survival Among Patients With Paraganglioma of the Head and Neck. OTO open Harley, R. J., Lee, J. H., Ostrander, B. T., Finegersh, A., Pham, T. B., Tawfik, K. O., Ren, Y., Faraji, F., Friedman, R. A. 2022; 6 (1): 2473974X221086872

  Abstract

  The purpose of this study was to evaluate the utility of ICD-O-3-classified local tumor behavior as a prognosticator of head and neck paraganglioma (HNP) outcomes.Retrospective cohort study.National Cancer Database between 2004 and 2016.This study included patients aged ≥18 years who were diagnosed with HNP. Clinical outcomes and clinicopathologic features were compared with regard to local tumor behavior.Our study included 525 patients, of which the majority had HNP classified as locally invasive (45.9%) or borderline (37.9%). The most common anatomic sites involved were the carotid body (33.7%), intracranial regions (29.0%), or cranial nerves (25.5%). Carotid body tumors were exclusively locally invasive, whereas intracranial and cranial nerve HNP were overwhelmingly benign or borderline (94% and 91%, respectively). One-fourth of patients underwent pathologic analysis of regional lymph nodes, of which the majority were positive for metastasis (80.6%). Metastasis to distant organs was twice as common in patients with locally invasive tumors vs benign (15% vs 7.1). For benign disease, surgery with radiotherapy (adjusted hazard ratio [aHR], 40.45; P = .006) and active surveillance (aHR, 24.23; P = .008) were associated with worse survival when compared with surgery alone. For locally invasive tumors, greater age (aHR, 1.07; P < .0001) and positive surgical margins (aHR, 4.13; P = .010) were predictors of worse survival, while combined surgery and radiotherapy were predictors of improved survival vs surgery alone (aHR, 0.31; P = .027).While criteria for tumor behavior could not be defined, our results suggest that such a classification system could be used to enhance HNP risk stratification and guide clinical management decisions.

  View details for DOI 10.1177/2473974X221086872

  View details for PubMedID 35571573

  View details for PubMedCentralID PMC9096223

• Circulating tumor DNA in head and neck cancer: Early successes and future promise. Cancer Soo, J., Jin, M. C., Beadle, B. M., Holsinger, F. C., Finegersh, A. 2022

  Abstract

  LAY SUMMARY: The genetic components (DNA) of human papillomavirus-related throat cancer (in the oropharynx) might be measured after surgery to help to predict whether treatment has been successful.

  View details for DOI 10.1002/cncr.34189

  View details for PubMedID 35298053

• Open and endoscopic surgery improve survival for squamous and non-squamous cell nasopharyngeal carcinomas: an NCDB cohort study. International forum of allergy & rhinology Finegersh, A., Said, M., Deconde, A., Hwang, P. H., Holsinger, F. C., Orosco, R. K. 2022

  Abstract

  Nasopharyngeal tumors (NPT) are primarily treated with nonsurgical therapy. Recent studies have demonstrated endoscopic salvage surgery for NPT recurrences may improve survival relative to re-irradiation. However, there is very limited data on open compared to endoscopic approaches for NPT. We investigated whether endoscopic and open surgical approaches to the nasopharynx improve overall survival for all histologic subtypes of NPT.A retrospective cohort study using the National Cancer Database (NCDB) was performed. All adult patients with NPT from 2004 - 2016 without distant metastasis who underwent treatment with curative intent were included. We extracted clinical and treatment variables to assess our primary outcome of overall survival.On univariate analysis, patients undergoing endoscopic surgery but not open surgery had significantly improved overall survival relative to those undergoing nonsurgical treatment. Post hoc analysis demonstrated significantly improved overall survival for surgery in patients with minor salivary gland histology but not squamous cell carcinoma (SCC) histology or by T- or N-classification. A Cox proportional hazards model was used for multivariate regression. After adjusting for covariates, both endoscopic and open approaches were associated with improved overall survival relative to nonsurgical treatment for all tumor types. A multivariate regression of SCC found that open but not endoscopic surgery was significantly associated with improved overall survival.Both endoscopic and open surgical approaches are associated with improved overall survival of patients with NPT. These findings offer important oncologic validity as endoscopic and robotic platforms to the nasopharynx become more widely adopted. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/alr.23000

  View details for PubMedID 35313077

• Quality improvement intervention to reduce time to postoperative radiation in head and neck free flap patients HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Voora, R. S., Stramiello, J. A., Sumner, W. A., Finegersh, A., Mohammadzadeh, A., Fouania, J., Ramsey, C., Blumenfeld, L., Sacco, A. G., Mell, L. K., Califano, J. A., Orosco, R. K. 2021; 43 (11): 3530-3539

  Abstract

  Best-practice guidelines for head and neck cancer patients advise postoperative radiation therapy (PORT) initiation within 6 weeks of surgery. We report our institutional experience improving timeliness of adjuvant radiation in free-flap patients.Thirty-nine patients met inclusion criteria in the 2017-2019 study period. We divided into "Early" (n = 19) and "Late" (n = 20) time-period groups to compare performance over time. The primary endpoint was time to PORT initiation, with success defined as <6 weeks.The number of patients achieving timely PORT improved from 10.5% in the Early group to 50.0% in the Late group (p = 0.014). Patients undergoing concurrent adjuvant chemoradiation were more likely to meet the PORT target in the Late group (p = 0.012).We ascribe this quality improvement in free-flap patients to increased communication among multidisciplinary care teams, proactive consultation referrals, and a targeted patient-navigator intervention. Though work is needed to further improve performance, insight gained from our experience may benefit other teams.

