The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality.

BACKGROUND: The association of body composition with epithelial ovarian carcinoma (EOC) mortality is poorly understood. To date, evidence suggests high adiposity associates with decreased mortality (an obesity paradox), but the impact of muscle on this association has not been investigated. Herein, we define associations of muscle and adiposity joint-exposure body composition phenotypes with EOC mortality. METHODS: Body composition from 500 women in The Body Composition and Epithelial Ovarian Cancer Survival Study was dichotomized as normal/low skeletal muscle index (SMI), a proxy for sarcopenia and high/low adiposity. Four phenotypes were classified as fit/reference (normal SMI/low adiposity; 16.2%), overweight/obese (normal SMI/high adiposity; 51.2%), sarcopenia/overweight-obese (low SMI/high adiposity; 15.6%), and sarcopenia/cachexia (low SMI/low adiposity; 17%). We used multivariable Cox models to estimate associations of each phenotype with mortality for EOC overall and high-grade serous ovarian carcinoma (HGSOC). RESULTS: Overweight/obesity was associated with up to 51% and 104% increased mortality in EOC and HGSOC (HR = 1.51, 95% CI: 1.05-2.19 and HR = 2.04, 95% CI: 1.29-3.21). Sarcopenia/overweight-obesity was associated with up to 66% and 67% increased mortality in EOC and HGSOC (HR = 1.66, 95% CI: 1.13-2.45 and HR = 1.67, 95% CI: 1.05-2.68). Sarcopenia/cachexia was associated with up to 73% and 109% increased mortality in EOC and HGSOC (HR = 1.73, 95% CI: 1.14-2.63 and HR = 2.09, 95% CI: 1.25-3.50). CONCLUSIONS: Overweight/obesity, sarcopenia/overweight-obesity and sarcopenia/cachexia phenotypes were each associated with increased mortality in EOC and HGSOC. Exercise and dietary interventions could be leveraged as ancillary treatment strategies for improving outcomes in the most fatal gynecological malignancy with no previously established modifiable prognostic factors.

Association of Insomnia and Obstructive Sleep Apnea with Worse Oral Mucositis and Quality of Life in Head and Neck Cancer Patients Undergoing Radiation Therapy.

BACKGROUND: Patients with head and neck cancer (HNC) undergoing radiation therapy (RT) often experience sleep disturbances that may contribute to oral mucositis (OM) and quality of life (QOL). METHODS: Patients with HNC treated with RT at a single institution were examined. Sleep questionnaires were given on the first day of RT to assess for insomnia and obstructive sleep apnea (OSA). Patient-reported QOL and oral mucositis were assessed during RT. Associations between insomnia and OSA with QOL were assessed using the Mann-Whitney U test. Linear mixed models assessed associations with OM. RESULTS: Among 87 patients, 34 patients (39%) had subthreshold or greater insomnia and 47 patients (54%) screened positive for OSA. Upon RT completion, patients with subthreshold or greater insomnia had worse physical function (p = 0.005), fatigue (p = 0.01), insomnia (p < 0.001), and sticky saliva (p = 0.002). Patients screening positive for OSA had worse physical function (p = 0.01), sticky saliva (p = 0.02), fatigue (p = 0.007), insomnia (p = 0.009), and pain (p = 0.005). Upon linear mixed model evaluation, subthreshold or greater insomnia (p = 0.01) and positive OSA screen (p = 0.002) were associated with worse OM. CONCLUSION: Insomnia and OSA are highly prevalent in patients with HNC undergoing RT. These sleep disturbances are associated with worse QOL and OM during treatment.

A Dataset of Amphibian Species in U.S. National Parks.

National parks and other protected areas are important for preserving landscapes and biodiversity worldwide. An essential component of the mission of the United States (U.S.) National Park Service (NPS) requires understanding and maintaining accurate inventories of species on protected lands. We describe a new, national-scale synthesis of amphibian species occurrence in the NPS system. Many park units have a list of amphibian species observed within their borders compiled from various sources and available publicly through the NPSpecies platform. However, many of the observations in NPSpecies remain unverified and the lists are often outdated. We updated the amphibian dataset for each park unit by collating old and new park-level records and had them verified by regional experts. The new dataset contains occurrence records for 292 of the 424 NPS units and includes updated taxonomy, international and state conservation rankings, hyperlinks to a supporting reference for each record, specific notes, and related fields which can be used to better understand and manage amphibian biodiversity within a single park or group of parks.

