Use of a Contralateral Nasoseptal Flap for Sino-Orbital Fistula Closure.

Sino-orbital fistulas can occur after orbital exenteration. Chronic nonhealing fistulas lead to bothersome symptoms including malodorous discharge, hypernasal speech, crusting, wound breakdown, or inability to wear an ocular prosthesis. Reconstruction can be difficult due to the complexity of the defects and the multitude of treatments patients often undergo for the management of the primary disease. Prior radiation, lack of available local tissue, or compromised blood supply are some of the issues that make successful fistula closure problematic. This report describes a method for autologous vascularized tissue coverage using a contralateral nasoseptal flap to successfully close a sino-orbital fistula.

Prevalence of cervical insufficiency in polycystic ovarian syndrome.

BACKGROUND: Pregnant women with polycystic ovarian syndrome (PCOS) experience a greater rate of adverse obstetrical outcomes compared with non-PCOS women. We examined the prevalence and incidence of cervical insufficiency (CI) in a community cohort of pregnant women with and without PCOS. METHODS: A retrospective cohort study was conducted within a large integrated health care delivery system among non-diabetic PCOS women with second or third trimester delivery during 2002-2005 (singleton or twin gestation). PCOS was defined by Rotterdam criteria. A non-PCOS comparison group matched for delivery year and hospital facility was used to estimate the background rate of CI. Women were designated as having new CI diagnosed in the index pregnancy (based on cervical dilation and/or cervical shortening) and prior CI based on prior diagnosis of CI with prophylactic cerclage placed in the subsequent pregnancy. RESULTS: We identified 999 PCOS women, of whom 29 (2.9%) had CI. There were 18 patients with new CI and 11 with prior CI having prophylactic cerclage placement; four CI patients had twin gestation. In contrast, only five (0.5%) non-PCOS women had CI: two with new CI and three with prior CI. The proportion of newly diagnosed incident CI (1.8 versus 0.2%) or prevalent CI (2.9 versus 0.5%) was significantly greater for PCOS compared with non-PCOS pregnant women (both P < 0.01). Among PCOS women, CI prevalence was particularly high among South Asians (7.8%) and Blacks (17.5%) compared with Whites (1%) and significantly associated with gonadotropin use (including in vitro fertilization). Overall, the PCOS status was associated with an increased odds of prevalent CI pregnancy (adjusted odds ratio 4.8, 95% confidence interval 1.5-15.4), even after adjusting for maternal age, nulliparity, race/ethnicity, body mass index and fertility treatment. CONCLUSION: In this large and ethnically diverse PCOS cohort, we found that CI occurred with a higher than expected frequency in PCOS women, particularly among South Asian and Black women. PCOS women with CI were also more likely to have received gonadotropin therapy. Future studies should examine whether natural and hormone-altered PCOS is a risk factor for CI, the role of race/ethnicity, fertility drugs and consideration for heightened mid-trimester surveillance in higher risk subgroups of pregnant women with PCOS.

Cancer registration and healthcare access in West Bank, Palestine: a GIS analysis of childhood cancer, 1998-2007.

In low and middle income countries (LMIC), high-quality disease registration is difficult to achieve in the setting of inadequate healthcare infrastructure and political or economical instability. In this article, we explore the potential of geographic information systems (GIS) to add value to the understanding of childhood cancer patterns in the West Bank, despite a variety of obstacles to disease registration. All incidence cases of childhood cancers (under the age 15) from 1998 to 2007 were collected from the West Bank Cancer Registry. Temporal, spatial and space-time analyses were performed using the SatScan software developed by Martin Kulldorff and the National Cancer Institute (NCI). The analyses were categorized into the following groups: all childhood cancer, leukemias, acute lymphocytic leukemia, lymphomas, brain and central nervous system (CNS) cancers and remaining cancers (excluding leukemia, lymphoma and CNS tumors). The temporal analysis revealed that cancer registration was more complete from 1998 to 2000 (p=0.0162), and that leukemia registration was severely deficient from 2003 to 2005 (p=0.0012). The spatial analysis showed a concentration of cancer in metropolitan districts where referral hospitals are based. Under registration was detected in the northern districts of Jenin and Tulkarm (RR=0.59, p=0.0059), more prominent from 2002 to 2005 (RR=0.33, p=0.0006). The analysis for high rates found a cluster of lymphoma in town of Dura and its surrounding agricultural villages (RR=4.10, p=0.0023). Our study reveals that the application of GIS tools to registry data in LMIC can help to identify geographical patterns in cancer registration and healthcare accessibility, generating priorities for future health research and policy in resource-limited areas.

