Osseous Changes Over Time in Free Fibular Flap Reconstruction.

OBJECTIVES/HYPOTHESIS: Evaluate bone resorption in free fibular grafts and document resorption behavior as compared to dentulous and edentulous autochthonous mandibular bone. STUDY DESIGN: Retrospective Chart review. METHODS: Postoperative computed tomography images were used to evaluate fibular graft resorption rates and corresponding sites of the dentulous or edentulous mandible. Bone height, width, and cortical thickness were measured. RESULTS: Eighteen patients underwent fibula free flap reconstruction following resection of a primary head and neck cancer. Mandibular defects were classified using Jewer's classification. The average interval loss of osseous height was 0.23 ± 0.09 mm/yr for fibula flap, 0.55 ± 0.13 mm/yr for dentulous native mandible, and 0.98 ± 0.41 mm/yr in edentulous native mandible. Change in osseous width was 0.19 ± 0.08 mm/yr, 0.55 ± 0.33 mm/yr, and 0.73 ± 0.15 mm/yr, respectively. Rate of superior cortical resorption was 0.33 ± 0.34 mm/yr, 0.35 ± 0.13 mm/yr, and 0.53 ± 0.11 mm/yr in fibula flap, dentulous, and edentulous mandible, respectively. Inferior cortical resorption rates were quantified as 0.30 ± 0.11 mm/yr, 0.35 ± 0.08 mm/yr, and 0.51 ± 0.08 mm/yr. CONCLUSIONS: Fibula free flap reconstruction of the mandible provides excellent functional results and allows for stable outcomes. Bone resorption is significantly lower in fibular graft compared with both edentulous and dentulous mandible. Edentulous bone displays significantly increased rates of atrophy in comparison to the dentulous mandible. This may have implications with regard to long-term viability of both the fibular flap and native mandible. The role of dental restoration on overall osseous stability warrants further research. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1113-1116, 2019.

High-throughput screens identify HSP90 inhibitors as potent therapeutics that target inter-related growth and survival pathways in advanced prostate cancer.

The development of new treatments for castrate resistant prostate cancer (CRPC) must address such challenges as intrinsic tumor heterogeneity and phenotypic plasticity. Combined PTEN/TP53 alterations represent a major genotype of CRPC (25-30%) and are associated with poor outcomes. Using tumor-derived, castration-resistant Pten/Tp53 null luminal prostate cells for comprehensive, high-throughput, mechanism-based screening, we identified several vulnerabilities among >1900 compounds, including inhibitors of: PI3K/AKT/mTOR, the proteasome, the cell cycle, heat shock proteins, DNA repair, NFκB, MAPK, and epigenetic modifiers. HSP90 inhibitors were one of the most active compound classes in the screen and have clinical potential for use in drug combinations to enhance efficacy and delay the development of resistance. To inform future design of rational drug combinations, we tested ganetespib, a potent second-generation HSP90 inhibitor, as a single agent in multiple CRPC genotypes and phenotypes. Ganetespib decreased growth of endogenous Pten/Tp53 null tumors, confirming therapeutic activity in situ. Fifteen human CRPC LuCaP PDX-derived organoid models were assayed for responses to 110 drugs, and HSP90 inhibitors (ganetespib and onalespib) were among the select group of drugs (<10%) that demonstrated broad activity (>75% of models) at high potency (IC50 <1 µM). Ganetespib inhibits multiple targets, including AR and PI3K pathways, which regulate mutually compensatory growth and survival signals in some forms of CRPC. Combined with castration, ganetespib displayed deeper PDX tumor regressions and delayed castration resistance relative to either monotherapy. In all, comprehensive data from near-patient models presents novel contexts for HSP90 inhibition in multiple CRPC genotypes and phenotypes, expands upon HSP90 inhibitors as simultaneous inhibitors of oncogenic signaling and resistance mechanisms, and suggests utility for combined HSP90/AR inhibition in CRPC.

Randomized Prospective Evaluation of Intraoperative Intravenous Acetaminophen in Pediatric Adenotonsillectomy.

Objective To establish the safety and efficacy of single-dose intraoperative intravenous (IV) acetaminophen in postoperative pain management following adenotonsillectomy in addition to a standardized regimen of oral pain medication. Study Design Randomized, controlled prospective clinical trial. Setting Single academic medical center. Subjects and Methods Patients between the ages of 3 and 17 years scheduled for tonsillectomy or adenotonsillectomy by a single surgeon between December 2014 and November 2016 were recruited. Patients were randomly assigned to 1 of 2 groups; group 1 received a single intraoperative dose of IV acetaminophen, and group 2 did not. Induction and maintenance of anesthesia, as well as operative technique, were standardized. Nursing pain scores, pain medications administered, and recovery times were reviewed during the 24-hour postoperative period. Postoperative pain regimen included standing alternating oral acetaminophen and ibuprofen. Results In total, 260 patients were included in the study, and 131 (50.4%) received a single intraoperative dose of IV acetaminophen. Patients receiving IV acetaminophen were more likely to experience postoperative nausea and vomiting than patients who did not receive IV acetaminophen (1.53% vs 0.00%, P = .016). There were no significant differences noted for postoperative pain scores, requirements for breakthrough pain medications, time to discharge from the recovery room or hospital, or postoperative complications. Conclusion The use of a single intraoperative dose of IV acetaminophen was associated with minimal additional adverse effects. However, a single intraoperative IV dose of acetaminophen added to standard narcotic and nonnarcotic pain medication does not provide a statistically significant improvement in pain control.

Salivary cotinine levels in children with otolaryngological disorders.

OBJECTIVE: To determine if salivary cotinine, a biomarker for tobacco smoke exposure, is elevated more often or to a higher degree in children meeting criteria for tonsillectomy or tympanostomy tube insertion. METHODS: Saliva samples were obtained from 3 groups of children for salivary cotinine measurement. Group 1 served as healthy controls. Group 2 consisted of subjects meeting tympanostomy tube criteria. Group 3 consisted of patients meeting tonsillectomy criteria. Environmental tobacco smoke (ETS) exposure was defined as a salivary cotinine concentration ≥1.0 ng/mL. Demographic data, smoke exposure history, and co-morbidities were also determined. RESULTS: 331 patients were included, with 112 in Group 1, 111 in Group 2, and 108 in Group 3. No differences were encountered for smoke exposure by history or smoker's identity, salivary cotinine level, or frequency of positive cotinine results. 42.6% of Group 1 had positive salivary cotinine compared to 51.8% of Group 2 and 47.7% of Group 3. Group 1 had a mean salivary cotinine level of 2.42 ng/mL compared to 2.54 ng/mL in Group 2 and 2.60 ng/mL in Group 3. The frequency of positive cotinine levels was higher than expected based on parental history. Among subjects with positive cotinine levels, 93 had no ETS exposure, and 64 had ETS exposure by history. CONCLUSION: Approximately 50% of children who undergo tonsillectomy and tympanostomy tube insertion have objective evidence of ETS exposure. Parental history underestimates passive smoke exposure, which can impact perioperative care.