All Publications

  • A narrative review of fluorescence imaging in robotic-assisted surgery. Laparoscopic surgery Lee, Y., van den Berg, N. S., Orosco, R. K., Rosenthal, E. L., Sorger, J. M. 2021; 5


    Objective: In this review, we provide examples of applications of fluorescence imaging in urologic, gynecologic, general, and endocrine surgeries.Background: While robotic-assisted surgery has helped increase the availability of minimally invasive procedures across surgical specialties, there remains an opportunity to reduce adverse events associated with open, laparoscopic, and robotic-assisted methods. In 2011, fluorescence imaging was introduced as an option to the da Vinci Surgical System, and has been standard equipment since 2014. Without interfering with surgical workflow, this fluorescence technology named Firefly allows for acquisition and display of near-infrared fluorescent signals that are co-registered with white light endoscopic images. As a result, robotic surgeons of all specialties have been able to explore the clinical utility of fluorescence guided surgery.Methods: Literature searches were performed using the PubMed and MEDLINE databases using the keywords "robotic-assisted fluorescence surgery", "ICG robotic surgery", and "fluorescence guided surgery" covering the years 2011-2020.Conclusions: Real-time intraoperative fluorescence guidance has shown great potential in helping guide surgeons in both simple and complex surgical interventions. Indocyanine green is one of the most widely-used imaging agents in fluorescence guided surgery, and other targeted, near-infrared imaging agents are in various stages of development. Fluorescence is becoming a reliable tool that can help surgeons in their decision-making process in some specialties, while explorations continue in others.

    View details for DOI 10.21037/ls-20-98

    View details for PubMedID 34549180

  • Intraoperative Fluorescence-Guided Surgery in Head and Neck Squamous Cell Carcinoma. The Laryngoscope Lee, Y. J., Krishnan, G., Nishio, N., van den Berg, N. S., Lu, G., Martin, B. A., van Keulen, S., Colevas, A. D., Kapoor, S., Liu, J. T., Rosenthal, E. L. 2021; 131 (3): 529-534


    The rate of positive margins in head and neck cancers has remained stagnant over the past three decades and is consistently associated with poor overall survival. This suggests that significant improvements must be made intraoperatively to ensure negative margins. We discuss the important role of fluorescence imaging to guide surgical oncology in head and neck cancer. This review includes a general overview of the principles of fluorescence, available fluorophores used for fluorescence imaging, and specific clinical applications of fluorescence-guided surgery, as well as challenges and future directions in head and neck surgical oncology. Laryngoscope, 131:529-534, 2021.

    View details for DOI 10.1002/lary.28822

    View details for PubMedID 33593036

  • Endoscopic vs. Microscopic Resection of Sellar Lesions-A Matched Analysis of Clinical and Socioeconomic Outcomes. Frontiers in surgery Azad, T. D., Lee, Y. J., Vail, D. n., Veeravagu, A. n., Hwang, P. H., Ratliff, J. K., Li, G. n. 2017; 4: 33


    Direct comparisons of microscopic and endoscopic resection of sellar lesions are scarce, with conflicting reports of cost and clinical outcome advantages.To determine if the proposed benefits of endoscopic resection are realized on a population level.We performed a matched cohort study of 9,670 adult patients in the MarketScan database who underwent either endoscopic or microscopic surgery for sellar lesions. Coarsened matching was applied to estimate the effects of surgical approach on complication rates, length of stay (LOS), costs, and likelihood of postoperative radiation.We found that LOS, readmission, and revision rates did not differ significantly between approaches. The overall complication rate was higher for endoscopy (47% compared to 39%, OR 1.37, 95% CI 1.22-1.53). Endoscopic approach was associated with greater risk of neurological complications (OR 1.32, 95% CI 1.11-1.55), diabetes insipidus (OR 1.65, 95% CI 1.37-2.00), and cerebrospinal fluid rhinorrhea (OR 1.83, 95% CI 1.07-3.13) compared to the microscopic approach. Although the total index payment was higher for patients receiving endoscopic resection ($32,959 compared to $29,977 for microscopic resection), there was no difference in long-term payments. Endoscopic surgery was associated with decreased likelihood of receiving post-resection stereotactic radiosurgery (OR 0.67, 95% CI 0.49-0.90) and intensity-modulated radiation therapy (OR 0.78, 95% CI 0.65-0.93).Our results suggest that the transition from a microscopic to endoscopic approach to sellar lesions must be subject to careful evaluation. Although there are evident advantages to transsphenoidal endoscopy, our analysis suggests that the benefits of the endoscopic approach are yet to be materialized.

    View details for PubMedID 28691009

  • Building operative care capacity in a resource limited setting: The Mongolian model of the expansion of sustainable laparoscopic cholecystectomy SURGERY Wells, K. M., Lee, Y., Erdene, S., Erdene, S., Sanchin, U., Sergelen, O., Zhang, C., Rodriguez, B. P., deVries, C. R., Price, R. R. 2016; 160 (2): 509-517


