Cardiac involvement in female carriers of duchenne or becker muscular dystrophy.

INTRODUCTION: The significance of abnormal cardiac measures in asymptomatic females who harbor dystrophin gene mutations is controversial. METHODS: Echo-measures of ventricular function were compared with published norms in a cross-sectional study of 130 (age, 39 ± 15.7 years) "carriers" of Duchenne or Becker muscular dystrophy (DMD/BMD). Correlations between cardiomyopathy (CM) and mutation, creatine kinase (CK) levels, age, and muscle symptoms were investigated. RESULTS: Depending on definition, CM prevalence was 3-33%. Ejection fraction (Simpson method) was < 55% in 9 (13%) and < 40% in 2 (2.9%). Eleven (8.5%) had wall motion abnormalities. Left ventricular end-systolic dimensions were increased in 7 (5.7%) and end-diastolic in 17 (13.9%). CM did not correlate with mutation type, DMD or BMD phenotype, CK level, muscle symptoms, or age. CONCLUSIONS: Occult CM can be found by screening in DMD/BMD carriers. Its lack of age-correlation suggests that not all abnormalities progress. Optimum screening schedules require a better understanding of progressive CM. Muscle Nerve 55: 810-818, 2017.

Hypermetabolism on (18)F-Fluorodeoxyglucose Positron Emission Tomography Scan Does Not Influence the Interpretation of Thyroid Cytopathology, and Nodules with a SUVmax <2.5 Are Not at Increased Risk for Malignancy.

BACKGROUND: Hypermetabolism of thyroid nodules on (18)F-fluorodeoxyglucose positron emission tomography (PET) is associated with a higher prevalence of malignancy. However, the definition of hypermetabolism and its impact on cytological interpretation are unclear. METHODS: Medical records of all patients with thyroid nodules who had undergone cytological evaluation at the Moffitt Cancer Center between October 2008 and May 2014 were retrospectively reviewed. Those with a PET scan performed within one year of the cytology composed the study group, and the rest were used as controls. The distribution of the cytological categories, percentage of resection, and prevalence of malignancy among each Bethesda category was compared between both groups. RESULTS: Fifteen percent (436) of all thyroid nodules with cytological evaluation were in the study group. Maximum standardized uptake values (SUVmax) were directly associated with the probability of having a malignant or a follicular neoplasm cytological diagnosis; and inversely associated with the probability of having a benign cytological diagnosis. However, the prevalence of cancer within each Bethesda category was not associated with SUVmax values. It was found that the prevalence of malignant cytology increased to >5% with SUVmax values ≥2.5. SUVmax values were significantly higher in malignant than in benign nodules on histology (mean values 10.8 vs. 5) but with significant overlap between both groups for either the whole cohort or nodules with indeterminate cytology only limiting its use for differential diagnosis. CONCLUSIONS: The prevalence of malignancy in thyroid nodules with a SUVmax <2.5 is similar to the general population, and management should not be modified in those patients. The increased prevalence of malignancy among hypermetabolic thyroid nodules (SUVmax ≥2.5) is well characterized by cytology and does not impact the interpretation of cytological categories. Therefore, SUVmax value does not add relevant information once cytology is available.

Effect of actionable somatic mutations on racial/ethnic disparities in head and neck cancer prognosis.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and minorities have the worst survival. However, the molecular mechanisms underlying survival disparities have not been elucidated. METHODS: In a retrospective study, we assessed association between HNSCC early death (<2 years) and 208 somatic mutations of 10 cancer-related genes in 214 patients: 98 non-Hispanic whites (46%), 72 Hispanic whites (34%), and 44 African Americans (20%). RESULTS: Hispanic whites and African Americans had significantly higher mutation rates for EGFR, HRAS, KRAS, and TP53. HNSCC early death was significantly associated with 3+ mutations (odds ratio [OR] = 2.78, 95% confidence interval [CI] = 1.16, 6.69), NOTCH1 mutations in non-Hispanic whites (OR = 5.51; 95% CI = 1.22-24.83) and TP53 mutations in Hispanic whites (OR = 3.84; 95% CI = 1.08-13.68) in multivariable analysis adjusted for age, sex, tumor site, and tumor stage. CONCLUSION: We have provided the proof-of-principal data to link racial/ethnic-specific somatic mutations and HNSCC prognosis and pave the way for precision medicine to overcome HNSCC survival disparities. © 2016 Wiley Periodicals, Inc. Head Neck 38:1234-1241, 2016.