  View details for DOI 10.1002/hed.26852

  View details for Web of Science ID 000693268100001

  View details for PubMedID 34492135

• Robotic surgery may improve overall survival for T1 and T2 tumors of the hypopharynx: An NCDB cohort study. Oral oncology Finegersh, A., Voora, R. S., Panuganti, B., Faraji, F., Christopher Holsinger, F., Brumund, K. T., Coffey, C., Califano, J., Orosco, R. K. 2021; 121: 105440

  Abstract

  BACKGROUND: Hypopharyngeal cancer is associated with poor survival. Robotic surgery is emerging as a treatment for hypopharyngeal tumors, but no rigorous data are available to assess its effect on survival.METHODS: The National Cancer Database (NCDB) was used to identify patients with T1 and T2 hypopharyngeal tumors undergoing robotic surgery, laser surgery, and primary radiation with or without chemotherapy from 2010 to 2016. All adult patients with available staging and no distant metastasis were included.RESULTS: We compared 57 patients undergoing robotic surgery, 236 undergoing laser surgery, and 5,742 undergoing primary radiation. Compared to laser surgery, patients undergoing robotic surgery were significantly more likely to have negative margins, neck dissection, lower incomes, and care at an academic center. Rates of robotic surgery also significantly increased from 2010 to 2015. After multivariate regression, robotic surgery was associated with significantly improved overall survival compared to laser surgery and primary radiation.CONCLUSION: Robotic surgery improves overall survival for T1 and T2 hypopharyngeal tumors compared to laser surgery and primary radiation in this NCDB cohort. This effect may be mediated by decreased positive margin rates relative to laser surgery. Rates of hypopharyngeal robotic surgery are expected to increase with wider adoption of robotic platforms and may improve overall survival rates for hypopharyngeal cancer.

  View details for DOI 10.1016/j.oraloncology.2021.105440

  View details for PubMedID 34329867

• Prognostic Significance of HPV Status in Laryngeal Squamous Cell Carcinoma: A Large-Population Database Study OTOLARYNGOLOGY-HEAD AND NECK SURGERY Panuganti, B. A., Finegersh, A., Flagg, M., Tu, X., Orosco, R., Weissbrod, P. A., Califano, J. 2021; 165 (1): 113-121

  Abstract

  To explore the survival implications of human papillomavirus (HPV) positivity and subtype in larynx cancer through a national cancer database. To investigate staging discrepancies in larynx cancer associated with HPV status.Retrospective observational cohort study.National Cancer Database.Data were extracted concerning adults with known HPV status who were treated between 2010 and 2016 for laryngeal squamous cell carcinoma. Patients without known HPV subtype were excluded. Cox multivariable regression models were fit to evaluate the survival impact of HPV status, characterized as a binary variable (HPV+ vs HPV-) and by subtype. Two- and 5-year survival rates were calculated via the Kaplan-Meier method and compared by stage between the HPV+ and HPV- cohorts per the log-rank test.Patients with HPV+ larynx cancer were younger (60.5 vs 64.3 years, P < .001), more likely to have private insurance (37.2% vs 31.2%, P < .001), more commonly White (84.6% vs 82.4%, P = .013), and more likely to present with nodal disease (42.6% vs 33.0%, P < .001). HPV positivity and HPV subtype 16 were associated with improved overall survival. One-stage discrepancies in 5-year survival were observed between the HPV+ and HPV- cohorts: stage II HPV+ (69.45%) vs stage I HPV- (65.77%); stage IV HPV+ (47.67%) vs stage III HPV- (46.80%).HPV positivity and infection with HPV subtype 16 are correlated with improved overall survival in patients with laryngeal squamous cell carcinoma, manifesting with a 1-stage incremental survival advantage. Future prospective studies are indicated to corroborate the findings from this large-population database retrospective study.

  View details for DOI 10.1177/0194599820976178

  View details for Web of Science ID 000669239300017

  View details for PubMedID 33256521

• Scirrhous carcinoma: A previously undescribed tumor of the oral cavity CLINICAL CASE REPORTS DeVries, J., Finegersh, A., Gold, K. A., Sharabi, A. B., Hu, J., Orosco, R. K. 2021; 9 (5): e03864

  Abstract

  This patient was found to have a scirrhous carcinoma with extensive perineural invasion and without any evidence of minor salivary gland carcinoma. To our knowledge, this is the first report of isolated scirrhous carcinoma of the oral cavity. Treatment was surgery and adjuvant chemoradiation, and there was complete disease response.

  View details for DOI 10.1002/ccr3.3864

  View details for Web of Science ID 000646522200001

  View details for PubMedID 34084475

  View details for PubMedCentralID PMC8142303

• Extrachromosomal DNA in HPV-Mediated Oropharyngeal Cancer Drives Diverse Oncogene Transcription. Clinical cancer research : an official journal of the American Association for Cancer Research Pang, J., Nguyen, N., Luebeck, J., Ball, L., Finegersh, A., Ren, S., Nakagawa, T., Flagg, M., Sadat, S., Mischel, P. S., Xu, G., Fisch, K., Guo, T., Cahill, G., Panuganti, B., Bafna, V., Califano, J. 2021

  Abstract

  Human papillomavirus (HPV) plays a major role in oncogenesis and circular extrachromosomal DNA (ecDNA) is found in many cancers. However, the relationship between HPV and circular ecDNA in human cancer is not understood.Forty-four primary tumor tissue samples were obtained from a cohort of patients with HPV-positive oropharynx squamous cell carcinoma (OPSCC). Twenty-eight additional HPV oropharyngeal cancer (HPVOPC) tumors from The Cancer Genome Atlas (TCGA) project were analyzed as a separate validation cohort. Genomic, transcriptomic, proteomic, computational, and functional analyses of HPVOPC were applied to these datasets.Our analysis revealed circular, oncogenic DNA in nearly all HPVOPC, with circular human and human-viral hybrid ecDNA present in over a third of HPVOPC and viral circular DNA in remaining tumors. Hybrid ecDNA highly express fusion transcripts from HPV promoters and HPV oncogenes linked to downstream human transcripts that drive oncogenic transformation and immune evasion, and splice multiple, diverse human acceptors to a canonical SA880 viral donor site. HPVOPC have high E6*I expression with specific viral oncogene expression pattern related to viral or hybrid ecDNA composition.Nonchromosomal circular oncogenic DNA is a dominant feature of HPVOPC, revealing an unanticipated link between HPV and ecDNA that leverages the power of extrachromosomal inheritance to drive HPV and somatic oncogene expression.