    The benefits of laparoscopic cholecystectomy, including rapid recovery and fewer infections, have been largely unavailable to the majority of people in developing countries. Compared to other countries, Mongolia has an extremely high incidence of gallbladder disease. In 2005, only 2% of cholecystectomies were performed laparoscopically. This is a retrospective review of the transition from open to laparoscopic cholecystectomy throughout Mongolia.A cross-sectional, retrospective review was conducted of demographic patient data, diagnosis type, and operation performed (laparoscopic versus open cholecystectomy) from 2005-2013. Trends were analyzed from 6 of the 21 provinces (aimags) throughout Mongolia, and data were culled from 7 regional diagnostic referral and treatment centers and 2 tertiary academic medical centers. The data were analyzed by individual training center and by year before being compared between rural and urban centers.We analyzed and compared 14,522 cholecystectomies (n = 4,086 [28%] men, n = 10,436 [72%] women). Men and women were similar in age (men 52.2, standard deviation 14.8; women 49.4, standard deviation 15.7) and in the percentage undergoing laparoscopic cholecystectomy (men 39%, women 42%). By 2013, 58% of gallbladders were removed laparoscopically countrywide compared with only 2% in 2005. In 2011, laparoscopic cholecystectomy surpassed open cholecystectomy as the primary method for gallbladder removal countrywide. More than 315 Mongolian health care practitioners received laparoscopic training in 19 of the country's 21 aimags (states).By 2013, 58% of cholecystectomies countrywide were performed laparoscopically, a dramatic increase over 9 years. The expansion of laparoscopic cholecystectomy has transformed the care of biliary tract disease in Mongolia despite the country's limited resources.

    View details for DOI 10.1016/j.surg.2016.04.001

    View details for Web of Science ID 000379888000029

    View details for PubMedID 27238353

  • Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA-the journal of the American Medical Association Osinusi, A., Meissner, E. G., Lee, Y., Bon, D., Heytens, L., Nelson, A., Sneller, M., Kohli, A., Barrett, L., Proschan, M., Herrmann, E., Shivakumar, B., Gu, W., Kwan, R., Teferi, G., Talwani, R., Silk, R., Kotb, C., Wroblewski, S., Fishbein, D., Dewar, R., Highbarger, H., Zhang, X., Kleiner, D., Wood, B. J., Chavez, J., Symonds, W. T., Subramanian, M., McHutchison, J., Polis, M. A., Fauci, A. S., Masur, H., Kottilil, S. 2013; 310 (8): 804-811


    The efficacy of directly acting antiviral agents in interferon-free regimens for the treatment of chronic hepatitis C infections needs to be evaluated in different populations.To determine the efficacy and safety of sofosbuvir with weight-based or low-dose ribavirin among a population with unfavorable treatment characteristics.Single-center, randomized, 2-part, open-label phase 2 study involving 60 treatment-naive patients with hepatitis C virus (HCV) genotype 1 enrolled at the National Institutes of Health (October 2011-April 2012).In the study's first part, 10 participants with early to moderate liver fibrosis were treated with 400 mg/d of sofosbuvir and weight-based ribavirin for 24 weeks. In the second part, 50 participants with all stages of liver fibrosis were randomized 1:1 to receive 400 mg of sofosbuvir with either weight-based or low-dose 600 mg/d of ribavirin for 24 weeks.The primary study end point was the proportion of participants with undetectable HCV viral load 24 weeks after treatment completion (sustained virologic response of 24 weeks [SVR24]).In the first part of the study, 9 participants (90%; 95% CI, 55%-100%) achieved SVR24. In the second part, 7 participants (28%) in the weight-based group and 10 (40%) in the low-dose group relapsed after treatment completion leading to SVR24 rates of 68% (95% CI, 46%-85%) in the weight-based group and 48% (95% CI, 28%-69%; P = .20) in the low-dose group. Twenty individuals participated in a pharmacokinetic-viral kinetic substudy, which demonstrated a slower loss rate of infectious virus in relapsers than in participants who achieved SVR (clearance, 3.57/d vs 5.60/d; P = .009). The most frequent adverse events were headache, anemia, fatigue, and nausea. There were 7 grade 3 events including anemia, neutropenia, nausea, hypophosphatemia, and cholelithiasis or pancreatitis. No one discontinued treatment due to adverse events.In a population of patients with a high prevalence of unfavorable traditional predictors of treatment response, a 24-week regimen of sofosbuvir and weight-based or low-dose ribavirin resulted in SVR24 rates of 68% and 48%, Identifier: NCT01441180.

    View details for DOI 10.1001/jama.2013.109309

    View details for PubMedID 23982366

    View details for PubMedCentralID PMC4254410

  • A Scoping Review of Ongoing Fluorescence-Guided Surgery Clinical Trials in Otolaryngology. The Laryngoscope Crawford, K. L., Pacheco, F. V., Lee, Y., Hom, M., Rosenthal, E. L., Nguyen, Q. T., Orosco, R. K. 2021


    OBJECTIVE: Fluorescence-guided surgery (FGS) is a rapidly developing intraoperative technology, and many contrast agents are currently under investigation. We sought to provide a review of the current state of FGS clinical trials in Otolaryngology, emphasizing its oncologic applications.METHODS: According to the preferred reporting Items for systematic reviews and meta-analyses (PRISMA) workflow for scoping reviews, a clinical trial search was performed across multiple international clinical trials registries, searching for permutations of "fluorescence," "tumor," "surgery," and "nerve" to identify all relevant studies. Studies that were active, enrolling, or soon to be enrolling patients undergoing head and neck surgery were included.RESULTS: Nineteen studies were eligible for inclusion. Seventeen studies are focused on FGS for oncologic resection and lymph node detection. One study assesses peripheral nerve fluorescence, and one evaluates normal parathyroid function after thyroidectomy. Contrast agents under development are conjugated to fluorophores that excite in the 800nm (indocyanine green), 410nm (5-aminolevulinic acid), 700nm (Cyanine 5.5), and 525nm ranges (fluorescein derivatives).CONCLUSION: Presently, there are 19 ongoing trials investigating novel FGS contrast agents for their safety, efficacy, and utility in Otolaryngology-Head and Neck Surgery. These agents rely on unique fluorophores and absorption ranges in the near-infrared and visible light spectra. FGS studies are expanding within Otolaryngology-Head and Neck Surgery with profound implications in oncologic surgery, lymph node detection, and anatomic and functional assessment. Laryngoscope, 2021.