Advancing PROTAC Characterization: Structural Insights through Adducts and Multimodal Tandem-MS Strategies.

Proteolysis targeting chimeras (PROTACs) are specialized molecules that bind to a target protein and a ubiquitin ligase to facilitate protein degradation. Despite their significance, native PROTACs have not undergone tandem mass spectrometry (MS) analysis. To address this gap, we conducted a pioneering investigation on the fragmentation patterns of two PROTACs in development, dBET1 and VZ185. Employing diverse cations (sodium, lithium, and silver) and multiple tandem-MS techniques, we enhanced their structural characterization. Notably, lithium cations facilitated comprehensive positive-mode coverage for dBET1, while negative polarity mode offered richer insights. Employing de novo structure determination on 2DMS data from degradation studies yielded crucial insights. In the case of VZ185, various charge states were observed, with [M + 2H]2+ revealing fewer moieties than [M + H]+ due to charge-related factors. Augmenting structural details through silver adducts suggested both charge-directed and charge-remote fragmentation. This comprehensive investigation identifies frequently dissociated bonds across multiple fragmentation techniques, pinpointing optimal approaches for elucidating PROTAC structures. The findings contribute to advancing our understanding of PROTACs, pivotal for their continued development as promising therapeutic agents.

Review of fragmentation of synthetic single-stranded oligonucleotides by tandem mass spectrometry from 2014 to 2022.

The fragmentation of oligonucleotides by mass spectrometry allows for the determination of their sequences. It is necessary to understand how oligonucleotides dissociate in the gas phase, which allows interpretation of data to obtain sequence information. Since 2014, a range of fragmentation mechanisms, including a novel internal rearrangement, have been proposed using different ion dissociation techniques. The recent publications have focused on the fragmentation of modified oligonucleotides such as locked nucleic acids, modified nucleobases (methylated, spacer, nebularine and aminopurine) and modification to the carbon 2'-position on the sugar ring; these modified oligonucleotides are of great interest as therapeutics. Comparisons of different dissociation techniques have been reported, including novel approaches such as plasma electron detachment dissociation and radical transfer dissociation. This review covers the period 2014-2022 and details the new knowledge gained with respect to oligonucleotide dissociation using tandem mass spectrometry (without priori sample digestion) during that time, with a specific focus on synthetic single-stranded oligonucleotides.

Skeletal muscle index is associated with long term outcomes after lobectomy for non-small cell lung cancer.

BACKGROUND: Skeletal muscle indices have been associated with improved peri-operative outcomes after surgical resection of non-small-cell lung cancer (NSCLC). However, it is unclear if these indices can predict long term cancer specific outcomes. METHODS: NSCLC patients undergoing lobectomy at our institute between 2009-2015 were included in this analysis (N = 492). Preoperative CT scans were used to quantify skeletal muscle index (SMI) at L4 using sliceOmatic software. Cox proportional modelling was performed for overall (OS) and recurrence free survival (RFS). RESULTS: For all patients, median SMI was 45.7 cm2/m2 (IQR, 40-53.8). SMI was negatively associated with age (R = -0.2; p < 0.05) and positively associated with BMI (R = 0.46; P < 0.05). No association with either OS or RFS was seen with univariate cox modelling. However, multivariable modelling for SMI with patient age, gender, race, smoking status, DLCO and FEV1 (% predicted), American Society of Anesthesiology (ASA) score, tumor histology and stage, and postoperative neoadjuvant therapy showed improved OS (HR = 0.97; P = 0.0005) and RFS (HR = 0.97; P = 0.01) with SMI. Using sex specific median SMI as cutoff, a lower SMI was associated with poor OS (HR = 1.65, P = 0.001) and RFS (HR = 1.47, P = 0.03). CONCLUSIONS: SMI is associated with improved outcomes after resection of NSCLC. Further studies are needed to understand the biological basis of this observation. This study provides additional rationale for designing and implementation of rehabilitation trials after surgical resection, to gain durable oncologic benefit.