  View details for DOI 10.1158/1078-0432.CCR-21-2484

  View details for PubMedID 34548317

• Immunotherapy in sinonasal melanoma: treatment patterns and outcomes compared to cutaneous melanoma INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Klebaner, D., Saddawi-Konefka, R., Finegersh, A., Yan, C. H., Califano, J. A., London, N. R., Deconde, A. S., Faraji, F. 2020; 10 (9): 1087-1095

  Abstract

  Although treatment with checkpoint blockade is now accepted as standard of care for cutaneous melanoma, few studies have investigated its role in sinonasal melanoma (SNM). We aimed to evaluate whether immunotherapy was associated with improved survival in SNM and to compare the effect of immunotherapy in metastatic sinonasal and cutaneous melanoma.This was a cohort study of patients included in the United States National Cancer Database who had been diagnosed with sinonasal or cutaneous melanoma between 2012 and 2015 and had complete information regarding immunotherapy status. The primary outcome was overall survival. The influence of immunotherapy on overall survival was compared by Kaplan-Meier and Cox proportional hazards models. Propensity score matched analyses between SNM patients who received immunotherapy and those who did not were based on clinicopathological covariates associated with survival in univariate Cox models.The analytic cohort consisted of 704 patients with SNM, 94 of whom were treated with immunotherapy and 152,896 patients with cutaneous melanoma, 8055 of whom were treated with immunotherapy. Immunotherapy was not associated with survival in the propensity-score matched cohort (n = 195; hazard ratio [HR] = 1.0; 95% confidence interval [CI], 0.7 to 1.5; p = 0.88) or in adjusted Cox proportional hazards model (n = 549; HR = 1.0; 95% CI, 0.74 to 1.4; p = 0.88). Regimens including immunotherapy were associated with improved overall survival in metastatic cutaneous melanoma (HR = 0.57; 95% CI, 0.49 to 0.66; p < 0.0001), but not metastatic SNM (HR = 1.1; 95% CI, 0.67 to 1.7; p = 0.75).Compared to current standard of care therapy, inclusion of immunotherapy as first-line therapy was not associated with improved survival in SNM.

  View details for DOI 10.1002/alr.22628

  View details for Web of Science ID 000545258400001

  View details for PubMedID 32623838

• Oral Cavity Cancer Outcomes in Remote, Betel Nut-Endemic Pacific Islands ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY Narayanan, A. M., Finegersh, A. F., Chang, M. P., Orosco, R. K., Moss, W. J. 2020; 129 (12): 1215-1220

  Abstract

  Oral cavity carcinomas individually are the fifth-leading cause of overall cancer mortality in the Northern Mariana Islands, which is likely a representative statistic for many other betel-nut-endemic Pacific islands. Factors associated with survival have been minimally evaluated in this region. The purpose of this study is to further characterize oral cavity carcinoma outcomes and associated prognostic factors in the United States commonwealth of the Northern Mariana Islands (CNMI).A single-institution retrospective review was undertaken for 81 patients diagnosed with head and neck cancers at the CNMI's only regional hospital complex from 2005 to 2019. A subset of patients diagnosed with oral cavity carcinoma was further evaluated for survival outcomes. Cox proportional hazard regressions were performed to evaluate for variables associated with survival.A majority of patients had cancer of the oral cavity (64/81, 79%). Fifty-five of these patients had sufficient data for review. The average age at the time of diagnosis was 48 and over half were diagnosed with stage IV disease (29/55, 53%). Five-year overall survival (OS) was 49.5% (95% CI, 33.3-63.7%). Factors associated with worse OS were lymph node metastases at presentation (P = .031), higher overall stage (III or IV vs I or II, P = .016), and higher T-stage (III or IV vs I or II, P = .027). Those who used betel nut were diagnosed at a significantly younger age than those who did not (47.2 vs 55.4, P = .001).The head and neck cancer burden in the CNMI is dominated by betel nut related oral cavity disease that is characterized by delayed presentations in younger patients and decreased OS. Future studies are indicated to improve health literacy as well as to investigate the potential for screening programs.

  View details for DOI 10.1177/0003489420934846

  View details for Web of Science ID 000542339500001

  View details for PubMedID 32546006

• Meta-analysis of risk of occult lymph node metastasis in the irradiated, clinically N0 neck HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK Finegersh, A., Moss, W. J., Saddawi-Konefka, R., Faraji, F., Coffey, C. S., Califano, J. A., Brumund, K. T., Orosco, R. K. 2020; 42 (9): 2355-2363

  Abstract

  Recurrent head and neck squamous cell carcinoma (HNSCC) after radiation is associated with poor survival, and management of the clinically negative (N0) neck during salvage surgery is controversial.Studies were selected according to preferred reporting items for systematic reviews and meta-analyses guidelines. Inclusion criteria were patients with HNSCC, prior radiation to the lateral neck nodal basin, undergoing salvage surgery for local recurrence, persistence or second primary, and N0 at time of salvage. Eleven studies with a total of 382 patients met inclusion criteria.The rate of occult metastasis was 15.4%. The pooled rate of occult nodal metastasis was 16.2% for oral cavity, 12.9% for oropharynx, 23.7% for hypopharynx, and 27.3% for supraglottic or transglottic tumors. There was a significantly higher relative risk of occult metastasis for locally advanced tumors.Elective neck dissection at time of salvage surgery should be considered based on subsite, T classification, and prior history of nodal metastasis.

  View details for DOI 10.1002/hed.26248

  View details for Web of Science ID 000533668900001

  View details for PubMedID 32432819

• A Survey of Areca (Betel) Nut Use and Oral Cancer in the Commonwealth of the Northern Mariana Islands. Hawai'i journal of health & social welfare Narayanan, A. M., Yogesh, A., Chang, M. P., Finegersh, A., Orosco, R. K., Moss, W. J. 2020; 79 (4): 112-116

  Abstract

  Areca nut use is a cause of higher rates of oral cavity cancer in the Commonwealth of the Northern Mariana Islands (CNMI). Little is known about patient insights into the risks of areca nut use worldwide. The purpose of this study is to evaluate perceptions of areca nut use and oral cancer among chewers in the CNMI. This is a survey study undertaken at the CNMI's only regional health center-300 adult participants completed a 21-question survey that assessed demographics, chewing behaviors, perceptions of areca nut use and oral cancer, and the willingness to participate in cessation and screening programs. Data was analyzed using chi-squared tests, at a significance value of P < .05. The participant average age was 38, and 41% were male. Almost all (92%) knew that chewing areca nut causes oral cancer, but only 13% correctly identified the actual areca nut as a carcinogen. About half (59%) believed that oral cancer could be treated. Most people (74%) were willing to participate in screening programs for oral cancer. Those who chewed areca nut daily were more likely to be interested in medicated replacement products relative to those who chewed less frequently (P = .048). In conclusion, there are drastic misperceptions about areca nut and oral cancer in the CNMI. Efforts should be made towards promoting awareness of the carcinogenicity of the actual areca nut, and the treatability of oral cancer. Mandated educational warnings should be required with areca nut sales. Further research evaluating substitution methods and screening programs is indicated.