    View details for DOI 10.1002/lary.29891

    View details for PubMedID 34633092

  • EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial. Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y. J., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L., Nagpal, S., Thomas, R., Patel, C., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143


    Rationale: First-line therapy for high-grade gliomas (HGGs) includes maximal safe surgical resection. The extent of resection predicts overall survival, but current neuroimaging approaches lack tumor specificity. The epidermal growth factor receptor (EGFR) is a highly expressed HGG biomarker. We evaluated the safety and feasibility of an anti-EGFR antibody, panitumuab-IRDye800, at subtherapeutic doses as an imaging agent for HGG. Methods: Eleven patients with contrast-enhancing HGGs were systemically infused with panitumumab-IRDye800 at a low (50 mg) or high (100 mg) dose 1-5 days before surgery. Near-infrared fluorescence imaging was performed intraoperatively and ex vivo, to identify the optimal tumor-to-background ratio by comparing mean fluorescence intensities of tumor and histologically uninvolved tissue. Fluorescence was correlated with preoperative T1 contrast, tumor size, EGFR expression and other biomarkers. Results: No adverse events were attributed to panitumumab-IRDye800. Tumor fragments as small as 5 mg could be detected ex vivo and detection threshold was dose dependent. In tissue sections, panitumumab-IRDye800 was highly sensitive (95%) and specific (96%) for pathology confirmed tumor containing tissue. Cellular delivery of panitumumab-IRDye800 was correlated to EGFR overexpression and compromised blood-brain barrier in HGG, while normal brain tissue showed minimal fluorescence. Intraoperative fluorescence improved optical contrast in tumor tissue within and beyond the T1 contrast-enhancing margin, with contrast-to-noise ratios of 9.5 ± 2.1 and 3.6 ± 1.1, respectively. Conclusions: Panitumumab-IRDye800 provided excellent tumor contrast and was safe at both doses. Smaller fragments of tumor could be detected at the 100 mg dose and thus more suitable for intraoperative imaging.

    View details for DOI 10.7150/thno.60582

    View details for PubMedID 34158840

    View details for PubMedCentralID PMC8210618

  • EGFR-targeted intraoperative fluorescence imaging detects high-grade glioma with panitumumab-IRDye800 in a phase 1 clinical trial Theranostics Zhou, Q., van den Berg, N. S., Rosenthal, E. L., Iv, M., Zhang, M., Vega Leonel, J. C., Walters, S., Nishio, N., Granucci, M., Raymundo, R., Yi, G., Vogel, H., Cayrol, R., Lee, Y., Lu, G., Hom, M., Kang, W., Hayden Gephart, M., Recht, L. D., Nagpal, S., Thomas, R. P., Patel, C. B., Grant, G. A., Li, G. 2021; 11 (15): 7130-7143

    View details for DOI 10.7150/thno.60582

  • Metastatic and sentinel lymph node mapping using intravenously delivered Panitumumab-IRDye800CW THERANOSTICS Krishnan, G., van den Berg, N. S., Nishio, N., Juniper, G., Pei, J., Zhou, Q., Lu, G., Lee, Y., Ramos, K., Iagaru, A. H., Baik, F. M., Colevas, A. D., Martin, B. A., Rosenthal, E. L. 2021; 11 (15): 7188-7198

    View details for DOI 10.7150/thno.55389

    View details for Web of Science ID 000655136400005

  • Safety and Stability of Antibody-Dye Conjugate in Optical Molecular Imaging. Molecular imaging and biology Pei, J. n., Juniper, G. n., van den Berg, N. S., Nisho, N. n., Broadt, T. n., Welch, A. R., Yi, G. S., Raymundo, R. C., Chirita, S. U., Lu, G. n., Krishnan, G. n., Lee, Y. J., Kapoor, S. n., Zhou, Q. n., Colevas, A. D., Lui, N. S., Poultsides, G. A., Li, G. n., Zinn, K. R., Rosenthal, E. L. 2020


