Matcher: An Open-Source Application for Translating Large Structure/Property Data Sets into Insights for Drug Design.

To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large data sets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here, we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise. Matcher enables unprecedented control over the search and clustering of MMP transformations based on both variable fragment and constant environment structure, which is critical for disentangling relevant and irrelevant data to a given problem. Users can exert such control through a built-in chemical sketcher and with a few mouse clicks can navigate between resulting MMP transformations, statistics, property distribution graphs, and structures with raw experimental data, for confident and accelerated decision making. Matcher can be used with any collection of structure/property data; here, we demonstrate usage with a public ChEMBL data set of about 20,000 small molecules with CYP3A4 and/or hERG inhibition data. Users can reproduce all examples demonstrated herein via unique links within Matcher's interface-a functionality that anyone can use to preserve and share their own analyses. Matcher and all its dependencies are open-source, can be used for free, and are available with containerized deployment from code at https://github.com/Merck/Matcher. Matcher makes large structure/property data sets more transparent than ever before and accelerates the data-driven solution of common problems in drug discovery.

Gamma and Decay Energy Spectroscopy Measurements of Trinitite.

We report gamma ray spectroscopy measurements of trinitite samples and analogous samples obtained from detonation sites in Nevada and Semipalatinsk, as well as in situ measurements of topsoil at the Trinity site. We also report the first isotopic composition measurements of trinitite using the novel forensics technique of decay energy spectroscopy (DES) as a complement to traditional forensics techniques. Our gamma spectroscopy and DES measurements are compared to other published results.

Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity.

Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior. In this study, we show that selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task. We further found that striatal GluD1 is preferentially found in dendritic shafts, and more frequently associated with thalamic than cortical glutamatergic terminals suggesting localization to projections from the thalamic parafascicular nucleus (Pf). Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. Optogenetic studies demonstrated functional changes at thalamostriatal synapses from the Pf, but no effect on the corticostriatal system, upon ablation of GluD1 in the dorsal striatum. These studies suggest a novel molecular mechanism by which genetic variations associated with neuropsychiatric disorders may impair behavioral flexibility, and reveal a unique principle by which GluD1 subunit regulates forebrain circuits.

34 S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds.

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on 2 H, 13 C, and 15 N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of 34 S. The synthetic utility of 34 S was demonstrated with the efficient synthesis of [34 S]phosphorothioates [34 S2 ]-PS-ODNs-TTT and [13 C, 15 N, 34 S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [34 S]phosphorothioates using elemental 34 S without isotope dilution was developed.

Undifferentiated Endometrial Carcinomas: Clinicopathologic Characteristics and Treatment Outcomes.

OBJECTIVE: Undifferentiated endometrial carcinoma (UEC) represents a recently recognized and rare diagnosis that is commonly misclassified on histopathologic evaluation. These cancers account for less than 10% of carefully reviewed series of endometrial cancers from academic medical centers. We reviewed a single-institutional experience with the management of UEC focusing on clinicopathologic characteristics and treatment outcomes. METHODS: The medical records of all patients treated for histologically proven endometrial carcinoma between 2007 through 2016 were reviewed. Analysis was limited to 24 consecutive patients with histologically proven endometrial carcinomas that had at least a component of undifferentiated carcinoma on central pathology review. All patients were initially treated by definitive surgical resection. Grade 3 endometrioid carcinomas treated over the same period were used as a control group. The Kaplan-Meier method was used to estimate survival outcomes. RESULTS: The median age at diagnosis was 66 years (range, 37-74 years). Ten patients presented with locally advanced or metastatic disease (42%). Fifteen patients (63%) received adjuvant chemotherapy with carboplatin and paclitaxel, 12 patients (50%) received adjuvant pelvic external beam radiation, and 10 patients (42%) received adjuvant vaginal cuff brachytherapy. With a median follow-up of 14 months (range, 0.5-115 months), 4 patients (21%) had developed disease recurrence and/or progression, 2 patients (11%) had died of disease, and 1 patient died of treatment complications. Twelve patients (63%) were alive with no evidence of disease at last contact. Outcomes were comparable to those with grade 3 endometrioid carcinoma. CONCLUSIONS: Our data are consistent with prior studies demonstrating that UEC represents a rare clinical entity characterized by high rates of locally advanced disease at presentation. However, survival outcomes appear to be comparable to other high-grade endometrial cancers. Further studies investigating optimal adjuvant therapy in these patients are warranted.