The Effects of Preoperative Embolization on Carotid Body Paraganglioma Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: There is no definitive consensus on the impact of preoperative embolization on carotid body paraganglioma management. The purpose of this study was to assess the effects of preoperative embolization on carotid body paraganglioma excision. DATA SOURCES: A systematic search was conducted without limits, and it included studies published on or before July 2013 from PubMed, CINAHL, Web of Knowledge, and the Cochrane Library. Relevant synonyms for the search terms "paraganglioma,""carotid body tumor," and "embolization" were applied. REVIEW METHODS: Studies evaluating patients undergoing surgical intervention with embolization for carotid body tumors were included. Two reviewers independently assessed the titles and abstracts for inclusion and extracted the data. The guidelines set forth by the Cochrane Collaboration were followed in the process of data extraction. Data were pooled with a fixed effects model, and standardized mean difference (SMD) and 95% confidence intervals (95% CIs) are reported. RESULTS: A total of 22 studies (15 nonrandomized studies with a comparator, 7 single-arm studies) were included, enrolling 578 patients with 607 tumors. Patients undergoing preoperative embolization had significantly less estimated blood loss compared with those of surgical excision only (12 studies; 295 tumors; SMD: -0.52; 95% CI: -0.77, -0.28). Patients undergoing preoperative embolization had less operative time compared with that of surgical excision only (6 studies; 174 tumors; SMD: -0.46; 95% CI: -0.77, -0.14). CONCLUSION: Surgical excision with preoperative embolization appears to decrease estimated blood loss and operative time when compared with that without preoperative embolization for carotid body paragangliomas.

Head and Neck Cancers, Version 1.2015.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (H&N) Cancers. These Insights describe the different types of particle therapy that may be used to treat H&N cancers, in contrast to traditional radiation therapy (RT) with photons (x-ray). Research is ongoing regarding the different types of particle therapy, including protons and carbon ions, with the goals of reducing the long-term side effects from RT and improving the therapeutic index. For the 2015 update, the NCCN H&N Cancers Panel agreed to delete recommendations for neutron therapy for salivary gland cancers, because of its limited availability, which has decreased over the past 2 decades; the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Head and neck cancers, version 2.2013. Featured updates to the NCCN guidelines.

These NCCN Guidelines Insights focus on nutrition and supportive care for patients with head and neck cancers. This topic was a recent addition to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers. The NCCN Guidelines Insights focus on major updates to the NCCN Guidelines and discuss the new updates in greater detail. The complete version of the NCCN Guidelines for Head and Neck Cancers is available on the NCCN Web site (NCCN.org).

EDNRB and DCC salivary rinse hypermethylation has a similar performance as expert clinical examination in discrimination of oral cancer/dysplasia versus benign lesions.

PURPOSE: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy. EXPERIMENTAL DESIGN: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR. RESULTS: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60-0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51-0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58-0.76). CONCLUSIONS: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available.

Intensity-modulated radiation therapy as primary treatment for oropharyngeal squamous cell carcinoma.

BACKGROUND: Over the past decade, intensity-modulated radiation therapy (IMRT) has gained widespread use in the treatment of head and neck cancer. METHODS: All patients with squamous cell carcinoma of the oropharynx treated with primary IMRT with or without chemotherapy over a 5-year period were reviewed. Outcomes and morbidity were analyzed and compared with previously published data. RESULTS: In all, 170 patients were included in the analysis. The 3-year local control, locoregional control, disease-free survival, and overall survival rates were 92%, 91%, 80%, and 87%, respectively. Feeding tubes were present in 55% of patients during treatment, but remained in only 1% 2 years following treatment. CONCLUSIONS: This study confirms that IMRT yields excellent treatment outcomes for oropharyngeal carcinoma. Although acute toxicity remains a problem, late toxicity rates are low and long-term feeding tube dependence is rare compared with conventional radiation therapy.