    The development of molecularly targeted tracers is likely to improve the accuracy of diagnostic, screening, and therapeutic tools. Despite the many therapeutic antibodies that are FDA-approved with known toxicity, only a limited number of antibody-dye conjugates have been introduced to the clinic. Thorough evaluation of the safety, stability, and pharmacokinetics of antibody conjugates in the clinical setting compared with their parental components could accelerate the clinical approval of antibodies as agents for molecular imaging. Here we investigate the safety and stability of a near-infrared fluorescent dye (IRDye800CW) conjugated panitumumab, an approved therapeutic antibody, and report on the product stability, pharmacokinetics, adverse events, and QTc interval changes in patients.Panitumumab-IRDye800CW was made under good manufacturing practice (GMP) conditions in a single batch on March 26, 2014, and then evaluated over 4.5 years at 0, 3, and 6 months, and then at 6-month intervals thereafter. We conducted early phase trials in head and neck, lung, pancreas, and brain cancers with panitumumab-IRDye800CW. Eighty-one patients scheduled to undergo standard-of-care surgery were infused with doses between 0.06 to 2.83 mg/kg of antibody. Patient ECGs, blood samples, and adverse events were collected over 30-day post-infusion for analysis.Eighty-one patients underwent infusion of the study drug at a range of doses. Six patients (7.4 %) experienced an adverse event that was considered potentially related to the drug. The most common event was a prolonged QTc interval which occurred in three patients (3.7 %). Panitumumab-IRDye800CW had two OOS results at 42 and 54 months while meeting all other stability testing criteria.Panitumumab-IRDye800CW was safe and stable to administer over a 54-month window with a low rate of adverse events (7.4 %) which is consistent with the rate associated with panitumumab alone. This data supports re-purposing therapeutic antibodies as diagnostic imaging agents with limited preclinical toxicology studies.

    View details for DOI 10.1007/s11307-020-01536-2

    View details for PubMedID 32880818

  • 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


    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

  • The Bilobe Flap for Nasal Reconstruction. Facial plastic surgery : FPS Okland, T. S., Lee, Y. J., Sanan, A. n., Most, S. P. 2020


    Repair of nasal defects is technically challenging due to inelastic nasal skin and unforgiving nasal geometry. The bilobe flap is a double transposition flap that can transpose skin from cephalad to caudad to repair defects of the lower third of the nose. However, pincushioning may complicate this flap, yielding untoward aesthetic outcomes. We review our single surgeon series of patients who underwent bilobe flap reconstruction of nasal defects, and describe our surgical technique to minimize pincushioning and poor aesthetic outcomes. This was a retrospective chart review of patients who underwent bilobe flap reconstruction of nasal defects at a tertiary referral facial plastic and reconstructive surgery clinic between January 1, 2010 and February 12, 2019. All postoperative clinic notes were analyzed for complications, reports of unfavorable cosmetic outcome, and rates of revision procedures. Surgical technique is described. In the analysis, 125 patients were included, of whom 84 (67%) patients were women, and the mean (standard deviation) age was 60.7 (12.5) years. Complications were reported in 20 (16%) patients, including scars, pincushioning, and nasal obstruction. Five patients underwent revision surgery (4%), including scar revision and z-plasty. Pincushioning was reported in four patients (3.2%), of whom three underwent scar revision procedures. One patient had alar notching requiring correction. There was no statistically significant association between ear cartilage graft and complications (p = 0.84) or requirement of intervention (p = 1.0). Univariate and multivariate logistic regression did not show statistically significant association between size of the defect and the presence of complications (p > 0.05). The bilobe flap is an excellent transposition flap for the repair of small nasal tip defects. By adequately thinning the transposition flap of excess subcutaneous tissue prior to inset, rates of poor aesthetic outcomes, revision procedures, and pincushioning are minimized.

    View details for DOI 10.1055/s-0040-1712160

    View details for PubMedID 32512603

  • Where Dysphagia Begins: Polypharmacy and Xerostomia. Federal practitioner : for the health care professionals of the VA, DoD, and PHS Marcott, S. n., Dewan, K. n., Kwan, M. n., Baik, F. n., Lee, Y. J., Sirjani, D. n. 2020; 37 (5): 234–41


    Xerostomia, the subjective sensation of dry mouth, contributes to dysarthria, dysphagia, and diminished quality of life. Polypharmacy is a known and modifiable risk factor for xerostomia. The objective of this study was to evaluate the prevalence of dry mouth, the relationship between dry mouth and other oral conditions, and the impact of polypharmacy on dry mouth.This study was a retrospective cross-sectional study of all patients seen in fiscal year (FY) 2015 (October 1, 2014 to September 30, 2015) at the VA Palo Alto Health Care System (VAPAHCS), a tertiary care US Department of Veterans Affairs (VA) hospital. Patients diagnosed with xerostomia were identified using ICD-9 codes (527.7, 527.8, R68.2) and Systemized Nomenclature of Medicine Clinical Terms (SNOMED CT) codes (87715008, 78948009).Of all the patients seen at VAPAHCS during FY 2015, 138 had a diagnostic code for xerostomia; of those patients, 84 had at least 1 documented speech, dentition, or swallowing (SDS) problem, and 55 (39.9%) were taking ≥ 12 medications, more than twice as many patients as in any one of the other groups studied (0-2, 3-5, 6-8, and 9-11 medications taken). Although 4,971 total patients seen at VAPAHCS had documented SDS problems during FY 2015, of those patients only 77 (1.5%) had an additional recorded diagnosis of xerostomia.Heightened physician awareness regarding the signs and symptoms of and risk factors for xerostomia is needed to improve health care providers' ability to diagnose dry mouth. Polypharmacy also must be considered when developing new strategies for preventing and treating xerostomia.