  View details for PubMedID 32328582

• Meta-analysis does not support routine traditional nuclear medicine studies for malignant otitis LARYNGOSCOPE Moss, W., Finegersh, A., Narayanan, A., Chan, J. 2020; 130 (7): 1812-1816

  Abstract

  The role of traditional nuclear medicine studies in the management of malignant otitis externa (MOE) is unclear and there are ongoing debates regarding their diagnostic value. The authors perform a systematic review and meta-analysis to assess the sensitivity and specificity of traditional nuclear medicine studies in the diagnosis of MOE.In accordance with PRISMA guidelines, a query of the Medline, Embase, Web of Science, and Cochrane databases was undertaken. The primary outcomes of interest were the sensitivity and specificity of traditional nuclear medicine studies to detect MOE.Of the initial 1317 hits from the four databases, 20 articles with a combined 608 patients were ultimately included in the review. The pooled sensitivities for Technetium-99 and Gallium-67 were 85.1% (95% CI, 72.0-98.1%) and 71.2% (95% CI, 55.1-87.3%) respectively. The available evidence suggested poor specificity of these modalities, but was insufficient for meta-analysis. Neither modality was shown to be effective in the assessment of disease resolution.The sensitivities of Technetium-99 and Gallium-67 to detect MOE are less favorable than was initially thought. Given this finding and their poor specificity, lack of anatomic resolution, unproven ability to detect disease resolution and variable availability, this review does not support the routine use of these studies in the management of MOE.N/A Laryngoscope, 130:1812-1816, 2020.

  View details for DOI 10.1002/lary.28411

  View details for Web of Science ID 000497599100001

  View details for PubMedID 31750969

• The profound oral cavity cancer burden in the United States Commonwealth of the Northern Mariana Islands: A global health opportunity AMERICAN JOURNAL OF OTOLARYNGOLOGY Narayanan, A. M., Finegersh, A., Chang, M. P., Ogo, J., Orosco, R. K., Moss, W. J. 2019; 40 (6): 102267

  Abstract

  Betel nut consumption contributes to higher rates of oral cavity cancer throughout Micronesia. The purpose of this study is to review local surveys and cancer data to further characterize these issues in the Northern Mariana Islands (CNMI).Two commonwealth-wide health inquiries were reviewed: The Non-Communicable Diseases Survey (NCDS), 2016 and The Youth Risk Behavior Survey (YRBS), 2013. Data pertaining to betel nut, tobacco and alcohol use was extracted. Relevant cancer data from the Commonwealth Healthcare Corporation (CHC) of Saipan and the Surveillance, Epidemiology, and End Results (SEER) databases was assessed.Betel nut chewing was reported by 43% of Asian Pacific Islander (API) adults, with 88% adding tobacco to the chew. Adults aged 20-30 had significantly higher rates of chewing relative to older groups (p < .0001). Tobacco smoking and alcohol use were reported by 25% and 23% of adults, respectively. Betel nut chewing was reported by 33% of high school students. From 2007 to 2016, oral cavity cancers contributed to 9% of all cancer diagnoses and 13% of cancer-related mortalities. SEER data supported oral cavity cancer diagnoses at younger ages in APIs.These results demonstrate concerning trends regarding alcohol, tobacco and betel nut use in the CNMI. Betel nut use is prevalent among APIs of nearly all ages, with the majority adding tobacco to their chew. The available data suggests a drastic oral cavity cancer burden in the CNMI. Efforts should be made to evaluate for effective means of primary and secondary prevention in API regions.

  View details for DOI 10.1016/j.amjoto.2019.07.011

  View details for Web of Science ID 000497599400006

  View details for PubMedID 31351740

• Characterizing Posterior Neck Masses: A Single-Institution Retrospective and Systematic Review ENT-EAR NOSE & THROAT JOURNAL Moss, W. J., Finegersh, A., Narayanan, A., Gillard, D., Califano, J., Brumund, K. T., Coffey, C. S., Orosco, R. K. 2021; 100 (5_SUPPL): 766S-770S

  Abstract

  Posterior neck masses are a relatively poorly characterized entity. The authors attempt to further characterize the anatomy and pathology of the posterior neck by way of a combined single-institution retrospective chart review and systematic review of the literature.A single-institution retrospective chart review was undertaken for all patients undergoing excision of a posterior neck mass between January 1, 2012, and January 1, 2017. A systematic review of the Medline, Embase, Web of Science, and Cochrane database was undertaken in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in search of case reports and series describing posterior neck masses.A total of 28 patients who underwent excision of a posterior neck mass were encountered during the retrospective chart review. All pathologies were benign, the most prevalent of which was lipoma (22/28, 79%). A total of 19 articles describing a collective 36 posterior neck masses were encountered during the systematic review. Lipomas were the most common pathology (15/36, 42%). All but one of the masses reported were benign (35/36, 97%).Patients presenting with posterior neck masses can be reassured of a low risk of malignancy. The majority of posterior neck masses can be appropriately evaluated via physical examination and ultrasound.

  View details for DOI 10.1177/0145561319881845

  View details for Web of Science ID 000581645800001

  View details for PubMedID 31608686

• Facial Paralysis Following Core Needle Biopsy of a Deep Lobe Parotid Tumor: A Case Report ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY Moss, W. J., Qualliotine, J. R., Finegersh, A., Brumund, K. T., Coffey, C. S. 2019; 128 (4): 357-359

  Abstract

  To report a case of total facial paralysis as the result of a core needle biopsy.Case report and literature review.A 70-year-old man was diagnosed with a deep lobe parotid tumor on computed tomography. During a core needle biopsy, he developed complete facial paralysis. The cause was discovered to be a direct stab injury to the main trunk of the facial nerve.When biopsying parotid lesions adjacent to the main trunk of the facial nerve, the use of smaller-gauge needles and additional patient counseling should be considered.