Association of Body Mass Index With Outcomes Among Patients With Head and Neck Cancer Treated With Chemoradiotherapy.

Importance: Combined modality therapy, such as chemoradiotherapy, often results in significant morbidity among patients with head and neck cancer. Although the role of body mass index (BMI) varies based on cancer subtypes, its association with treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer remains unclear. Objective: To evaluate the role of BMI in treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer undergoing chemoradiotherapy. Design, Setting, and Participants: This retrospective, observational, single-institution cohort study conducted at a comprehensive cancer center included 445 patients with nonmetastatic head and neck cancer who underwent chemoradiotherapy from January 1, 2005, to January 31, 2021. Exposure: Normal vs overweight or obese BMI. Main Outcomes and Measures: Metabolic response after chemoradiotherapy, locoregional failure (LRF), distant failure (DF), overall survival (OS), and progression-free survival (PFS), with Bonferroni correction used to adjust for multiple comparisons and P < .025 being considered statistically significant. Results: A total of 445 patients (373 men [83.8%]; median age, 61 years [IQR, 55-66 years]; 107 [24.0%] with normal BMI, 179 [40.2%] with overweight BMI, and 159 [35.7%] with obese BMI) were included for analysis. Median follow-up was 48.1 months (IQR, 24.7-74.9 months). On Cox proportional hazards regression multivariable analysis, only overweight BMI was associated with improved OS (5-year OS, 71.5% vs 58.4%; adjusted hazard ratio [AHR], 0.59 [95% CI, 0.39-0.91]; P = .02) and PFS (5-year PFS, 68.3% vs 50.8%; AHR, 0.51 [95% CI, 0.34-0.75]; P < .001). On logistic multivariable analysis, overweight BMI (91.6% vs 73.8%; adjusted odds ratio [AOR], 0.86 [95% CI, 0.80-0.93]; P < .001) and obese BMI (90.6% vs 73.8%; AOR, 0.89 [95% CI, 0.81-0.96]; P = .005) were associated with complete metabolic response on follow-up positron emission tomography-computed tomography after treatments. On Fine-Gray multivariable analysis, overweight BMI was associated with reduction in LRF (5-year LRF, 7.0% vs 25.9%; AHR, 0.30 [95% CI, 0.12-0.71]; P = .01), but not DF (5-year DF, 17.4% vs 21.5%; AHR, 0.92 [95% CI, 0.47-1.77]; P = .79). Obese BMI was not associated with LRF (5-year LRF, 10.4% vs 25.9%; AHR, 0.63 [95% CI, 0.29-1.37]; P = .24) or DF (5-year DF, 15.0% vs 21.5%; AHR, 0.70 [95% CI, 0.35-1.38]; P = .30). Conclusion: In this cohort study of patients with head and neck cancer, when compared with normal BMI, overweight BMI was an independent factor favorably associated with complete response after treatments, OS, PFS, and LRF. Further investigations are warranted to improve understanding on the role of BMI among patients with head and neck cancer.

Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.

BACKGROUND: Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. METHODS: A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. RESULTS: A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82-0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72-0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12-2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08-2.63, p = 0.02). CONCLUSION: Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone Containing Different Degrees of Crystal Disorder.

Ball-milling and harsh manufacturing processes often generate crystal disorder which have practical implications on the physical and chemical stabilities of solid drugs during subsequent storage, transport, and handling. The impact of the physical state of solid drugs, containing different degrees/levels of crystal disorder, on their autoxidative stability under storage has not been widely investigated. This study investigates the impact of differing degrees of crystal disorder on the autoxidation of Mifepristone (MFP) to develop a predictive (semi-empirical) stability model. Crystalline MFP was subjected to different durations of ambient ball milling, and the resulting disorder/ amorphous content was quantified using a partial least square (PLS) regression model based on Raman spectroscopy data. Samples of MFP milled to generate varying levels of disorder were subjected to a range of (accelerated) stability conditions, and periodically sampled to examine their recrystallization and degradation extents. Crystallinity was monitored by Raman spectroscopy, and the degradation was evaluated by liquid chromatography. The analyses of milled samples demonstrated a competition between recrystallization and degradation via autoxidation of MFP, to different extents depending on stability conditions/exposure time. The degradation kinetics were analyzed by accounting for the preceding amorphous content, and fitted with a diffusion model. An extended Arrhenius equation was used to predict the degradation of stored samples under long-term (25°C/60% RH) and accelerated (40°C/75% RH, 50°C/75% RH) stability conditions. This study highlights the utility of such a predictive stability model for identifying the autoxidative instability in non-crystalline/partially crystalline MFP, owing to the degradation of the amorphous phases. This study is particularly useful for identifying drug-product instability by leveraging the concept of material sciences.