    View details for PubMedID 32454578

    View details for PubMedCentralID PMC7241606

  • 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
  • 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


    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
  • Rapid changes in peripheral lymphocyte concentrations during interferon-free treatment of chronic hepatitis C virus infection. Hepatology communications Meissner, E. G., Kohli, A. n., Higgins, J. n., Lee, Y. J., Prokunina, O. n., Wu, D. n., Orr, C. n., Masur, H. n., Kottilil, S. n. 2017; 1 (7): 586–94


    Treatment of chronic hepatitis C virus infection with direct acting antivirals results in a rapid decline in viral load and markers of hepatic inflammation, including serum CXCL10 concentration, which is followed in most cases by a sustained virologic response. Whether parallel changes of significance occur in the cellular composition of peripheral blood is relatively unknown. We hypothesized that longitudinal characterization of peripheral blood during treatment would provide insight into cellular migration and immune activation, which would have implications for understanding host immunity both before and after HCV treatment and may relate to HCV clearance. We analyzed longitudinal peripheral innate and adaptive immune cell populations by flow cytometry from 95 subjects enrolled in two direct acting antiviral clinical trials, and examined chemokine receptor expression on T-lymphocytes in 43 patients. Within 1-2 weeks of initiating treatment, significant increases were observed in the concentration of peripheral CD4+ and CD8+ T-lymphocytes, but not monocyte or natural killer cells. In tandem with these changes, the percent of both CD4+ and CD8+ T-lymphocytes with an activated phenotype (HLA-DR+ and CD38+) decreased, and T-lymphocyte surface expression of CXCR3, the chemokine receptor for CXCL10, increased.Rapid changes in peripheral cellular populations occur during DAA -treatment of HCV infection, which could potentially relate to hepatic efflux of tissue lymphocytes due to altered inflammation and chemokine receptor signaling, providing critical insight into the relationship between host immunity and viral clearance during hepatitis C virus infection.

    View details for PubMedID 29202115

    View details for PubMedCentralID PMC5703427

  • Interferon Stimulated Gene Expression in HIV/HCV Coinfected Patients Treated with Nitazoxanide/Peginterferon-Alfa-2a and Ribavirin AIDS RESEARCH AND HUMAN RETROVIRUSES Petersen, T., Lee, Y., Osinusi, A., Amorosa, V. K., Wang, C., Kang, M., Matining, R., Zhang, X., Dou, D., Umbleja, T., Kottilil, S., Peters, M. G. 2016; 32 (7): 660-667


    A combination of nitazoxanide (NTZ), peginterferon (PegIFN), and ribavirin (RBV) may result in higher sustained virologic response (SVR) rates in hepatitis C virus (HCV) monoinfected patients. This study evaluated the effect of NTZ on interferon-stimulated gene (ISG) expression in vitro and in vivo among HIV/HCV genotype-1 (GT-1) treatment-naive patients. The ability of NTZ to enhance host response to interferon (IFN) signaling using the HCV cell culture system was initially evaluated. Second, ISG expression in 53 patients with treatment outcomes [21 SVR and 32 nonresponders (NR)] in the ACTG A5269 trial, a phase-II study (4-week lead in of NTZ 500 mg daily followed by 48 weeks of NTZ, PegIFN, and weight-based RBV), was assessed. The relative expression of 48 ISGs in peripheral blood mononuclear cells (PBMCs) was measured at baseline, week 4, and week 8 of treatment in a blinded manner. In vitro NTZ produced a direct and additive antiviral effect with IFN-alfa, with pretreatment of NTZ resulting in maximal HCV suppression. NTZ augmented IFN-mediated ISG induction in PBMCs from relapsers and SVRs (p < 0.05), but not NR. In ACTG A5269, baseline expression of most ISGs was similar between NR and SVR. NTZ minimally induced 17 genes in NR and 13 genes in SVR after 4 weeks of therapy. However, after initiation of PegIFN and RBV, ISG induction was predominantly observed in the SVR group and not NR group. NTZ treatment facilitates IFN-induced suppression of HCV replication. Inability to achieve SVR with IFN-based therapy in this clinical trial is associated with diminished ISG response to therapy that is refractory to NTZ.

    View details for DOI 10.1089/aid.2015.0236

    View details for Web of Science ID 000379609100007

    View details for PubMedID 26974581

    View details for PubMedCentralID PMC4931749

  • Expansion of laparoscopic cholecystectomy in a resource limited setting, Mongolia: a 9-year cross-sectional retrospective review. Lancet Wells, K. M., Lee, Y., Erdene, S., Erdene, S., Sanchin, U., Sergelen, O., Presson, A., Zhang, C., Rodriguez, B., Devries, C., Price, R. 2015; 385: S38-?