Chondrosarcoma of the subglottic larynx: submucosal microdissection with the operating microscope.

OBJECTIVES/HYPOTHESIS: Chondrosarcoma is a rare malignancy of the head and neck with fewer than 600 cases described in the literature. Treatment typically consists of conservation surgery with preservation of airway and preoperative voice quality. We describe five patients treated with a conservative transcervical approach utilizing the operating microscope for submucosal microdissection. STUDY DESIGN: Retrospective case series at a National Cancer Institute-designated comprehensive cancer center. METHODS: A retrospective case series from February 2004 to February 2011 was performed for all consecutive patients with laryngeal chondrosarcoma treated by the senior author with transcervical submucosal microdissection utilizing the operating microscope. RESULTS: Five patients with laryngeal chondrosarcoma were treated between February 2004 and February 2011. There were three male and two female patients who ranged in age from 56 to 87 years (mean, 72 years) at presentation. All five tumors were located at the level of the cricoid cartilage. Hoarseness was the most common presenting symptom (60%). Eighty percent of patients had limited vocal cord mobility. No patients required neck dissection or received radiation or chemotherapy. None of the five patients had recurrence after this approach. CONCLUSIONS: Laryngeal chondrosarcoma is a rare tumor. Conservative surgical resection remains the mainstay of treatment. The use of an operating microscope can aid in successful resection of laryngeal chondrosarcoma while preserving laryngeal mucosa and function. LEVEL OF EVIDENCE: 4.

Endoscopic repair of Zenker's diverticulum by harmonic scalpel.

PURPOSE: Although endoscopic staple-assisted esophagodiverticulostomy (ESED) has become the initial treatment of choice for most patients with Zenker's diverticulum (ZD), anatomical restraints prevent its use in all cases. We describe an endoscopic approach for treating ZD using the harmonic scalpel, which can be used in certain cases where diverticulum anatomy precludes ESED. MATERIALS AND METHODS: Medical records of 7 consecutive patients who underwent endoscopic repair of ZD using the harmonic scalpel (Harmonic Ace, Ethicon Endo-Surgery, Inc, Cincinnati, OH) were reviewed. Data collected included demographics, symptoms, surgical details, complications, and postoperative outcomes. Main outcome measures were time to resumption of oral diet, symptom resolution, and complications. RESULTS: All patients (N = 7) who underwent endoscopic repair of ZD using the harmonic scalpel resumed an oral diet at initial follow-up visit after surgery (mean, 7 days; range, 4-9 days) and rated their symptoms as being completely resolved at subsequent follow-up (mean, 4 months; range, 1.5-8 months). There were no complications. CONCLUSIONS: Endoscopic repair of ZD using the ultrasonic cutting shears is a safe and efficacious procedure that allows for endoscopic treatment in certain cases that cannot be treated by ESED. Further study is warranted in larger series to determine efficacy and safety compared with established endoscopic techniques.

HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a major component of the immune-suppressive network described in cancer and many other pathological conditions. We demonstrate that although MDSCs from peripheral lymphoid organs and the tumor site share similar phenotype and morphology, these cells display profound functional differences. MDSC from peripheral lymphoid organs suppressed antigen-specific CD8(+) T cells but failed to inhibit nonspecific T cell function. In sharp contrast, tumor MDSC suppressed both antigen-specific and nonspecific T cell activity. The tumor microenvironment caused rapid and dramatic up-regulation of arginase I and inducible nitric oxide synthase in MDSC, which was accompanied by down-regulation of nicotinamide adenine dinucleotide phosphate-oxidase and reactive oxygen species in these cells. In contrast to MDSC from the spleen, MDSC from the tumor site rapidly differentiated into macrophages. Exposure of spleen MDSC to hypoxia resulted in the conversion of these cells to nonspecific suppressors and their preferential differentiation to macrophages. Hypoxia-inducible factor (HIF) 1α was found to be primarily responsible for the observed effects of the tumor microenvironment on MDSC differentiation and function. Thus, hypoxia via HIF-1α dramatically alters the function of MDSC in the tumor microenvironment and redirects their differentiation toward tumor-associated macrophages, hence providing a mechanistic link between different myeloid suppressive cells in the tumor microenvironment.