Advances in the Specificity of Mass Spectrometry and Nuclear Magnetic Resonance Spectroscopy Based Structural Characterisation Methods for Synthetic Oligonucleotides.

Identity testing is a critical part in the development of a therapeutic synthetic oligonucleotide. Tandem Mass Spectrometry (MS/MS) is commonly used for the analysis of oligonucleotides to obtain structural and sequence information, however there are challenges resulting from chemical modifications introduced to improve their pharmacokinetics and stability. For these structurally complex oligonucleotides, Nuclear Magnetic Resonance (NMR) Spectroscopy has found limited use for characterisation and identity testing, as only partial NMR resonance assignment for oligonucleotides is achieved without isotopic labelling methodologies. Regardless of the choice of method used for oligonucleotide analysis, the specificity is of critical importance. In this work, in-source dissociation mass spectrometry and proton (1H) and carbon (13C) NMR at high temperature were used to analyse danvatirsen, a 16 nucleotide phosphorothioate antisense oligonucleotide, and its closely related switch sequences. Both approaches have shown specificity to distinguish danvatirsen from these similar sequences.

Screening Autoxidation Propensities of Drugs in the Solid-State Using PVP and in the Solution State Using N-Methyl Pyrrolidone.

Oxidative degradation of drugs is one of the major routes of drug substance and drug product instability. Among the diverse routes of oxidation, autoxidation is considered to be challenging to predict and control, potentially due to the multi-step mechanism involving free radicals. C-H bond dissociation energy (C-H BDE) is evidenced to be a calculated descriptor shown to predict drug autoxidation. While computational predictions for the autoxidation propensity of drugs are both swift and possible, no literature to date has highlighted the relationship between the computed C-H BDE and the experimentally-derived autoxidation propensities of solid drugs. The objective of this study is to investigate this missing relationship. The present work is an extension to the previously reported novel autoxidation approach that involves subjecting a physical mixture of pre-milled polyvinyl pyrrolidone (PVP) K-60 and a crystalline drug under high temperature and pressurized oxygen setup. The drug degradation was measured using chromatographic methods. An improved trend between the extent of solid autoxidation and C-H BDE could be observed after normalizing the effective surface area of drugs in the crystalline state, pointing to a positive relationship. Additional studies were conducted by dissolving the drug in N-methyl pyrrolidone (NMP) and exposing the solution under a pressurized oxygen setup at diverse elevated temperatures. Chromatographic results of these samples indicated a similarity in the formed degradation products to the solid-state experiments pointing to the utility of NMP, a PVP monomer surrogate, as a stressing agent for faster and relevant autoxidation screening of drugs in formulations.

Theoretical and Experimental Investigation of Autoxidation Propensity of Selected Drugs in Solution State.

The C-H bond dissociation energy (BDE) of drug molecules is often used to estimate their relative propensities to undergo autoxidation. BDE calculations based on electronic structures provide a convenient means to estimate the risk for a given compound to degrade via autoxidation. This study aimed to verify the utility of calculated C-H BDEs of a range of drug molecules in predicting their autoxidation propensities, in the solution state. For the autoxidation study, 2,2'-azobis (2-methylpropionitrile) was employed as the solution state stressor, and the experimental reaction rate constants were determined employing ultraperformance liquid chromatographic (UPLC) methods. Reaction rates in the solution state were compared to the calculated C-H BDE values of the respective compounds. The results indicated a poor correlation for compounds in the solution state, and their relative stabilities could not be explained with C-H BDE. On the other hand, a favorable relationship was observed between the relative extent of ionization and the autoxidation rates of the selected compounds. In the solution state, factors such as the type and extent of drug ionization, degree and type of solvation have been shown to contribute to differences in reactivity. By applying the computational method involving the effect of H-atom abstraction and potential ionization sites in the molecule, the calculated C-H BDE should relate better to the experimental autoxidation rates.

