Little is known about the effects of common cooking processes on cocoa flavanols. Antioxidant activity, total polyphenols (TP), flavanol monomers, and procyanidin oligomers were determined in chocolate frosting, a hot cocoa drink, chocolate cookies, and chocolate cake made with natural cocoa powder. Recoveries of antioxidant activity, TP, flavanol monomers, and procyanidins ranged from 86% to over 100% in the chocolate frosting, hot cocoa drink, and chocolate cookies. Losses were greatest in the chocolate cake with recoveries ranging from 5% for epicatechin to 54% for antioxidant activity. The causes of losses in baked chocolate cakes were investigated by exchanging baking soda with baking powder or combinations of the 2 leavening agents. Use of baking soda as a leavening agent was associated with increased pH and darkening color of cakes. Losses of antioxidant activity, TP, flavanol monomers, and procyanidins were associated with an increased extractable pH of the baked cakes. Chocolate cakes made with baking powder for leavening resulted in an average extractable pH of 6.2 with essentially complete retention of antioxidant activity and flavanol content, but with reduced cake heights and lighter cake color. Commercially available chocolate cake mixes had final pHs above 8.3 and contained no detectable monomeric flavanols after baking. These results suggest that baking soda causes an increase in pH and subsequent destruction of flavanol compounds and antioxidant activity. Use of an appropriate leavening agent to moderate the final cake pH to approximately 7.25 or less results in both good leavening and preservation of cocoa flavanols and procyanidins.

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.

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

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.

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This study is the first to offer insight into C1-INH-HAE education and management principles in otolaryngology training programs. Surveyed program directors believe residents need a strong knowledge base in the management of C1-INH-HAE but less than half feel their trainees acquire the necessary exposure to this emergent disease process. Future research efforts in this area should aim to determine optimal educational activities as well as how to best incorporate this into otolaryngology residency curricula.

The worst commercial nuclear accident and the first large‐scale voluntary evacuation due to a nuclear event in United States history took place at Three Mile Island (TMI) in 1979. Within a short time, there was a well‐recognized impact of the TMI accident by public health officials and academicians upon mental health of nearby residents—particularly pregnant women. Despite long‐term and detailed follow‐up of this population for cancer outcomes, community concerns continue. Herein, we conduct a scoping and process review of fetal/maternal/child health (MCH) and cancer health outcomes, and consider the findings in light of subsequent accidents. The process evaluation is enhanced by unpublished transcripts of the Pennsylvania Department of Health's (PA DOH) TMI Advisory Panel on Health Research Studies (APHRS), comprised of experts from prominent US research institutions. Research and process strengths included a rapid initial house‐to‐house health census of over 35,000 individuals, intense medical record reviews, in‐person interviews of pregnant women within a 10‐mile radius, and coordination of multiple parallel studies by PA DOH with APHRS collaboration. Major limitations include (1) errors in causal inference, (2) limited radiation exposure assessment, (3) failure to include TMI never‐exposed groups in risk estimates, (4) exclusion of vulnerable populations, (5) nonindexed/never published investigations, and (6) government‐stated need for long‐term MCH follow‐up that was never conducted. Lingering unaddressed actual and perceived risks were identified as major common themes among TMI, Chernobyl and Fukushima accidents. These findings underscore the need for the establishment of mechanisms to ensure long‐term follow‐up and preaccident protocols designed to address major health issues with inclusion of vulnerable populations and perceived risks.

Androgen-deprivation therapy (ADT) remains the gold-standard therapy for prostate cancer (PrCa), and although ADT is initially effective, most men progress to castrate-resistant prostate cancer (CRPC) within 2-3 years. Advanced CRPC is challenging to treat because intrinsic tumor heterogeneity and phenotypic plasticity engender short-lived responses and underlie resistance to conventional therapies. Combined PTEN/TP53 alterations represent a major genotype of advanced CRPC (25-30%) and are associated with poor clinical outcomes. Established PrCa cell lines do not accurately represent the heterogeneity of advanced CRPC, and therefore, nonbiased pharmacogenomics screens have not been done. The development of clinically representative, tractable models suitable for high-throughput target identification and validation is crucial for advancing novel CRPC therapies to the clinic. A comprehensive nonbiased high-throughput screen performed on seven cell lines derived from a genetically engineered mouse model (GEMM) of Pten/Tp53 null PrCa identified strongly active compounds, including inhibitors of PI3K/AKT/mTOR signaling, the proteasome, cell cycle regulatory proteins, heat shock proteins, DNA repair signaling, NFKB signaling, MAPK signaling, and several types of epigenetic modifiers. HSP90 inhibitors were one of the most efficacious classes of compounds in the screen, and ganetespib, a clinically used second-generation HSP90 inhibitor with a favorable safety profile, was the most potent. Although HSP90 inhibitors have yet to be successful as single agents, they have not been thoroughly investigated in clinically representative models of advanced PrCa and have shown potential as “network drugs,” prompting our investigations into their utility in polytherapy. We first validated ganetespib as a single agent, where it displayed strong activity against several GEMM-derived and LuCaP PDX-derived organoid models encompassing genotypic, phenotypic, and lineage heterogeneity. These 10 novel LuCaP PDX-derived organoids are representative of the numerous categories of CRPC, including adenocarcinomas with wild-type AR, adenocarcinomas with altered AR, adenocarcinoma with neuroendocrine features, and neuroendocrine disease. Single-agent ganetespib was also strongly inhibitory in vivo, decreasing growth of Pten/Tp53 null endogenous GEMM tumors as well as a human PDX tumor. Mechanistic interrogation of cell lines, organoids, and tumors exposed to ganetespib revealed inhibition of targets from several inter-related networks including AR and pAKT, two central and mutually compensatory growth and survival pathways for PrCa. The efficacy of ganetespib against a diverse group of CRPC organoids and the simultaneous inhibition of PrCa survival signaling suggested it may work well in combination. We performed a proof-of-principle high-throughput matrix screen on organoids derived from a Pten/Tp53 null GEMM and identified docetaxel and etoposide to be synergistic when combined with ganetespib. Preclinical in vivo studies to validate these findings are ongoing. In all, comprehensive data from multiple near-patient models suggest novel contexts for second-generation HSP90-directed intervention against a variety of CRPC genotypes and phenotypes and expand upon the potential of HSP90 inhibitors to simultaneously inhibit oncogenic signaling and compensatory resistance mechanisms. Citation Format: Keith H. Jansson, John B. Tucker, Lauren E. Stahl, John K. Simmons, Caitlyn Fuller, Michael L. Beshiri, Supreet Agarwal, Yasmine Abbey, Lei Fang, Paul G. Hynes, Alilin Aian Neil, Jacob Cawley, Ross Lake, Crystal Tran, Caitlin M. Tice, JuanJuan Yin, Xiahu Zhang, Rajarshi Guha, Shelley Hoover, R. Mark Simpson, Holly Nguyen, Eva Corey, Craig J. Thomas, David Proia, Kathleen Kelly. A high-throughput screen identifies HSP90 inhibitors as potent therapeutics across multiple clinically representative organoid models of advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B018.