Endothelin receptor type B gene promoter hypermethylation in salivary rinses is independently associated with risk of oral cavity cancer and premalignancy.

Endothelin receptor type B (EDNRB) and kinesin family member 1A (KIF1A) are candidate tumor suppressor genes that are inactivated in cancers. In this study, we evaluated the promoter hypermethylation of EDNRB and KIF1A and their potential use for risk classification in prospectively collected salivary rinses from patients with premalignant/malignant oral cavity lesions. Quantitative methylation-specific PCR was performed to analyze the methylation status of EDNRB and KIF1A in salivary rinses of 191 patients. We proceeded to determine the association of methylation status with histologic diagnosis and estimate classification accuracy. On univariate analysis, diagnosis of dysplasia/cancer was associated with age and KIF1A or EDNRB methylation. Methylation of EDNRB highly correlated with that of KIF1A (P < 0.0001). On multivariable modeling, histologic diagnosis was independently associated with EDNRB (P = 0.0003) or KIF1A (P = 0.027) methylation. A subset of patients analyzed (n = 161) without prior biopsy-proven malignancy received clinical risk classification based on examination. On univariate analysis, EDNRB and risk classification were associated with diagnosis of dysplasia/cancer and remained significant on multivariate analysis (EDNRB: P = 0.047, risk classification: P = 0.008). Clinical risk classification identified dysplasia/cancer with a sensitivity of 71% and a specificity of 58%. The sensitivity of clinical risk classification combined with EDNRB methylation improved to 75%. EDNRB methylation in salivary rinses was independently associated with histologic diagnosis of premalignancy and malignancy and may have potential in classifying patients at risk for oral premalignant and malignant lesions in settings without access to a skilled dental practitioner. This may also potentially identify patients with premalignant and malignant lesions that do not meet the criteria for high clinical risk based on skilled dental examination.

Lipid accumulation and dendritic cell dysfunction in cancer.

Dendritic cells (DCs), a type of professional antigen-presenting cells, are responsible for initiation and maintenance of immune responses. Here we report that a substantial proportion of DCs in tumor-bearing mice and people with cancer have high amounts of triglycerides as compared with DCs from tumor-free mice and healthy individuals. In our studies, lipid accumulation in DCs was caused by increased uptake of extracellular lipids due to upregulation of scavenger receptor A. DCs with high lipid content were not able to effectively stimulate allogeneic T cells or present tumor-associated antigens. DCs with high and normal lipid levels did not differ in expression of major histocompatibility complex and co-stimulatory molecules. However, lipid-laden DCs had a reduced capacity to process antigens. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. These findings suggest that immune responses in cancer can be improved by manipulating the lipid levels in DCs.

Otolaryngologic management of delayed pharyngoesophageal perforation following anterior cervical spine surgery.

Delayed pharyngoesophageal perforation is a rare complication following anterior cervical spine surgery. Patients usually present weeks to years after surgery with vague symptoms, such as dysphagia and neck pain. We report five cases of delayed pharyngoesophageal perforation following anterior cervical spine surgery with hardware fixation. Successful surgical management of these patients required removal of hardware and closure of the defect supported with a vascularized flap.

Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSC) are a major component of the immune suppressive network described in cancer and many other pathological conditions. Recent studies have demonstrated that one of the major mechanisms of MDSC-induced immune suppression is mediated by reactive oxygen species (ROS). However, the mechanism of this phenomenon remained unknown. In this study, we observed a substantial up-regulation of ROS by MDSC in all of seven different tumor models and in patients with head and neck cancer. The increased ROS production by MDSC is mediated by up-regulated activity of NADPH oxidase (NOX2). MDSC from tumor-bearing mice had significantly higher expression of NOX2 subunits, primarily p47(phox) and gp91(phox), compared with immature myeloid cells from tumor-free mice. Expression of NOX2 subunits in MDSC was controlled by the STAT3 transcription factor. In the absence of NOX2 activity, MDSC lost the ability to suppress T cell responses and quickly differentiated into mature macrophages and dendritic cells. These findings expand our fundamental understanding of the biology of MDSC and may also open new opportunities for therapeutic regulation of these cells in cancer.