Post-Operative Outcomes of Pre-Thoracic Surgery Respiratory Muscle Training vs Aerobic Exercise Training: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To compare the postoperative outcomes of preoperative respiratory muscle training (RMT) with a device to preoperative aerobic exercise training (AET) in patients undergoing thoracic surgeries (cardiac and lung). DATA SOURCES: PubMed, EMBASE, Cochrane, and Web of Science were comprehensively searched upon inception to 9/2020. STUDY SELECTION: All randomized control studies, including preoperative RMT and preoperative AET compared with a non-training control group, were included. DATA EXTRACTION: The meta-analysis was performed for outcomes including postoperative pulmonary complications (PPC), pneumonia, postoperative respiratory failure (PRF), hospital length of stay (HLOS), and mortality. We performed a network meta-analysis based on Bayesian random-effects regression models. DATA SYNTHESIS: A total of 25 studies, 2070 patients were included in this meta-analysis. Pooled data for the patients who performed RMT with a device showed a reduction in PPCs, pneumonia, PRF with odds ratio (OR) of 0.35 (P value .006), 0.38 (P value .002), and 0.22 (P value .008), respectively. Pooled data for the patients who performed AET showed reduction in PPC, pneumonia with a OR of 0.33 (P value <.00001) and OR of 0.54 (P value .01), respectively. HLOS was decreased by 1.69 days (P value <.00001) by performing RMT and 1.79 days (P value .0008) by performing AET compared with the usual group. No significant difference in all-cause mortality compared with usual care in both RMT and AET intervention groups. No significant difference in the incidence of PRF compared with usual group in RMT + AET and AET alone intervention groups (OR 0.32; P=.21; OR 0.94; P=.87). Based on rank probability plots analysis, on network meta-analysis, RMT and AET ranked similarly on the primary outcome of PPC and secondary outcomes of pneumonia, PRF and HLOS. CONCLUSIONS: In thoracic surgeries, preoperative RMT is comparable with preoperative AET to prevent PPC, pneumonia, and PRF and reduce HLOS. It can be considered in patients in resource-limited settings.

The Global Characterisation of a Drug-Dendrimer Conjugate - PEGylated poly-lysine Dendrimer.

The recent emergence of drug-dendrimer conjugates within pharmaceutical industry research and development introduces a range of challenges for analytical and measurement science. These molecules are very high molecular weight (100-200kDa) with a significant degree of structural complexity. The characteristics and quality attributes that require understanding and definition, and impact efficacy and safety, are diverse. They relate to the intact conjugate, the various building blocks of these complex systems and the level of the free and bound active pharmaceutical ingredient (API). From an analytical and measurement science perspective, this necessitates the measurement of the molecular weight, impurity characterisation, the quantitation of the number of conjugated versus free API molecules, the determination of the impurity profiles of the building blocks, primary structure and both particle size and morphology. Here we report the first example of a global characterisation of a drug-dendrimer conjugate - PEGylated poly-lysine dendrimer currently under development (AZD0466). The impact of the wide variety of analytical and measurement techniques on the overall understanding of this complex molecular entity is discussed, with the relative capabilities of the various approaches compared. The results of this study are an essential platform for the research and development of the future generations of related dendrimer-based medicines.

Metatarsal fusion resisted bending as jerboas (Dipodidae) transitioned from quadrupedal to bipedal.

