Sarah M. Kidwai

iNOS Expression in CD4+ T Cells Limits Treg Induction by Repressing TGFβ1: Combined iNOS Inhibition and Treg Depletion Unmask Endogenous Antitumor Immunity

Purpose: Expression of inducible nitric oxide synthase (iNOS) in different cellular compartments may have divergent effects on immune function. We used a syngeneic tumor model to functionally characterize the role of iNOS in regulation of CD4+FOXP3+ regulatory T cells (Treg), and optimize the beneficial effects of iNOS inhibition on antitumor immunity. Experimental Design: Wild-type (WT) or iNOS knockout mice bearing established MT-RET-1 melanoma were treated with the small-molecule iNOS inhibitor L-NIL and/or cyclophosphamide alone or in combination. The effect of iNOS inhibition or knockout on induction of Treg from mouse and human CD4+ T cells in ex vivo culture was determined in parallel in the presence or absence of TGFβ1-depleting antibodies, and TGFβ1 levels were assessed by ELISA. Results: Whereas intratumoral myeloid-derived suppressor cells (MDSC) were suppressed by iNOS inhibition or knockout, systemic and intratumoral FOXP3+ Treg levels increased in tumor-bearing mice. iNOS inhibition or knockout similarly enhanced induction of Treg from activated cultured mouse splenocytes or purified human or mouse CD4+ T cells in a TGFβ1-dependent manner. Although either iNOS inhibition or Treg depletion with low-dose cyclophosphamide alone had little effect on growth of established MT-RET1 melanoma, combination treatment potently inhibited MDSC and Treg, boosted tumor-infiltrating CD8+ T-cell levels, and arrested tumor growth in an immune-dependent fashion. Conclusions: iNOS expression in CD4+ T cells suppresses Treg induction by inhibiting TGFβ1 production. Our data suggest that iNOS expression has divergent effects on induction of myeloid and lymphoid-derived regulatory populations, and strongly support development of combinatorial treatment approaches that target these populations simultaneously. Clin Cancer Res; 20(24); 6439–51. ©2014 AACR.

A Systematic Review of Eligibility and Outcomes in Tinnitus Trials Reassessment of Tinnitus Guideline

Objective To analyze existing tinnitus treatment trials with regard to eligibility criteria, outcome measures, study quality, and external validity and to recognize the effect of patient demographics, symptom duration, severity, and otologic comorbidity on research findings to help practitioners apply them to patient encounters. Data Sources Systematic literature search conducted by an information specialist for development of the American Academy of Otolaryngology—Head and Neck Surgery Foundation’s tinnitus clinical practice guideline. Review Methods Articles were assessed for eligibility with the PRISMA protocol (Preferred Reporting Items for Systematic Reviews and Meta-analyses) and data extracted by 2 independent investigators. Studies were assessed for methodological quality, inclusion and exclusion criteria, patient demographics, and outcome measures. Results A total of 147 randomized trials met inclusion criteria. Nearly all studies took place in a specialist setting. More than 50% did not explicitly define tinnitus, and 44% used a subjective severity threshold, such as “severely disturbing.” Fifty-four percent required symptom duration of at least 6 months for study eligibility, and up to 33% excluded patients with “organic” hearing loss or otologic conditions. Mean age was 52.2 years, and median follow-up was 3 months. Only 20% had a low risk of bias. Conclusion Randomized trials of tinnitus interventions are most applicable to older adults with tinnitus lasting ≥6 months who are evaluated in specialty settings. High risk of bias, short follow-up, and outcome reporting raise concerns about the validity of findings and may influence how clinicians apply trial results to individual patients and establish treatment expectations, thus demonstrating the need for further quality research in this field.

An unusual presentation of NK/T-cell lymphoma, nasal-type in the United States.

INTRODUCTION NK/T-cell lymphoma (NKCL), nasal-type is rare in the United States, representing only 1.5% of non-Hodgkin lymphomas. Classically, patients initially present with nasal obstruction (70%), caused by invasion of the localized lesion into the sinuses and nasal cavities. Initial presentation with persistent sore throat and odynophagia due to oropharyngeal tumor extension is rare, and thus, is often overlooked as viral or bacterial pharyngitis. By studying a case of NKTCL nasal type, we emphasize the need to apply high clinical suspicion for NKTCL, nasal type for early diagnosis and improved survival. METHODS A case report of a rare presentation of NKTCL, nasal-type is discussed. A literature review is provided to define clinical signs crucial for early diagnosis, appropriate work-up, and expedient treatment of this aggressive, rapidly progressive malignancy. RESULTS In the present case, a 25year-old healthy male presented with a 2-week history of sore throat and odynophagia. On exam, the patient had an ulcerative lesion of the soft palate, an enlarged uvula, and tonsillar exudate with tender submandibular lymphadenopathy. After the patient failed to respond to antibiotic therapy for presumptive pharyngitis, a biopsy of the oropharyngeal tissue was completed, which identified necrotizing sialometaplasia. High clinical suspicion led to repeat deep-tissue biopsy, where a final diagnosis of NKTCL, nasal type was made. The patient then began definitive treatment with chemotherapy and radiation. CONCLUSIONS High clinical suspicion is key to early diagnosis and improved survival of NKTCL, nasal-type. Otolaryngologists who encounter prolonged, complicated cases of pharyngitis or necrotizing sialometaplasia should consider a diagnosis of NKTCL, nasal-type, in order to prevent rapid disease progression.

High-resolution microendoscope imaging of inverted papilloma and normal sinonasal mucosa: evaluation of interobserver concordance

High‐resolution microendoscopy (HRME) enables real‐time imaging of epithelial tissue. The utility of this novel imaging modality for inverted papilloma has not been previously described. This study examines the ability of otolaryngologists to differentiate between images of inverted papilloma and normal sinonasal mucosa obtained with a HRME.

Costs in Pituitary Surgery: Racial, Socioeconomic, and Hospital Factors

Abstract Objective To investigate the influence of patient demographic factors and hospital factors on cost and length of stay in patients undergoing pituitary surgery. Design/Setting A retrospective cross‐sectional study of the 2008 to 2012 Nationwide/National Inpatient Sample. Participants Patient demographics and hospital characteristics for patients undergoing pituitary surgery were compared between white, black, and Hispanic patients. Main Outcome Measures Variables associated with increased cost and increased length of hospital stay were ascertained and compared against each racial and ethnic group via multiple linear regression analysis. Results Of 8,812 patients who underwent pituitary surgery, 5,924 (67.2%) patients were white, 1,590 (18.0%) were black, and 1,296 (14.7%) were Hispanic. Patient variables found to be significantly different between racial groups via univariate analysis were age, chronic conditions, gender, income, and primary payer. Hospital variables found to be significantly different were location/teaching status, region, and ownership. Hospitalization cost was significantly lower for whites (−

Navigation of Sinus and Skull Base Surgery

3,082, 95% confidence interval [CI] −

Percutaneous versus surgical tracheostomy: timing, outcomes, and charges: Percutaneous Versus Surgical Tracheostomy

3,961 to −

The socioeconomic determinants for transsphenoidal pituitary surgery: a review of New York State from 1995 to 2015: Outcome determinants in pituitary surgery

2,202) and significantly higher for both blacks (

Postoperative pain management after sinus surgery: a survey of the American Rhinologic Society: Pain management after sinus surgery

1,889, 95% CI

Optical imaging with a high-resolution microendoscope to identify sinonasal pathology

842‐