Allen L. Feng

Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery

Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg.

Feasibility of rapid discharge after transoral robotic surgery of the oropharynx

To investigate the use of an algorithm for rapid discharge after transoral robotic surgery (TORS) and its effect on postoperative complications.

Characterization of Vestibulopathy in Individuals with Type 2 Diabetes Mellitus

Objective Previous observational studies suggest higher rates of vestibular dysfunction among patients with type 2 diabetes mellitus (DM) compared with those without diabetes. This study aims to functionally localize vestibular dysfunction in adults with type 2 DM. Study Design Prospective cohort study. Setting Tertiary academic medical center. Subjects and Methods Adults 50 years of age and older with ≥10-year history of type 2 DM were recruited (December 2011–February 2013, n = 25). Vestibular function was assessed by cervical and ocular vestibular-evoked myogenic potentials (VEMPs), testing the saccule and utricle, respectively. Head thrust dynamic visual acuity testing assessed semicircular canal (SCC) function in all canal planes. Results were compared with nondiabetic age-matched controls (n = 25). Results Subjects were 64.7 ± 7.6 years old, were 40% female, and had a mean hemoglobin A1c of 8.3% ± 1.7%. SCC dysfunction was more common than otoconial organ dysfunction, with 70% of subjects with DM demonstrating impaired performance of at least 1 SCC (ΔlogMAR ≥0.18) and 50% demonstrating otoconial organ impairment (absent ocular VEMP and/or cervical VEMP). Adults with type 2 DM had poorer lateral and superior SCC performance (P < .05) but similar posterior SCC performance compared with controls (P = .16). Both cervical VEMP peak-to-peak amplitude and ocular VEMP n1 amplitude were also decreased with diabetes (P < .01). Conclusion Adults with type 2 DM have poorer performance on tests of vestibular function related to both SCC and otoconial organ function compared with nondiabetic age-matched adults. Future studies are needed to better understand the relationship between vestibular function and functional disability in persons with diabetes.

Open-Label Single-Arm Phase II Trial of Sorafenib Therapy with Drug-eluting Bead Transarterial Chemoembolization in Patients with Unresectable Hepatocellular Carcinoma: Clinical Results

PURPOSE To determine the efficacy of combined continuous sorafenib therapy and drug-eluting bead (DEB) transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS This study was conducted in accordance with the principles of the Declaration of Helsinki, and all patients provided written informed consent prior to enrollment. Inclusion criteria included unresectable HCC, a treatment naïve status, an Eastern Cooperative Oncology Group score of 0-1, and a Child-Pugh score of A-B7. Continuous sorafenib therapy (400 mg twice daily) was started 1 week before the first round of DEB TACE, which was performed in 6-week cycles. Up to four rounds of DEB TACE therapy were allowed on demand within 6 months. The primary end point was safety. Secondary end points were time to progression (TTP), response rate, and overall survival (OS) and were stratified by the Barcelona Clinic Liver Cancer (BCLC) stage and the duration of sorafenib therapy. OS was assessed with Kaplan-Meier estimates, and the Mantel-Cox log-rank test was used to determine differences in survival. A two-sided P value of less than .05 was considered to indicate a significant difference. The study was approved by the Johns Hopkins institutional review board and remained open from March 2009 to January 2012. RESULTS Fifty patients--of whom 76% were male, 92% had a Child-Pugh score of A, and 62% had BCLC stage C disease--underwent a median of three cycles of therapy. The 6-month disease control rate (defined as complete response plus partial response plus stable disease) was 94% according to the response evaluation criteria in solid tumors. Median TTP and OS were 13.9 and 20.4 months, respectively, and 81% of toxicities were grades 1-2. There was one death that was possibly treatment related. CONCLUSION Combined continuous sorafenib therapy and on-demand DEB TACE provided excellent local disease control and did not lead to multiplicative toxicities. Long-term administration of sorafenib therapy in combination with DEB TACE may have a survival benefit in patients with advanced HCC.

Ethanol induced impairment of glucose metabolism involves alterations of GABAergic signaling in pancreatic β-cells

Alcohol overindulgence is a risk factor of type 2 diabetes mellitus. However, the mechanisms by which alcohol overindulgence damages glucose metabolism remain unclear. Pancreatic islet β-cells are endowed with type-A γ-aminobutyric acid receptor (GABAAR) mediated autocrine signaling mechanism, which regulates insulin secretion and fine-tunes glucose metabolism. In neurons GABAAR is one of the major targets for alcohol. This study investigated whether ethanol alters glucose metabolism by affecting GABAAR signaling in pancreatic β-cells. Blood glucose level of test mice was measured using a blood glucose meter. Insulin secretion by the pancreatic β-cell line INS-1 cells was examined using a specific insulin ELISA kit. Whole-cell patch-clamp recording was used to evaluate GABA-elicited current in INS-1 cells. Western blot and immunostaining were used to measure the expression of GABAAR subunits in mouse pancreatic tissues or in INS-1 cells. Intraperitoneal (i.p.) administration of ethanol (3.0g/kg body weight) to mice altered glucose metabolism, which was associated with decreased expression of GABAAR α1- and δ- subunits on the surface of pancreatic β-cells. Acute treatment of cultured INS-1cells with ethanol (60mM) decreased the GABA-induced current and reduced insulin secretion. In contrast, treating INS-1 cells with GABA (100μM) largely prevented the ethanol-induced reduction of insulin release. Importantly, pre-treating mice with GABA (i.p., 1.5mg/kg body weight) partially reversed ethanol-induced impairment of glucose homeostasis in mice. Our data suggest a novel role of pancreatic GABA signaling in protecting pancreatic islet β-cells from ethanol-induced dysfunction.