Association of tea consumption and cutaneous squamous cell carcinoma.

Laboratory and epidemiologic studies suggest a protective effect of tea consumption on risk of cutaneous squamous cell carcinoma (SCC). We designed a case-control study to examine the association between putative protective exposures, including tea consumption, and SCC risk using a large health maintenance organization population. Cases (n=415) were defined as Kaiser Permanente Northern California (KPNC) members with a pathology-verified SCC in 2004 and controls (n=415) were age-, gender-, and race-matched members with no previous history of skin cancer. Tea consumption and SCC risk factors were ascertained by questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, as well as dose and duration of tea consumption. Risk factor adjusted models included education, smoking, hair and eye color, skin type, family history of skin cancer, and history of freckling, sunburns, sun exposure, and tanning bed use. Adjusted analyses showed no reduction in SCC risk with regular consumption of tea (OR=1.11, 95% CI: 0.81-1.54). Examining duration, dose, and combined duration and dose exposure variables did not alter findings. We found no evidence that tea consumption was associated with cutaneous SCC risk.

Benign tumoral melanosis of a cervical lymph node in a child.

We present a pediatric case of benign tumoral melanosis in a cervical lymph node arising from congenital pigmented lesions of the anterior neck. This is the first reported pediatric case not associated with regressed melanoma or trauma. Tumoral melanosis is a rare phenomenon which describes a pigmented lesion like melanoma; however, histology demonstrates melanin-laden macrophages without malignant cells. In the few reported cases, tumoral melanosis has arisen in the skin or lymph node and associated with a regressed melanoma, pigmented basal cell carcinoma or mycosis fungoides. We discuss the pathology of this disease process, and the work up in a pediatric patient.

Epidemiology and treatment trends for primary tracheal squamous cell carcinoma.

OBJECTIVE: Management of tracheal squamous cell carcinoma (TSCC) has been complicated by the lack of prognostic data and staging. We describe the epidemiology of TSCC and current treatment approaches. METHODS: Five hundred thirty-two adult patients with primary TSCC from 2004 to 2012 in the National Cancer Database were identified. Demographic, clinical factors, and 5-year overall survival were analyzed. Staging was classified as localized, regional extension, and distant spread. Treatment modality was defined as "no treatment (NT)," "limited surgery (LS)," "curative surgery (CS)," "LS with any adjuvant therapy (AT) (LS+AT)," "CS with AT (CS+AT)," "radiation therapy (RT)," or "chemoradiation (CRT)." RESULTS: Overall survival was 25%. Majority of cases were males, white, and occurred in sixth/seventh decades. Twenty-six percent of cases received CRT, 20% underwent LS+AT or CS+AT, 20% underwent LS or CS only, and 17% underwent RT alone. On multivariate analysis, CS (HR 0.42, 95% CI: 0.26-0.69), CS+AT (HR 0.44, 95% CI: 0.36-0.77), CRT (HR 0.48, 95% CI: 0.35-0.67), and RT (HR, 0.66 95% CI: 0.46-0.94) were associated with decreased likelihood of death compared to NT. Elderly patients and those with poor performance status had worse outcomes even on multivariate analysis. CONCLUSIONS: TSCC is increasingly treated with surgery and systemic therapy in addition to RT, with improved survival outcomes. CS, CS+AT, CRT, or RT provided improved survival advantage in patients with variable levels of improvement based on the extent of the disease. Prospective trials would help differentiate survival advantages between treatment modalities. Patients' goals of care, comorbidities, and age should be considered when deciding appropriate treatment recommendations. LEVEL OF EVIDENCE: NA Laryngoscope, 130:405-412, 2020.

Nomogram for preoperative prediction of nodal extracapsular extension or positive surgical margins in oropharyngeal squamous cell carcinoma.