    The benefits of laparoscopic cholecystectomy have been largely unavailable to most people in developing countries. Mongolia has an extremely high incidence of gallbladder disease. In 2005, only 2% of cholecystectomies were being done laparoscopically. Open cholecystectomies were associated with high rates of wound infections, complications, and increased recovery time. Because of the unacceptable complications associated with open cholecystectomies, and nearly 50% of the nomadic population needing faster post-operative recovery times, a national project for the development of laparoscopic surgery was organised. Multi-institutional collaboration between the Mongolia Health Sciences University, the Dr W C Swanson Family Foundation (SFF), the University of Utah, Intermountain Healthcare, and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) led to the promulgation of a formalised countrywide laparoscopic training programme during the past 9 years. This is a retrospective review of the transition from open to laparoscopic cholecystectomy throughout Mongolia.Demographic patient data, diagnosis, and operation preformed-laparoscopic versus open cholecystectomy, between January, 2005, and September, 2013, were collected and trends were analysed from seven regional diagnostic referral and treatment centres, and two tertiary academic medical centres from six of the 21 provinces (Aimags) throughout Mongolia. Data were analysed by individual training centre, by year, and then compared between rural and urban centres.Nearly 16 000 cholecystectomies were analysed and compared (4417 [28·2%] men; 11 244 [71·8%] women). Men and women underwent laparoscopic cholecystectomy with the same frequency (41·2% men, 43·2% women) and had similar age (men, mean 52·2 years [SD 14·8]; women, mean 49·4 years [SD 15·7]). By 2013, 62% of gallbladders were removed laparoscopically countrywide as opposed to only 2% in 2005. More than 315 Mongolian practitioners have received laparoscopic training in 19 of 21 Aimags. On average 60% of cholecystectomies are done laparoscopically in urban surgical centres, up from 2%, versus 55% in rural surgical centres, up from 0%, in 2005. Laparoscopic cholecystectomy surpassed open cholecystectomy as the primary method for gallbladder removal countrywide in 2011.By 2013, 62% of cholecystectomies countrywide were done laparoscopically, a great increase from 9 years ago. Despite being a resource limited country, the expansion of laparoscopic cholecystectomy has transformed the care of biliary tract disease in Mongolia.The University of Utah Center for Global Surgery.

    View details for DOI 10.1016/S0140-6736(15)60833-9

    View details for PubMedID 26313086

  • Effect of sofosbuvir and ribavirin treatment on peripheral and hepatic lipid metabolism in chronic hepatitis C virus, genotype 1-infected patients. Hepatology Meissner, E. G., Lee, Y., Osinusi, A., Sims, Z., Qin, J., Sturdevant, D., McHutchison, J., Subramanian, M., Sampson, M., Naggie, S., Patel, K., Remaley, A. T., Masur, H., Kottilil, S. 2015; 61 (3): 790-801


    Hepatitis C virus (HCV) modulates intrahepatic cholesterol biosynthetic pathways to promote viral replication. Chronic HCV infection is associated with altered metabolism, including dyslipidemia and insulin resistance (IR), which contributes to disease progression and influences response to therapy. To further understand the impact of HCV infection on host metabolism, we examined changes in serum lipid profiles and intrahepatic expression of lipid-related genes during interferon (IFN)-free treatment of chronic HCV, genotype 1 infection with sofosbuvir and ribavirin (RBV), and explored associations with treatment outcome. Serum lipids (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TGs]) and hemoglobin A1C (HbA1C) were measured during treatment, while gene expression of lipid-related genes was assessed using paired pre- and end-of-treatment (EOT) liver biopsies from 8 patients (n=7 sustained virologic response [SVR]; n=1 relapse) and unpaired EOT liver biopsies from 25 patients (n=17 SVR; n=8 relapse). Serum LDL concentration and particle size increased early in therapy, whereas TG concentration and very-low-density lipoprotein particle size decreased concomitantly, irrespective of treatment outcome. Whereas LDL increased in patients regardless of treatment outcome, average LDL concentration was lower at baseline and post-treatment in patients who relapsed. Analysis of paired liver biopsies revealed altered expression of genes associated with lipid transport, assembly, and signaling. In unpaired EOT liver biopsies, intrahepatic expression of fatty acid metabolism and lipid transport genes was lower in patients who experienced treatment relapse.Clearance of HCV using an IFN-free antiviral regimen results in rapid changes in peripheral and intrahepatic metabolic pathways, implicating a direct effect of HCV replication on lipid homeostasis.

    View details for DOI 10.1002/hep.27424

    View details for PubMedID 25203718

    View details for PubMedCentralID PMC4340816

  • Comparative Efficacy, Pharmacokinetic, Pharmacodynamic Activity, and Interferon Stimulated Gene Expression of Different Interferon Formulations in HIV/HCV Genotype-1 Infected Patients JOURNAL OF MEDICAL VIROLOGY Osinusi, A., Bon, D., Nelson, A., Lee, Y., Poonia, S., Shivakumar, B., Cai, S. Y., Wood, B., Haagmans, B., Lempicki, R., Herrmann, E., Sneller, M., Polis, M., Masur, H., Kottilil, S. 2014; 86 (2): 177-185


    The effect of different formulations of interferon on therapeutic response in patients coinfected with HIV and HCV is unclear. In this study, the safety, tolerability, viral kinetics (VK) modeling and host responses among HIV/HCV coinfected patients treated with pegylated-IFN or albinterferon alfa-2b (AlbIFN) with weight-based ribavirin were compared. Three trials treated 57 HIV/HCV coinfected genotype-1 patients with PegIFN alfa-2b (1.5 µg/kg/week) (n = 30), PegIFN alfa-2a (180 µg/week) (n = 10), and AlbIFN (900 µg/q2week) (n = 17) in combination with weight-based ribavirin (RBV). HCV RNA, safety labs, and interferon stimulated gene expression (ISG) was evaluated. Adverse events were documented at all study visits. HCV viral kinetics using a full pharmacokinetic/pharmacodynamic model was also evaluated. Baseline patient characteristics were similar across the three studies. All three formulations exhibited comparable safety and tolerability profiles and efficacy. VK/PK/PD parameters for all three studies as measured by mean efficiency and rate of infected cell loss were similar between the three groups. Host responses (ISG expression and immune activation markers) were similar among the three groups. All three regimens induced significant ISG at week 4 (P < 0.05) and ISG expression strongly correlated with therapeutic response (r = 0.65; P < 0.01). In summary, a comprehensive analysis of responses to three different interferon formulations in HIV/HCV coinfected patients demonstrated similar effects. Notably, interferon-based therapy results in a blunted host response followed by modest antiviral effect in HIV/HCV coinfected patients. This suggests that future treatment options that do not rely on host immune responses such as direct antiviral agents would be particularly beneficial in these difficult to treat patients.