  View details for DOI 10.1177/0003489418820886

  View details for Web of Science ID 000461696100012

  View details for PubMedID 30600694

• Robotic Head and Neck Surgery. Surgical oncology clinics of North America Finegersh, A., Holsinger, F. C., Gross, N. D., Orosco, R. K. 2019; 28 (1): 115–28

  Abstract

  Robotic head and neck surgery applies minimally invasive principles to unique anatomy and natural orifices for surgical access. Expanding from a tradition of minimally invasive endoscopic otolaryngology procedures, surgical robotics has transformed head and neck surgery. However, surgeons are faced with significant challenges, and anatomic constraints impede visualization and constrain surgical maneuvers. Transoral robotic surgery (TORS) has been developed over the past decade with favorable oncologic and functional outcomes, changing the way head and neck surgeons approach both malignant and benign diseases. As new robotic platforms emerge, access will continue to improve and push the boundaries of minimally invasive approaches.

  View details for PubMedID 30414677

• Needle Biopsy of Routine Thyroid Nodules Should Be Performed Using a Capillary Action Technique with 24-to 27-Gauge Needles: A Systematic Review and Meta-Analysis THYROID Moss, W. J., Finegersh, A., Pang, J., Califano, J. A., Coffey, C. S., Orosco, R. K., Brumund, K. T. 2018; 28 (7): 857-863

  Abstract

  Fine-needle biopsy is the international standard for diagnostic evaluation of thyroid nodules. There is a lack of consensus regarding the optimal needle biopsy technique. The implementation of capillary action versus aspiration and the optimal needle gauge remain topics of debate.A systematic review of the Medline, Embase, and Cochrane databases was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Articles evaluating the effects of capillary action versus aspiration and needle gauge on success rates of fine-needle biopsy of the thyroid were assessed for inclusion. The primary outcome of interest was the rate of non-diagnostic cytopathology.Twenty-four articles with a collective 4428 nodules were ultimately included in the review. Twenty articles evaluated capillary action versus aspiration, and six evaluated needle gauge. All but two studies were prospective, most of which were blinded trials with or without randomization. Using a random-effects model, capillary action was associated with a statistically significant reduction in the relative risk of non-diagnostic cytopathology (relative risk = 0.57 [confidence interval 0.34-0.92]; p = 0.02). There was a nonsignificant trend in favor of smaller needle gauges.Given the statistically significant deceased rate of non-diagnostic cytopathology with capillary action and the potential for increased pain and complications with larger needles without a proven benefit, needle biopsy of routine thyroid nodules should be performed without aspiration and with smaller needle gauges (24-27G).

  View details for DOI 10.1089/thy.2017.0643

  View details for Web of Science ID 000434363500001

  View details for PubMedID 29742978

• Isolated sphenoid sinus opacifications: a systematic review and meta-analysis INTERNATIONAL FORUM OF ALLERGY & RHINOLOGY Moss, W. J., Finegersh, A., Jafari, A., Panuganti, B., Coffey, C. S., DeConde, A., Husseman, J. 2017; 7 (12): 1201-1206

  Abstract

  Isolated sphenoid sinus opacifications (ISSOs) represent a relatively uncommon disease with the potential for serious complications. To better understand this disease, we performed a systematic review to further characterize the underlying pathologies, associated symptoms, and treatment outcomes of patients with ISSOs.A systematic review of ISSO case series was performed utilizing the Medline, Embase, Web of Science, and Cochrane databases in accordance with guidelines established by PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Data of interest included disease pathology, associated symptoms, and treatment outcomes.Of the initial 1051 hits from the 4 databases, 17 articles, with a combined 1133 ISSO patients, were ultimately included in the review. On a weighted analysis, the underlying pathologies were classified as chronic rhinosinusitis without nasal polyps (CRSsNP) (28.3%), mucoceles (20.3%), fungal sinusitis (12.5%), malignant neoplasms (7.7%), intracranial lesions (7.0%), benign neoplasms (5.7%), chronic rhinosinusitis with nasal polyps (CRSwNP) (3.4%), and other lesions (4.7%). Cranial neuropathies were present in 16.3% (95% confidence interval [CI], 10.1-22.5%) of ISSO patients. A favorable surgical complication rate of 1.5% (95% CI, -0.1% to 3.2%) was found in patients undergoing surgery for an ISSO.ISSOs are caused by diverse pathologies. Given the considerable rates of neoplastic disease and cranial neuropathies, patients affected by an ISSO should be monitored closely and treated aggressively. Prompt surgical intervention, with either diagnostic or therapeutic intent, is often indicated.

  View details for DOI 10.1002/alr.22023

  View details for Web of Science ID 000417284900014

  View details for PubMedID 29024448

• DNA methylation regulates TMEM16A/ANO1 expression through multiple CpG islands in head and neck squamous cell carcinoma SCIENTIFIC REPORTS Finegersh, A., Kulich, S., Guo, T., Favorov, A. V., Fertig, E. J., Danilova, L. V., Gaykalova, D. A., Califano, J. A., Duvvuri, U. 2017; 7: 15173

  Abstract

  ANO1 is a calcium-activated chloride channel that is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and other cancers. While ANO1 expression negatively correlates with survival in several cancers, its epigenetic regulation is poorly understood. We analyzed HNSCC samples from TCGA and a separate dataset of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) samples to identify differentially methylated regions. E6 and E7 transfected normal oral keratinocytes (NOK) were used to induce hypermethylation of the ANO1 promoter. We found three CpG islands that correlated with ANO1 expression, including two positively correlated with expression. Using two HNSCC datasets with differential expression of ANO1, we showed hypermethylation of positively correlated CpG islands potentiates ANO1 expression. E7 but not E6 transfection of NOK cells led to hypermethylation of a positively correlated CpG island without a change in ANO1 expression. ANO1 promoter methylation was also correlated with patient survival. Our results are the first to show the contribution of positively correlated CpG's for regulating gene expression in HNSCC. Hypermethylation of the ANO1 promoter was strongly correlated with but not sufficient to increase ANO1 expression, suggesting methylation of positively correlated CpG's likely serves as an adjunct to other mechanisms of ANO1 activation.