Hind limbs undergo dramatic changes in loading conditions during the transition from quadrupedal to bipedal locomotion. For example, the most early diverging bipedal jerboas (Rodentia: Dipodidae) are some of the smallest mammals in the world, with body masses that range between 2-4 g. The larger jerboa species exhibit developmental and evolutionary fusion of the central three metatarsals into a single cannon bone. We hypothesize that small body size and metatarsal fusion are mechanisms to maintain the safety factor of the hind limb bones despite the higher ground reaction forces associated with bipedal locomotion. Using finite-element analysis to model collisions between the substrate and the metatarsals, we found that body size reduction was insufficient to reduce bone stress on unfused metatarsals, based on the scaled dynamics of larger jerboas, and that fused bones developed lower stresses than unfused bones when all metatarsals are scaled to the same size and loading conditions. Based on these results, we conclude that fusion reinforces larger jerboa metatarsals against high ground reaction forces. Because smaller jerboas with unfused metatarsals develop higher peak stresses in response to loading conditions scaled from larger jerboas, we hypothesize that smaller jerboas use alternative dynamics of bipedal locomotion to reduce the impact of collisions between the foot and substrate.

Defining the optimal threshold and prognostic utility of pre-treatment hemoglobin level as a biomarker for survival outcomes in head and neck cancer patients receiving chemoradiation.

OBJECTIVES: We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker. MATERIALS AND METHODS: A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes. RESULTS: A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p < 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p < 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p < 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82). CONCLUSION AND RELEVANCE: Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Assessment of Diverse Solid-State Accelerated Autoxidation Methods for Droperidol.

The present study aimed to investigate methods for accelerating autoxidation of crystalline drugs in the solid-state that can potentially predict real-time stability. Solid droperidol (DPD) was selected as the model drug. A common free-radical initiator, 2,2'-azobisisobutyronitrile (AIBN), was used to induce autoxidation in solutions. AIBN decomposes at elevated temperatures to yield carbon-centred cyano-isopropyl free radicals that can auto-oxidize neighboring drug molecules. Although the reaction of AIBN is relatively straightforward in solution, it is less so in solids. In this study, we used solid AIBN mixed with DPD powder in the presence and absence of pressurized oxygen headspace. Samples were prepared directly in the form of binary mixtures with DPD and additionally in the form of powder compact/pellet with DPD. The main challenge in carrying out the reaction was related to the preservation of AIBN at elevated temperatures due to the disintegration of the pellet containing the latter. A commercially available free-radical coated silica particle (i.e., 2,2,6,6-tetramethyl-1-piperinyloxy (TEMPO) or (SiliaCATTM TEMPO)) was tested as a potential stressor, but with limited success to induce autoxidation. The most valuable results were obtained when a physical mixture of pre-milled PVP K-60 containing free radicals and DPD was exposed to elevated oxygen-temperature conditions, which yielded significant degradation of DPD. The study highlights the practical challenges for conducting accelerated solid-state stress studies to assess the autoxidation susceptibility of drugs using traditional free-radical initiators and presents a proof of application of milled PVP with free-radical as a potential alternative.

Effect of musculature on mortality, a retrospective cohort study.

BACKGROUND: While often life-saving, treatment for head and neck cancer (HNC) can be debilitating resulting in unplanned hospitalization. Hospitalizations in cancer patients may disrupt treatment and result in poor outcomes. Pre-treatment muscle quality and quantity ascertained through diagnostic imaging may help identify patients at high risk of poor outcomes early. The primary objective of this study was to determine if pre-treatment musculature was associated with all-cause mortality. METHODS: Patient demographic and clinical characteristics were abstracted from the cancer center electronic database (n = 403). Musculature was ascertained from pre-treatment CT scans. Propensity score matching was utilized to adjust for confounding bias when comparing patients with and without myosteatosis and with and without low muscle mass (LMM). Overall survival (OS) was evaluated using the Kaplan-Meier method and Cox multivariable analysis. RESULTS: A majority of patients were male (81.6%), white (89.6%), with stage IV (41.2%) oropharyngeal cancer (51.1%) treated with definitive radiation and chemotherapy (93.3%). Patients with myosteatosis and those with LMM were more likely to die compared to those with normal musculature (5-yr OS HR 1.55; 95% CI 1.03-2.34; HR 1.58; 95% CI 1.04-2.38). CONCLUSIONS: Musculature at the time of diagnosis was associated with overall mortality. Diagnostic imaging could be utilized to aid in assessing candidates for interventions targeted at maintaining and increasing muscle reserves.