    View details for DOI 10.1002/jmv.23773

    View details for Web of Science ID 000328212900001

    View details for PubMedID 24166150

  • Impaired HCV Clearance in HIV/HCV Coinfected Subjects Treated with PegIFN and RBV Due to Interference of IFN Signaling by IFNaR2a. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research Lee, Y., Zhang, X., Vazquez, E., Shivasabesan, G., Young, H. A., Murphy, A., Wang, H., Suffredini, A. F., Siebenlist, U., Kottilil, S. 2014; 34 (1): 28-34


    Enhanced endogenous interferon (IFN) stimulated gene (ISG) signature has been associated with nonresponsiveness to hepatitis C treatment using pegylated-IFNα (pegIFNα) and ribavirin (RBV) in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected patients. Using a proteomic approach, we identified high levels of IFNα receptor 2a (IFNαR2a) in the serum of null responders to pegIFNα/RBV. IFNαR2a inhibited antiviral activity of all formulations of IFNα in JFH/Huh7.5 cells. Furthermore, serum from null responders, but not from those who achieved sustained virologic response, suppressed IFN-signaling and ISG expression in IFNα-stimulated PBMCs of healthy donors in an IFNαR2a specific fashion. An IFNαR2a transgenic mice model (C57BL/6) was generated that had significantly higher levels of IFNαR2a in the serum than the controls (P=0.001). Total ISG expression in the lymph nodes was significantly higher compared to wild-type mice (P value=0.0016). In addition, IFITM1 and SP110 had significantly increased expression in the liver, IFITM1 and ISG15 in the lymph node, and ISG15 and PLSCR1 in the spleen (P value<0.05). The underlying mechanism of resistance to hepatitis C treatment may involve transsignaling of the JAK/STAT pathway by the sIFNαR2a-IFNα/β complex and result in the enhanced ISG signature observed in null responders. In this regard, the transgenic mice model simulated nonresponders to IFNα therapy and provides valuable insights into the role of sIFNαR2a-IFNα interactions in vivo.

    View details for DOI 10.1089/jir.2013.0032

    View details for PubMedID 24171456

    View details for PubMedCentralID PMC3887437

  • A whole recombinant yeast-based therapeutic vaccine elicits HBV x, s and core specific T cells in mice and activates human T cells recognizing epitopes linked to viral clearance. PloS one King, T. H., Kemmler, C. B., Guo, Z., Mann, D., Lu, Y., Coeshott, C., Gehring, A. J., Bertoletti, A., Ho, Z. Z., Delaney, W., Gaggar, A., Subramanian, G. M., McHutchison, J. G., Shrivastava, S., Lee, Y. L., Kottilil, S., Bellgrau, D., Rodell, T., Apelian, D. 2014; 9 (7)


    Chronic hepatitis B infection (CHB) is characterized by sub-optimal T cell responses to viral antigens. A therapeutic vaccine capable of restoring these immune responses could potentially improve HBsAg seroconversion rates in the setting of direct acting antiviral therapies. A yeast-based immunotherapy (Tarmogen) platform was used to make a vaccine candidate expressing hepatitis B virus (HBV) X, surface (S), and Core antigens (X-S-Core). Murine and human immunogenicity models were used to evaluate the type and magnitude of HBV-Ag specific T cell responses elicited by the vaccine. C57BL/6J, BALB/c, and HLA-A*0201 transgenic mice immunized with yeast expressing X-S-Core showed T cell responses to X, S and Core when evaluated by lymphocyte proliferation assay, ELISpot, intracellular cytokine staining (ICS), or tumor challenge assays. Both CD4+ and CD8+ T cell responses were observed. Human T cells transduced with HBc18-27 and HBs183-91 specific T cell receptors (TCRs) produced interferon gamma (IFNγ following incubation with X-S-Core-pulsed dendritic cells (DCs). Furthermore, stimulation of peripheral blood mononuclear cells (PBMCs) isolated from CHB patients or from HBV vaccine recipients with autologous DCs pulsed with X-S-Core or a related product (S-Core) resulted in pronounced expansions of HBV Ag-specific T cells possessing a cytolytic phenotype. These data indicate that X-S-Core-expressing yeast elicit functional adaptive immune responses and supports the ongoing evaluation of this therapeutic vaccine in patients with CHB to enhance the induction of HBV-specific T cell responses.