  View details for DOI 10.1038/s41598-017-15634-9

  View details for Web of Science ID 000414810600056

  View details for PubMedID 29123240

  View details for PubMedCentralID PMC5680248

• Paternal preconception alcohol exposure imparts intergenerational alcohol-related behaviors to male offspring on a pure C57BL/6J background ALCOHOL Rompala, G. R., Finegersh, A., Slater, M., Homanics, G. E. 2017; 60: 169-177

  Abstract

  While alcohol use disorder (AUD) is a highly heritable condition, the basis of AUD in families with a history of alcoholism is difficult to explain by genetic variation alone. Emerging evidence suggests that parental experience prior to conception can affect inheritance of complex behaviors in offspring via non-genomic (epigenetic) mechanisms. For instance, male C57BL/6J (B6) mice exposed to chronic intermittent vapor ethanol (CIE) prior to mating with Strain 129S1/SvImJ ethanol-naïve females produce male offspring with reduced ethanol-drinking preference, increased ethanol sensitivity, and increased brain-derived neurotrophic factor (BDNF) expression in the ventral tegmental area (VTA). In the present study, we tested the hypothesis that these intergenerational effects of paternal CIE are reproducible in male offspring on an inbred B6 background. To this end, B6 males were exposed to 6 weeks of CIE (or room air as a control) before mating with ethanol-naïve B6 females to produce ethanol (E)-sired and control (C)-sired male and female offspring. We observed a sex-specific effect, as E-sired males exhibited decreased two-bottle free-choice ethanol-drinking preference, increased sensitivity to the anxiolytic effects of ethanol, and increased VTA BDNF expression; no differences were observed in female offspring. These findings confirm and extend our previous results by demonstrating that the effects of paternal preconception ethanol are reproducible using genetically identical, inbred B6 animals.

  View details for DOI 10.1016/j.alcohol.2016.11.001

  View details for Web of Science ID 000401205300017

  View details for PubMedID 27876231

  View details for PubMedCentralID PMC5419883

• Paternal preconception ethanol exposure blunts hypothalamic-pituitary-adrenal axis responsivity and stress-induced excessive fluid intake in male mice ALCOHOL Rompala, G. R., Finegersh, A., Homanics, G. E. 2016; 53: 19-25

  Abstract

  A growing number of environmental insults have been shown to induce epigenetic effects that persist across generations. For instance, paternal preconception exposures to ethanol or stress have independently been shown to exert such intergenerational effects. Since ethanol exposure is a physiological stressor that activates the hypothalamic-pituitary-adrenal (HPA) axis, we hypothesized that paternal ethanol exposure would impact stress responsivity of offspring. Adult male mice were exposed to chronic intermittent vapor ethanol or control conditions for 5 weeks before being mated with ethanol-naïve females to produce ethanol (E)- and control (C)-sired offspring. Adult male and female offspring were tested for plasma corticosterone (CORT) levels following acute restraint stress and the male offspring were further examined for stress-evoked 2-bottle choice ethanol-drinking. Paternal ethanol exposure blunted plasma CORT levels following acute restraint stress selectively in male offspring; females were unaffected. In a stress-evoked ethanol-drinking assay, there was no effect of stress on ethanol consumption. However, C-sired males exhibited increased total fluid intake (polydipsia) in response to stress while E-sired males were resistant to this stress-induced phenotype. Taken together, these data suggest that paternal ethanol exposure imparts stress hyporesponsivity to male offspring.

  View details for DOI 10.1016/j.alcohol.2016.03.006

  View details for Web of Science ID 000378015100003

  View details for PubMedID 27286933

  View details for PubMedCentralID PMC4904231

• Chromatin immunoprecipitation and gene expression analysis of neuronal subtypes after fluorescence activated cell sorting JOURNAL OF NEUROSCIENCE METHODS Finegersh, A., Homanics, G. E. 2016; 263: 81-88

  Abstract

  With advances in cell capture, gene expression can now be studied in neuronal subtypes and single cells; however, studying epigenetic mechanisms that underlie these changes presents challenges. Moreover, chromatin immunoprecipitation (ChIP) protocols optimized for low cell number do not adequately address technical issues and cell loss while preparing tissue for fluorescence activated cell sorting (FACS). Developing a reliable FACS-ChIP protocol without the need for pooling tissue from multiple animals would enable study of epigenetic mechanisms in neuronal subtypes.FACS was used to isolate dopamine 1 receptor (D1R) expressing cells from the nucleus accumbens (NAc) of a commercially available BAC transgenic mouse strain. D1R+ cells were used to study gene expression as well as histone modifications at gene promoters using a novel native ChIP protocol.Isolated cells had enrichment of the dopamine 1 receptor (D1R) mRNA and nearly undetectable levels of GFAP and D2R mRNA. ChIP analysis demonstrated the association of activating or repressive histone modifications with highly expressed or silent gene promoters, respectively.The ChIP protocol developed in this paper enables characterization of histone modifications from ∼30,000 FAC-sorted neurons.We describe a one day FACS-ChIP protocol that can be applied to epigenetic studies of neuronal subtypes without pooling tissue.

  View details for DOI 10.1016/j.jneumeth.2016.02.006

  View details for Web of Science ID 000374199500010

  View details for PubMedID 26868730

  View details for PubMedCentralID PMC4801782

• Repeated vapor ethanol exposure induces transient histone modifications in the brain that are modified by genotype and brain region FRONTIERS IN MOLECULAR NEUROSCIENCE Finegersh, A., Ferguson, C., Maxwell, S., Mazariegos, D., Farrell, D., Homanics, G. E. 2015; 8: 39

