Rahul Seth

Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene

Background— Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded IKs cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder. Methods and Results— We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (≤50%) reduction in cardiac repolarizing IKs potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors. Conclusions— This genotype–phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

Outcomes of vascularized bone graft reconstruction of the mandible in bisphosphonate-related osteonecrosis of the jaws†‡

To describe the clinical entity and therapeutic challenges of bisphosphonate‐related osteonecrosis of the jaws (BRONJ). The use of vascularized bone grafts for reconstruction of the mandible in extensive BRONJ is proposed.

The utility of intrathecal fluorescein in cerebrospinal fluid leak repair

OBJECTIVE To evaluate the utility of intrathecal fluorescein (IF) for intraoperative localization and successful repair of cerebrospinal fluid (CSF) leaks. STUDY DESIGN Case series with chart review. SETTING Tertiary-care medical center. SUBJECTS AND METHODS Subjects included those undergoing endoscopic CSF leak repair with or without the use of IF. Informed consent was obtained from all patients undergoing the administration of IF (total dose 10 mg). RESULTS A total of 103 patients underwent CSF leak repair, and in 47 cases (45.6%), IF was used. Patients who were administered IF were more likely to have spontaneous CSF leak etiology (61.7% vs 16.1%; P < 0.001). Of the 47 cases with IF use, fluorescein was visualized at the skull base in 31 cases (66.0%), 11 (23.4%) had visible CSF leak without fluorescein coloration, and five (10.6%) had neither clear nor fluorescein-colored CSF visualized. Sensitivity and specificity for fluorescein detection was 73.8 percent (95% confidence interval [CI] 57.7%-85.6%) and 100 percent (95% CI 46.3%-100%), respectively. The false-negative rate was 26.2 percent (95% CI 15.8%-43.5%). Localization of the leak site was greater when fluorescein-colored CSF was visualized (100% vs 81.3%; P = 0.035). When fluorescein-colored CSF was not visualized intraoperatively, recurrence rates were 31.3 percent versus 9.7 percent when fluorescein coloration was seen, although this finding was not statistically significant (P = 0.10). CONCLUSION The use of IF facilitates the accurate localization of CSF leaks and may assist the surgeon in confirming a watertight closure. The lack of intraoperative fluorescein visualization should not rule out the presence of CSF leak, as evidenced by a false-negative rate of 26.2 percent.

HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with more than half a million people being diagnosed with the disease annually. Within the last 2 decades, the human papillomavirus (HPV) has been found to be associated with this malignancy. More recently, HPV‐infected HNSCC has been found to exhibit higher levels of global DNA methylation. In a recent study, we identified five tumor suppressive genes (IRX1, EBF3, SLC5A8, SEPT9, and FUSSEL18) as frequently methylated in HNSCC biopsies using a global methylation analysis via restriction landmark genomic scanning. In this study, we verify these genes as valid methylation markers in two separate sets of HNSCC specimens. By using the available clinical information linked to the patient specimens, we found a strong association between promoter methylation of FUSSEL18, IRX1, and EBF3 and prior radiation therapy (P < 0.0001) irrespective of HPV status. Also, promoter methylation of FUSSEL18 and SEPTIN9 was found to correlate significantly with exposure to alcohol and tobacco (P = 0.021). Importantly, in this study, we preliminarily show a trend between HPV16 positivity and specific target gene hypermethylation of IRX1, EBF3, SLC5A8, and SEPT9. If replicated in a larger study, the HPV status may be a patient selection biomarker when determining the most efficacious treatment modality for these different subsets of patients (e.g., inclusion or exclusion of epigenetic therapies). Equally notable and independent of HPV status, hypermethylation of the promoters of a subset of these genes in recurrences especially in the setting of prior radiation or in the setting of alcohol and tobacco use might help guide adjunctive inclusion or exclusion or epigenetic therapy.

Human Satellite Cell Transplantation and Regeneration from Diverse Skeletal Muscles

Summary Identification of human satellite cells that fulfill muscle stem cell criteria is an unmet need in regenerative medicine. This hurdle limits understanding how closely muscle stem cell properties are conserved among mice and humans and hampers translational efforts in muscle regeneration. Here, we report that PAX7 satellite cells exist at a consistent frequency of 2–4 cells/mm of fiber in muscles of the human trunk, limbs, and head. Xenotransplantation into mice of 50–70 fiber-associated, or 1,000–5,000 FACS-enriched CD56+/CD29+ human satellite cells led to stable engraftment and formation of human-derived myofibers. Human cells with characteristic PAX7, CD56, and CD29 expression patterns populated the satellite cell niche beneath the basal lamina on the periphery of regenerated fibers. After additional injury, transplanted satellite cells robustly regenerated to form hundreds of human-derived fibers. Together, these findings conclusively delineate a source of bona-fide endogenous human muscle stem cells that will aid development of clinical applications.

Spontaneous CSF leaks: factors predictive of additional interventions.

Spontaneous cerebrospinal fluid (CSF) leaks represent a significant challenge due to frequent association with elevated intracranial pressure (ICP) and higher risk of surgical failure. The study objective was to review management strategy and identify factors associated with need for acetazolamide and/or ventriculoperitoneal shunt (VPS) placement.