    View details for DOI 10.1371/journal.pone.0101904

    View details for PubMedID 25051027

    View details for PubMedCentralID PMC4106793

  • High Efficacy Of GS-7977 In Combination With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis From The SPARE Trial 63rd Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) Osinusi, A., Heytens, L., Lee, Y., Bon, D., Shivakumar, B., Nelson, A., Meissner, E. G., Kohli, A., Barrett, L., Proschan, M., Silk, R., Kwan, R., Herrmann, E., Sneller, M., Teferi, G., Talwani, R., Symonds, W. T., Polis, M. A., Masur, H., McHutchison, J. G., Fauci, A. S., Kottilil, S. WILEY-BLACKWELL. 2012: 1518–18
  • Real-time Polymerase Chain Reaction Analysis of Sewage Samples to Determine Oral Polio Vaccine Circulation Duration and Mutation After Mexican National Immunization Weeks. Journal of the Pediatric Infectious Diseases Society Troy, S. B., Ferreyra-Reyes, L., Canizales-Quintero, S., Huang, C., Lee, Y., Báez-Saldaña, R., Ferreira-Guerrero, E., García-García, L., Maldonado, Y. 2012; 1 (3): 223-229


    Oral polio vaccine (OPV) can mutate and cause outbreaks of paralytic poliomyelitis with prolonged replication. After poliovirus eradication, global use of inactivated polio vaccine (IPV) may be needed until all OPV stops circulating. Mexico, where children receive routine IPV but where OPV is given only during biannual national immunization weeks (NIWs), provides a natural setting to study duration of OPV circulation in a community primarily vaccinated with IPV.One-liter sewage samples from four separate arroyos (creeks) near Orizaba, Mexico, were collected monthly for 12 months. Concentrated sewage underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3 and their variants containing the serotype-specific point mutation in the 5' untranslated region associated with neurovirulence.OPV was detected 3, 4, 5, and 7 months after the May 2010 NIW, but was not detected at 6 or 8 months. A second and third NIW occurred in February 2011 and May 2011, and OPV was detected in the sewage monthly after both of these NIW through July 2011 when collection stopped. The OPV detected was primarily serotype 2 and predominantly contained the point mutations in the 5' untranslated region associated with increased neurovirulence.OPV was detected in sewage as late as 7 months after an NIW in a Mexican community primarily vaccinated with IPV, but was not detected at 8 months, suggesting that OPV circulation may have ceased. These data suggest that in communities with high vaccination rates, 1 or 2 years of IPV administration after OPV cessation could be sufficient to prevent outbreaks of paralytic poliomyelitis from vaccine-derived strains.

    View details for DOI 10.1093/jpids/pis062

    View details for PubMedID 23667738

  • Use of a Novel Real-Time PCR Assay To Detect Oral Polio Vaccine Shedding and Reversion in Stool and Sewage Samples after a Mexican National Immunization Day JOURNAL OF CLINICAL MICROBIOLOGY Troy, S. B., Ferreyra-Reyes, L., Huang, C., Mahmud, N., Lee, Y., Canizales-Quintero, S., Flaster, H., Baez-Saldana, R., Garcia-Garcia, L., Maldonado, Y. 2011; 49 (5): 1777-1783


    During replication, oral polio vaccine (OPV) can revert to neurovirulence and cause paralytic poliomyelitis. In individual vaccinees, it can acquire specific revertant point mutations, leading to vaccine-associated paralytic poliomyelitis (VAPP). With longer replication, OPV can mutate into vaccine-derived poliovirus (VDPV), which causes poliomyelitis outbreaks similar to those caused by wild poliovirus. After wild poliovirus eradication, safely phasing out vaccination will likely require global use of inactivated polio vaccine (IPV) until cessation of OPV circulation. Mexico, where children receive routine IPV but where OPV is given biannually during national immunization days (NIDs), provides a natural setting to study the duration of OPV circulation in a population primarily vaccinated with IPV. We developed a real-time PCR assay to detect and distinguish revertant and nonrevertant OPV serotype 1 (OPV-1), OPV-2, and OPV-3 from RNA extracted directly from stool and sewage. Stool samples from 124 children and 8 1-liter sewage samples from Orizaba, Veracruz, Mexico, collected 6 to 13 weeks after a NID were analyzed. Revertant OPV-1 was found in stool at 7 and 9 weeks, and nonrevertant OPV-2 and OPV-3 were found in stool from two children 10 weeks after the NID. Revertant OPV-1 and nonrevertant OPV-2 and -3 were detected in sewage at 6 and 13 weeks after the NID. Our real-time PCR assay was able to detect small amounts of OPV in both stool and sewage and to distinguish nonrevertant and revertant serotypes and demonstrated that OPV continues to circulate at least 13 weeks after a NID in a Mexican population routinely immunized with IPV.

    View details for DOI 10.1128/JCM.02524-10

    View details for PubMedID 21411577

  • Fatal H1N1-Related Acute Necrotizing Encephalopathy in an Adult. Case reports in critical care Lee, Y., Smith, D. S., Rao, V. A., Siegel, R. D., Kosek, J., Glaser, C. A., Flint, A. C. 2011; 2011: 562516-?


    Acute necrotizing encephalopathy (ANE) is a severe neurological complication of influenza infection, including H1N1 influenza. Many cases of ANE have been reported in the pediatric literature, but very few cases have been described in adults. The cause of ANE remains unknown-the influenza virus is not known to be neurotropic, and evidence of direct viral involvement of the central nervous system (CNS) has not been demonstrated in the limited cases of ANE in which pathological specimens have been obtained. Here we report a fatal case of ANE from H1N1 influenza infection in an adult. Neuroimaging and postmortem analysis both showed widespread brain edema, necrosis, and hemorrhage, but molecular studies and postmortem pathology revealed no evidence of direct viral involvement of the CNS. This case of fatal ANE in an adult is consistent with the hypothesis generated from pediatric cases that the host immune response, and not direct viral invasion of the CNS, is responsible for pathogenesis of ANE.

    View details for DOI 10.1155/2011/562516

    View details for PubMedID 24826323

    View details for PubMedCentralID PMC4010007