  Abstract

  Emerging research implicates ethanol (EtOH)-induced epigenetic modifications in regulating gene expression and EtOH consumption. However, consensus on specific epigenetic modifications induced by EtOH has not yet emerged, making it challenging to identify mechanisms and develop targeted treatments. We hypothesized that chronic intermittent EtOH (CIE) induces persistent changes in histone modifications across the cerebral cortex (CCx), nucleus accumbens (NAc), and prefrontal cortex (PFC), and that these histone modifications are altered in a knock-in mouse strain with altered sensitivity to EtOH.C57BL/6J (B6) mice and α1SHLA knockin mice on a B6 background were exposed to 16 h of vapor EtOH or room air followed by 8 h of room air for 4 consecutive days and sacrificed at multiple time points up to 72 h following exposure. Histone modifications were assessed using Western blot and dot blot. RT-qPCR was used to study expression of chromatin modifying enzymes in NAc and PFC.In NAc, CIE significantly increased acetylation of histone subunit H3 at lysine 9 (H3K9ac) but not lysine 14 (H3K14ac) or lysine 27 (H3K27ac). In PFC, CIE significantly increased H3K9ac but not H3K14 or H3K27ac. There were no significant changes at 8 or 72 h after EtOH exposure in either NAc or PFC. CIE was also associated with increased expression of Kat2b, Kat5, and Tet1 in NAc but not PFC. In CCx, CIE had a significant effect on levels of H3K18ac; there was also a significant effect of the α1SHLA mutation on levels of H3K27me3, H3K14ac, and H3K18ac as well as a trend for H3S10pK14ac.The EtOH-induced histone modifications observed were transient and varied significantly between brain regions. A genetic mutation that altered sensitivity to EtOH was associated with altered induction of histone modifications during CIE. These results have implications for studying EtOH-induced histone modifications and EtOH sensitivity.

  View details for DOI 10.3389/fnmol.2015.00039

  View details for Web of Science ID 000370541300001

  View details for PubMedID 26300722

  View details for PubMedCentralID PMC4524924

• Drinking beyond a lifetime: New and emerging insights into paternal alcohol exposure on subsequent generations ALCOHOL Finegersh, A., Rompala, G. R., Martin, D. K., Homanics, G. E. 2015; 49 (5): 461-470

  Abstract

  Alcohol-use disorder (AUD) is prevalent and associated with substantial socioeconomic costs. While heritability estimates of AUD are ∼50%, identifying specific gene variants associated with risk for AUD has proven challenging despite considerable investment. Emerging research into heritability of complex diseases has implicated transmission of epigenetic variants in the development of behavioral phenotypes, including drug preference and drug-induced behavior. Several recent rodent studies have specifically focused on paternal transmission of epigenetic variants, which is especially relevant because sires are not present for offspring rearing and changes to offspring phenotype are assumed to result from modifications to the sperm epigenome. While considerable interest in paternal transmission of epigenetic variants has emerged recently, paternal alcohol exposures have been studied for 30+ years with interesting behavioral and physiologic effects noted on offspring. However, only recently, with improvements in technology to identify epigenetic modifications in germ cells, has it been possible to identify mechanisms by which paternal ethanol exposure alters offspring behavior. This review presents an overview of epigenetic inheritance in the context of paternal ethanol exposure and suggests future studies to identify specific effects of paternal ethanol exposure on offspring behavior and response to ethanol.

  View details for DOI 10.1016/j.alcohol.2015.02.008

  View details for Web of Science ID 000356907200003

  View details for PubMedID 25887183

  View details for PubMedCentralID PMC4469624

• Acute Ethanol Alters Multiple Histone Modifications at Model Gene Promoters in the Cerebral Cortex ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH Finegersh, A., Homanics, G. E. 2014; 38 (7): 1865-1873

  Abstract

  Ethanol (EtOH) exposure alters gene expression in the cerebral cortex (CCx); however, mechanisms of EtOH-induced gene regulation are not well understood. We hypothesized that EtOH regulates gene expression by differentially altering histone modifications at gene promoters that are up- and down-regulated by EtOH. Such epigenetic mechanisms may ultimately contribute to EtOH-induced neuro-adaptations that underlie tolerance, dependence, and EtOH-use disorders.Eight-week-old, male C57BL/6J mice were treated with 3 g/kg EtOH (intraperitoneally) or saline and sacrificed 6 hours after injection; the CCx and hippocampus (HC) were immediately removed and flash frozen. Chromatin immunoprecipitation was used to study the association of model gene promoters with histone modifications. Western blot was used to detect global changes in the histone modifications studied. We also used a polymerase chain reaction (PCR) array to identify changes in expression of chromatin-modifying enzymes.In CCx, acute EtOH decreased expression of Gad1, Hdac2, and Hdac11, which was associated with decreased histone acetylation at the Gad1 and Hdac2 promoters; we also identified increased expression of Mt1, Mt2, Egr1, which was associated with increased H3K4me3 levels at the Mt2 promoter and decreased H3K27me3 levels at the Mt1 promoter. We identified an increase in global levels of H3K4me3 in CCx as well as a global increase in H3K9ac and H3K14ac in HC. The PCR array identified decreased expression of Csrp2 bp, Hdac2, and Hdac11 as well as increased expression of Kat2b in CCx.Acute EtOH induces chromatin remodeling at model up- and down-regulated genes in CCx. Different patterns of histone modifications at these gene promoters indicate that EtOH may be acting through multiple histone-modifying enzymes to alter gene expression; in particular, differential expression of Kat2b, Hdac2, Hdac11, and Csrp2 bp in CCx may mediate EtOH-induced chromatin remodeling. Additional studies are necessary to determine the relationship between EtOH-induced changes in histone-modifying enzymes, specific EtOH-induced histone modifications, and gene expression.

  View details for DOI 10.1111/acer.12465

  View details for Web of Science ID 000340597600008

  View details for PubMedID 24942484

  View details for PubMedCentralID PMC4107049

• Paternal Alcohol Exposure Reduces Alcohol Drinking and Increases Behavioral Sensitivity to Alcohol Selectively in Male Offspring PLOS ONE Finegersh, A., Homanics, G. E. 2014; 9 (6): e99078

  Abstract

  Alcohol use disorder (AUD) is heritable, but the genetic basis for this disease remains poorly understood. Although numerous gene variants have been associated with AUD, these variants account for only a small fraction of the total risk. The idea of inheritance of acquired characteristics, i.e. "epigenetic inheritance," is re-emerging as a proven adjunct to traditional modes of genetic inheritance. We hypothesized that alcohol drinking and neurobiological sensitivity to alcohol are influenced by ancestral alcohol exposure. To test this hypothesis, we exposed male mice to chronic vapor ethanol or control conditions, mated them to ethanol-naïve females, and tested adult offspring for ethanol drinking, ethanol-induced behaviors, gene expression, and DNA methylation. We found that ethanol-sired male offspring had reduced ethanol preference and consumption, enhanced sensitivity to the anxiolytic and motor-enhancing effects of ethanol, and increased Bdnf expression in the ventral tegmental area (VTA) compared to control-sired male offspring. There were no differences among ethanol- and control-sired female offspring on these assays. Ethanol exposure also decreased DNA methylation at the BdnfÆpromoter of sire's germ cells and hypomethylation was maintained in the VTA of both male and female ethanol-sired offspring. Our findings show that paternal alcohol exposure is a previously unrecognized regulator of alcohol drinking and behavioral sensitivity to alcohol in male, but not female, offspring. Paternal alcohol exposure also induces epigenetic alterations (DNA hypomethylation) and gene expression changes that persist in the VTA of offspring. These results provide new insight into the inheritance and development of alcohol drinking behaviors.