Microbiomic subprofiles and MDR1 promoter methylation in head and neck squamous cell carcinoma

Clinical observations and epidemiologic studies suggest that the incidence of head and neck squamous cell carcinoma (HNSCC) correlates with dental hygiene, implying a role for bacteria-induced inflammation in its pathogenesis. Here we begin to explore the pilot hypothesis that specific microbial populations may contribute to HNSCC pathogenesis via epigenetic modifications in inflammatory- and HNSCC-associated genes. Microbiomic profiling by 16S rRNA sequencing of matched tumor and adjacent normal tissue specimens in 42 individuals with HNSCC demonstrate a significant association of specific bacterial subpopulations with HNSCC over normal tissue (P < 0.01). Furthermore, microbial populations can separate tumors by tobacco status (P < 0.008), but not by alcohol status (P = 0.41). If our subhypothesis regarding a mechanistic link from microorganism to carcinogenesis via inflammation and consequent aberrant DNA methylation is correct, then we should see hypermethylation of relevant genes associate with specific microbiomic profiles. Methylation analysis in four genes (MDR1, IL8, RARB, TGFBR2) previously linked to HNSCC or inflammation shows significantly increased methylation in tumor samples compared with normal oral mucosa. Of these, MDR1 promoter methylation associates with specific microbiomic profiles in tumor over normal mucosa. Additionally, we report that MDR1 methylation correlates with regional nodal metastases in the context of two specific bacterial subpopulations, Enterobacteriaceae and Tenericutes (P < 0.001 for each). These associations may lead to a different, and potentially more comprehensive, perspective on the pathogenesis of HNSCC, and support further exploration of mechanistic linkage and, if so, novel therapeutic strategies such as demethylating agents and probiotic adjuncts, particularly for patients with advanced or refractory disease.

Total parotidectomy defect reconstruction using the buried free flap

OBJECTIVE 1) Present an alternative method of total parotidectomy with or without neck dissection defect reconstruction that results in improved cosmesis. 2) Describe applications of free tissue transfer in parotidectomy defect reconstruction. STUDY DESIGN Case series with chart review. SETTING Two tertiary-care medical centers. SUBJECTS AND METHODS A two-institution retrospective review from 2002 to 2009 was conducted for buried free flaps utilized in reconstruction of defects from total parotidectomy with or without neck dissection. Patients with temporal bone or skin resections were excluded. Demographic information, tumor characteristics, surgical interventions, flap details, and adjunctive facial reconstructive techniques were recorded. Postoperative cosmetic results were evaluated by patient and physician satisfaction. RESULTS Eighteen patients with a mean age of 57.4 years underwent flap reconstruction. Total parotidectomy was performed in all cases, 11 cases required facial nerve sacrifice, and 14 cases included neck dissection. The anterolateral thigh flap was the most often utilized free flap. Mean flap area was 65.5 cm2. Adjunctive static facial reanimation was employed in eight patients. All flaps survived. Ten patients underwent adjuvant radiation. Free flap reconstruction resulted in cosmetic patient and surgeon satisfaction, despite adjuvant radiation therapy. CONCLUSION Free flap reconstruction of total parotidectomy (with or without neck dissection) defects is safe and effective. It does not preclude adjunctive facial reanimation and provides sufficient tissue bulk to match the contralateral facial contour despite radical resections and adjuvant radiation therapy in most cases.

Patient reported outcomes in endoscopic and open transcervical treatment for Zenker's diverticulum

To compare long‐term symptomatic outcomes between external transcervical (ET) and endoscopic stapling diverticulotomy (ESD) surgeries for Zenkers diverticulum.

Minimally invasive endoscopic resection of sinonasal undifferentiated carcinoma

PURPOSE The purpose of the study was to review a single-institution experience with endoscopic resection of sinonasal undifferentiated carcinoma (SNUC). MATERIALS AND METHODS Thirteen patients underwent treatment of SNUC between January 2002 and July 2009. Retrospective data were collected including demographics, tumor characteristics, surgical strategy, adjuvant therapies, local and regional recurrence, distant metastasis, overall survival, and disease-free survival. RESULTS The mean age was 51.8 years. The most common tumor stage at presentation was T4 (92%). Seven patients (53%) were treated with minimally invasive endoscopic resection (MIER) with negative intraoperative margins. Endoscopic anterior skull base resection was performed in 5 patients, and endoscopic-assisted bifrontal craniotomy was performed in 1 patient to clear the superior tumor margin. Six patients received pre- or postoperative chemoradiation. One patient underwent palliative chemoradiation, and one patient underwent open craniofacial resection. In the MIER group, simultaneous local and regional recurrence was observed in 1 patient (14%) after 30 months. Distant metastases were observed in 2 other patients (28%) without local or regional recurrence. All 3 patients with recurrences died of their disease. The remaining 4 patients were clinically, endoscopically, and radiographically free of disease, resulting in overall and disease-free survival rates of 57% with mean follow-up of 32.3 months. CONCLUSIONS These preliminary data suggest a potential role for MIER in the comprehensive management algorithm of SNUC in appropriately selected patients. Patient outcomes including local and regional recurrence, distant metastases, and overall and disease-free survival were comparable to a treatment strategy using traditional craniofacial resection. LEVEL OF EVIDENCE 2b.