INTRODUCTION: Extracapsular extension (ECE) in regional lymph nodes and positive surgical margins (PSM) are considered high-risk adverse pathologic features in patients with oropharyngeal squamous cell carcinoma (OPSCC) that each constitute an indication for postoperative adjuvant chemoradiation. We identify pre-operative clinical factors that can predict post-operative ECE and/or PSM and create a nomogram to help clinical decision making. METHODS: Adult patients with non-metastatic OPSCC with initial surgical treatment and confirmed HPV status diagnosed between 2010 and 2014 were selected from the National Cancer Database. Clinical staging was modified to American Joint Committee on Cancer 8th edition parameters. Logistic regression was used for multivariate analysis to identify predictors of pathologic ECE and/or PSM. RESULTS: 5065 patients were included. 47.5% of the 3336 HPV-positive (HPV+) patients had ECE/PSM. 40.4% of the 1729 HPV-negative (HPV-) patients with had ECE/PSM. A model was built that included age, clinical ECE, tumor grade, and clinical T and N staging for HPV+ patients. Increasing N-classification was highly predictive of pathologic ECE and/or PSM (N1 OR = 3.6, N2 OR = 7.0, N3 OR = 11.2, p < 0.01). Clinical ECE (OR = 4.1, p < 0.01), tumor grade (ORs 2.2-4.4 with p < 0.05), and increasing clinical T-classification (ORs 1.2-1.8, p < 0.05) were also associated with ECE and/or PSM. A similar model was built for HPV- with similar predictive capability. Two internally validated nomograms were designed that demonstrated good discrimination (HPV+ AUC = 0.66, 95% CI: 0.64-0.68, and HPV- AUC = 0.70, 95% CI: 0.67-0.72) and good calibration (goodness-of-fit statistic of HPV+ 6.32, p = 0.61 and HPV- 11.66, p = 0.17). CONCLUSIONS: These are the first nomograms designed to help predict ECE or PSM for both HPV+ and HPV- OPSCC. The nomograms can facilitate shared decision-making between clinicians and patients as they consider upfront treatment selection for OPSCC.

Survival impact and toxicity of metformin in head and neck cancer: An analysis of the SEER-Medicare dataset.

OBJECTIVES: Recent preclinical research has renewed interest in the interplay between glucose dysregulation and cancer. Metformin holds promise as an adjunctive antineoplastic agent in head and neck cancer (HNC). We aimed to explore the impact of metformin in HNC patients from a population-based dataset. PATIENTS & METHODS: Patients diagnosed with HNC from 2008 to 2011 were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked dataset and categorized into three groups: non-diabetics (nD), diabetics not taking metformin (DnM), and diabetics taking metformin (D + M). Overall survival (OS) and cancer-specific survival (CSS) were compared between groups using Kaplan-Meier and Cox regression controlling for sociodemographic, clinical, and treatment covariates. The incidence of toxicities associated with HNC therapy was compared among groups using χ2 analysis. RESULTS: Among 1646 patients, there were 1144 nD, 378 DnM, and 124 D + M. 2-year OS rates was 65.6% for nD, 57.7% for DnM, and 73.4% for D + M by Kaplan-Meier (p < 0.01), and corresponding rates of 2-year CSS were 73.7%, 66.1%, and 88.8% (p < 0.01), respectively. On Cox multivariable analysis, OS among the three groups did not significantly differ; however, CSS was significantly worse among both nD versus DnM as compared to D + M. Toxicity rates were not significantly increased among D + M. CONCLUSION: HNC patients with diabetes taking metformin experience improved CSS. Prospective investigation of the addition of metformin to standard-of-care HNC therapy is warranted.

Hypofractionated Radiotherapy Is Superior to Conventional Fractionation in an Orthotopic Model of Anaplastic Thyroid Cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive and highly lethal disease with poor outcomes and resistance to therapy. Despite multimodality treatment, including radiation therapy and chemotherapy, response rates remain <15%, with a median time to progression of less than three months. Recent advances in radiotherapy (RT) delivery and gene-expression profiling may help guide patient selection for personalized therapy. The purpose of this study was to characterize the response to radiation in a panel of ATC cell lines and to test alternative RT fractionation schedules for overcoming radioresistance. MATERIALS AND METHODS: The cellular response to radiation was characterized based on clonogenic assays. Radiation response was correlated with microarray gene-expression data. Hypofractionated and conventional RT was tested in an orthotopic ATC tumor model, and tumor growth was assayed locally and distantly with in vivo and ex vivo bioluminescence imaging. RESULTS: A spectrum of radiosensitivities was observed in ATC cell lines. Radioresistant cell lines had higher levels of CXCR4 compared to radiosensitive cell lines. Compared to conventionally fractionated RT, hypofractionated RT resulted in significantly improved tumor growth delay, decreased regional and distant metastases, and improved overall survival. CONCLUSIONS: The findings demonstrate the heterogeneity of response to radiation in ATC tumors and the superiority of hypofractionated RT in improving local control, metastatic spread, and survival in preclinical models. These data support the design of clinical trials targeting radioresistant pathways in combination with hypofractionated RT.

Resistance to Radiotherapy and PD-L1 Blockade Is Mediated by TIM-3 Upregulation and Regulatory T-Cell Infiltration.