A validated model for the 22-item Sino-Nasal Outcome Test subdomain structure in chronic rhinosinusitis

Previous studies have identified subdomains of the 22‐item Sino‐Nasal Outcome Test (SNOT‐22), reflecting distinct and largely independent categories of chronic rhinosinusitis (CRS) symptoms. However, no study has validated the subdomain structure of the SNOT‐22. This study aims to validate the existence of underlying symptom subdomains of the SNOT‐22 using confirmatory factor analysis (CFA) and to develop a subdomain model that practitioners and researchers can use to describe CRS symptomatology.

Association between systemic antibiotic and corticosteroid use for chronic rhinosinusitis and quality of life

We sought to establish the significance of querying chronic rhinosinusitis (CRS) patients about their past CRS‐related oral antibiotic and corticosteroid usage by determining the association between these metrics and patients’ quality of life (QoL).

Long-term Functional Outcomes of Total Glossectomy With or Without Total Laryngectomy

IMPORTANCE The optimal reconstruction of total glossectomy defects with or without total laryngectomy is controversial. Various pedicled and free tissue flaps have been advocated, but long-term data on functional outcomes are not available to date. OBJECTIVES To compare various total glossectomy defect reconstructive techniques used by multiple institutions and to identify factors that may lead to improved long-term speech and swallowing function. DESIGN, SETTING, AND PARTICIPANTS A multi-institutional, retrospective review of electronic medical records of patients undergoing total glossectomy at 8 participating institutions between June 1, 2001, and June 30, 2011, who had a minimal survival of 2 years. INTERVENTION Total glossectomy with or without total laryngectomy. MAIN OUTCOMES AND MEASURES Demographic and surgical factors were compiled and correlated with speech and swallowing outcomes. RESULTS At the time of the last follow-up, 45% (25 of 55) of patients did not have a gastrostomy tube, and 76% (42 of 55) retained the ability to verbally communicate. Overall, 75% (41 of 55) of patients were tolerating at least minimal nutritional oral intake. Feeding tube dependence was not associated with laryngeal preservation or the reconstructive techniques used, including flap suspension, flap innervation, or type of flap used. Laryngeal preservation was associated with favorable speech outcomes, such as the retained ability to verbally communicate in 97% of those not undergoing total laryngectomy (35 of 36 patients) vs 44% (7 of 16) in those undergoing total laryngectomy (P < .001), as well as those not undergoing total laryngectomy achieving some or all intelligible speech in 85% (29 of 34 patients) compared with 31% (4 of 13) undergoing total laryngectomy achieving the same intelligibility (P < .001). CONCLUSIONS AND RELEVANCE In patients with total glossectomy, feeding tube dependence was not associated with laryngeal preservation or the reconstructive technique, including flap innervation and type of flap used. Laryngeal preservation was associated with favorable speech outcomes such as the retained ability to verbally communicate and higher levels of speech intelligibility.

The robotic ENT microsurgery system: A novel robotic platform for microvascular surgery

Assess the feasibility of a novel robotic platform for use in microvascular surgery.

Neck Incision Planning for Total Laryngectomy with Pharyngectomy

Objectives To investigate the effect of skin incision location for total laryngectomy with pharyngectomy (TLP) on postoperative outcomes including wound dehiscence and infection rate. Study Design Case series with chart review. Setting Academic tertiary care center. Methods A retrospective analysis was conducted of all patients undergoing TLP with flap closure at Johns Hopkins Medical Institutes between August 2005 and February 2013. The effects of patient characteristics and skin incision technique on postoperative wound dehiscence and infection were analyzed using cross-tabulations and multivariate regression modeling. Results A total of 49 patients were included in the analysis; 31 received low-neck apron (LNA) incisions with an incorporated tracheostoma, while the remaining 18 had mid-neck apron (MNA) incisions with separate tracheostoma fashioned inferior to their incisions. Of these patients, 17 experienced incisional wound dehiscence (35%), and 18 contracted postoperative infections (37%). Generalized linear regression models demonstrated a significantly increased odds of wound dehiscence for patients with LNA incisions (odds ratio 29.8; 95% CI, 1.4-631.5, P = .029). There were no significant predictive variables for postoperative infection. Conclusions These results demonstrate that the use of a separately fashioned tracheostoma with MNA incision is associated with decreased rate of wound dehiscence in patients undergoing TLP.