  View details for DOI 10.1371/journal.pone.0099078

  View details for Web of Science ID 000338430700114

  View details for PubMedID 24896617

  View details for PubMedCentralID PMC4045990

• The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy NEUROLOGY Martinez, A., Finegersh, A., Cannon, D. M., Dustin, I., Nugent, A., Herscovitch, P., Theodore, W. H. 2013; 80 (16): 1465-1471

  Abstract

  To study 5-HT transport and 5-HT1A receptors in temporal lobe epilepsy (TLE) and depression.Thirteen patients had PET with [(11)C]DASB for 5-HTT and [(18)F]FCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [(11)C]DASB, 19 had [(18)F]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [(11)C]DASB binding. [(18)F]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci.Mean regional [(11)C]DASB binding and asymmetry did not differ between patients and controls. [(18)F]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [(11)C]DASB asymmetry, with significantly higher [(11)C]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [(18)F]FCWAY asymmetry and [(11)C]DASB asymmetry.Our study showed increased [(11)C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression.

  View details for DOI 10.1212/WNL.0b013e31828cf809

  View details for Web of Science ID 000318606300008

  View details for PubMedID 23516322

  View details for PubMedCentralID PMC3662359

• Bilateral hippocampal atrophy in temporal lobe epilepsy: Effect of depressive symptoms and febrile seizures EPILEPSIA Finegersh, A., Avedissian, C., Shamim, S., Dustin, I., Thompson, P. M., Theodore, W. H. 2011; 52 (4): 689-697

  Abstract

  Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE).We used radial atrophy mapping (RAM), a three-dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy.Subjects with a history of febrile seizures (n =15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI-II) score ≥ 14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI-II <14 (n = 29).Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression.

  View details for DOI 10.1111/j.1528-1167.2010.02928.x

  View details for Web of Science ID 000289156700007

  View details for PubMedID 21269286

  View details for PubMedCentralID PMC3071425

• fMRI language dominance and FDG-PET hypometabolism NEUROLOGY Gaillard, W. D., Berl, M. M., Duke, E. S., Ritzl, E., Miranda, S., Liew, C., Finegersh, A., Martinez, A., Dustin, I., Sato, S., Theodore, W. H. 2011; 76 (15): 1322-1329

  Abstract

  Atypical language dominance is common in patients with temporal lobe epilepsy. We examined the association of left temporal hypometabolism with laterality of fMRI activation in a language task in a cross-sectional study.Thirty patients with temporal lobe epilepsy (mean age 32.4 ± 11.0 years [range 18-55]; epilepsy onset 15.3 ± 11.3 years [range 0.8-40]; 22 left focus, 8 right focus) had (18)fluoro-deoxyglucose (FDG)-PET using noninvasive cardiac input function. After MRI-based partial volume correction, regional glucose metabolism (CMRglc) was measured and asymmetry index, AI = 2(l - R)/(L + R), calculated. fMRI language dominance was assessed with an auditory definition decision paradigm at 3 T. fMRI data were analyzed in SPM2 using regions of interest from Wake Forest PickAtlas (Wernicke area [WA], inferior frontal gyrus [IFG], middle frontal gyrus [MFG]) and bootstrap laterality index, LI = (l - R/L + R).Nineteen patients had ipsilateral temporal hypometabolism; 3 of 4 patients with atypical language had abnormal FDG-PET. Increasing left midtemporal hypometabolism correlated with decreased MFG LI (r = -0.41, p < 0.05) and showed trends with WA LI (r = -0.37, p = 0.055) and IFG LI (r = -0.31, p = 0.099); these relationships became more significant after controlling for age at onset. Increasing hypometabolism was associated with fewer activated voxels in WA ipsilateral to the focus and more activated voxels contralaterally, but overall, activation amount in left WA was similar to subjects without left temporal hypometabolism (t = -1.39, p > 0.10).We did not find evidence of impaired blood oxygenation level-dependent response in hypometabolic cortex. Regional hypometabolism appears to be a marker for the temporal lobe dysfunction that leads to displacement of language function.

  View details for DOI 10.1212/WNL.0b013e31821527b5

  View details for Web of Science ID 000289407100010

  View details for PubMedID 21368285

  View details for PubMedCentralID PMC3090059

• Cerebellar Atrophy in Human and Murine Succinic Semialdehyde Dehydrogenase Deficiency JOURNAL OF CHILD NEUROLOGY Acosta, M. T., Munasinghe, J., Pearl, P. L., Gupta, M., Finegersh, A., Gibson, K., Theodore, W. H. 2010; 25 (12): 1457-1461

  Abstract

  Human succinic semialdehyde dehydrogenase deficiency, an autosomal recessive disorder of γ-aminobutyric acid (GABA) catabolism, was modeled by a murine model sharing the phenotype of ataxia and seizures. Magnetic resonance imaging (MRI) with volumetry was obtained on 7 patients versus controls, and MRI with stereology was derived in 3 murine genotypes: null, wild-type, and heterozygous mutants. All patients had T1 hypointensity and T2 hyperintensity in globus pallidus, and 5 also had similar changes in subthalamic and cerebellar dentate nuclei. There was a trend for patients to have a smaller cerebellar vermis. Homozygous null mice had significantly lower total brain and cerebellar volumes than wild-types and heterozygotes. Stereology confirmed cerebellar atrophy and was otherwise normal in multiple regions. Cerebellar volume loss is present in the murine disorder with a trend for cerebellar atrophy in patients. Reduced cerebellar volume can reflect neurodegeneration and may be related to the clinical manifestations.

  View details for DOI 10.1177/0883073810368137

  View details for Web of Science ID 000285147100001

  View details for PubMedID 20445195

  View details for PubMedCentralID PMC3155424