Purpose: Radiotherapy (RT) can transform the immune landscape and render poorly immunogenic tumors sensitive to PD-L1 inhibition. Here, we established that the response to combined RT and PD-L1 inhibition is transient and investigated mechanisms of resistance.Experimental Design: Mechanisms of resistance to RT and PD-L1 blockade were investigated in orthotopic murine head and neck squamous cell carcinoma (HNSCC) tumors using mass cytometry and whole-genome sequencing. Mice were treated with anti-PD-L1 or anti-TIM-3 alone and in combination with and without RT. Tumor growth and survival were assessed. Flow cytometry was used to assess phenotypic and functional changes in intratumoral T-cell populations. Depletion of regulatory T cells (Treg) was performed using anti-CD25 antibody.Results: We show that the immune checkpoint receptor, TIM-3, is upregulated on CD8 T cells and Tregs in tumors treated with RT and PD-L1 blockade. Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC. Despite this treatment combination, the response was not durable, and analysis of relapsed tumors revealed resurgence of Tregs. Targeted Treg depletion, however, restored antitumor immunity in mice treated with RT and dual immune checkpoint blockade and resulted in tumor rejection and induction of immunologic memory.Conclusions: These data reveal multiple layers of immune regulation that can promote tumorigenesis and the therapeutic potential of sequential targeting to overcome tumor resistance mechanisms. We propose that targeted Treg inhibitors may be critical for achieving durable tumor response with combined radiotherapy and immunotherapy. Clin Cancer Res; 24(21); 5368-80. ©2018 AACR.

Risk of Type 2 Diabetes Mellitus following Gestational Diabetes Pregnancy in Women with Polycystic Ovary Syndrome.

BACKGROUND: This study examines gestational diabetes mellitus (GDM) in women with polycystic ovary syndrome (PCOS) and the risk of type 2 diabetes mellitus (DM) following GDM pregnancy. METHODS: A cohort of 988 pregnant women with PCOS who delivered during 2002-2005 was examined to determine the prevalence and predictors of GDM, with follow-up through 2010 among those with GDM to estimate the risk of DM. RESULTS: Of the 988 pregnant women with PCOS, 192 (19%) developed GDM. Multivariable predictors of GDM included older age, Asian race, prepregnancy obesity, family history of DM, preconception metformin use, and multiple gestation. Among women with PCOS and GDM pregnancy, the incidence of DM was 2.8 (95% confidence interval (CI) 1.9-4.2) per 100 person-years and substantially higher for those who received pharmacologic treatment for GDM (6.6 versus 1.5 per 100 person-years, p < 0.01). The multivariable adjusted risk of DM was fourfold higher in women who received pharmacologic treatment for GDM (adjusted hazard ratio 4.1, 95% CI 1.8-9.6). The five-year incidence of DM was 13.1% overall and also higher in the pharmacologic treatment subgroup (27.0% versus 7.1%, p < 0.01). CONCLUSIONS: The strongest predictors of GDM among women with PCOS included Asian race and prepregnancy obesity. Pharmacologic treatment of GDM is associated with fourfold higher risk of subsequent DM.

Oral health considerations in older women receiving oral bisphosphonate therapy.

Recent reports of bisphosphonate-related osteonecrosis of the jaw (BRONJ) have increased awareness of oral health in patients receiving osteoporosis therapy. This study describes the demographic, oral health, and clinical characteristics of a contemporary population of women aged 50 and older undergoing oral bisphosphonate treatment who returned a mailed questionnaire pertaining to dental symptoms. The study, as previously reported, was conducted within Kaiser Permanente Northern California, a large, integrated healthcare delivery system. The cohort included 7,909 women with bisphosphonate exposure of at least 1 year, with a subset of 923 women reporting dental symptoms who underwent clinical examination. Overall, the average age was 71 ± 9; 70% were white, and 74% had at least some college education. Nearly two-thirds had received oral bisphosphonate therapy for 3 or more years. Most reported daily tooth brushing, 85% had had a dental examination in the past year, 22% reported denture use, and 6% reported moderate to severe periodontal disease. Oral healthcare patterns varied according to age and race and ethnicity. Five hundred seven (6.4%) women reported a tooth extraction in the prior year, of whom two developed BRONJ (0.4%). Tori or exostoses were found in 28% of examined participants with dental symptoms; these were predominantly in the lingual mandible and palate, with palatal BRONJ occurring in 1.6% of symptomatic participants with palatal tori. In summary, among older women with bisphosphonate exposure, oral health varied according to patient characteristics, and BRONJ occurred more frequently after tooth extraction or on palatal tori. These data support efforts to optimize oral health and to identify risk factors for BRONJ in older individuals receiving bisphosphonate drugs.