Palladium(II)-Mediated C-H Tritiation of Complex Pharmaceuticals.

Tritium-labeled molecules are critical tools for elucidating the binding and metabolic properties of bioactive compounds, particularly during pharmaceutical discovery. Direct tritiation of inert C-H bonds with T2 gas is an ideal approach for tritium labeling, but significant gaps remain for direct tritiation of structurally complex molecules with diverse functional groups. Here we report the first application of palladium(II) C-H activation chemistry for tritiation with T2 gas. This practical transformation exhibits novel substrate scope and greater functional group tolerance compared to previous state of the art tritiation methods, and has been applied to directly tritiate 9 complex pharmaceuticals and an unprotected dipeptide. The isolated tritium-labeled products exhibit >15 Ci mmol-1 specific activity, exceeding the typical requirements for application in studies of molecular interaction and metabolism.

Measurement of the 240Pu/239Pu mass ratio using a transition-edge-sensor microcalorimeter for total decay energy spectroscopy.

We have developed a new category of sensor for measurement of the (240)Pu/(239)Pu mass ratio from aqueous solution samples with advantages over existing methods. Aqueous solution plutonium samples were evaporated and encapsulated inside of a gold foil absorber, and a superconducting transition-edge-sensor microcalorimeter detector was used to measure the total reaction energy (Q-value) of nuclear decays via heat generated when the energy is thermalized. Since all of the decay energy is contained in the absorber, we measure a single spectral peak for each isotope, resulting in a simple spectral analysis problem with minimal peak overlap. We found that mechanical kneading of the absorber dramatically improves spectral quality by reducing the size of radioactive inclusions within the absorber to scales below 50 nm such that decay products primarily interact with atoms of the host material. Due to the low noise performance of the microcalorimeter detector, energy resolution values of 1 keV fwhm (full width at half-maximum) at 5.5 MeV have been achieved, an order of magnitude improvement over α-spectroscopy with conventional silicon detectors. We measured the (240)Pu/(239)Pu mass ratio of two samples and confirmed the results by comparison to mass spectrometry values. These results have implications for future measurements of trace samples of nuclear material.

A new class of hybrid anticancer agents inspired by the synergistic effects of curcumin and genistein: Design, synthesis, and anti-proliferative evaluation.

Inspired by the synergistic effects of dietary natural products with different scaffolds on the inhibition of cancer cell proliferation, incorporation of central (1E,4E)-1,4-penta-dien-3-one linker (an optimal substitute for the central metabolically unstable diketone linker of curcumin), 1-alkyl-1H-imidazol-2-yl (a promising bioisostere of terminal aryl group in curcumin), and chromone (the common pharmacophore in genistein and quercetin) into one chemical entity resulted in ten new hybrid molecules, 3-((1E,4E)-5-(1-alkyl-1H-imidazol-2-yl)-3-oxopenta-1,4-dien-1-yl)-4H-chromen-4-ones. They were synthesized through a three-step transformation using acid-catalyzed aldol condensation as key step. The WST-1 cell proliferation assay showed that they have greater anti-proliferative potency than curcumin, quercetin, and genistein on both androgen-dependent and androgen-independent human prostate cancer cells.

State variation in neighborhood COVID-19 burden across the United States.

BACKGROUND: A lack of fine, spatially-resolute case data for the U.S. has prevented the examination of how COVID-19 infection burden has been distributed across neighborhoods, a key determinant of both risk and resilience. Without more spatially resolute data, efforts to identify and mitigate the long-term fallout from COVID-19 in vulnerable communities will remain difficult to quantify and intervene on. METHODS: We leveraged spatially-referenced data from 21 states collated through the COVID Neighborhood Project to examine the distribution of COVID-19 cases across neighborhoods and states in the U.S. We also linked the COVID-19 case data with data on the neighborhood social environment from the National Neighborhood Data Archive. We then estimated correlations between neighborhood COVID-19 burden and features of the neighborhood social environment. RESULTS: We find that the distribution of COVID-19 at the neighborhood-level varies within and between states. The median case count per neighborhood (coefficient of variation (CV)) in Wisconsin is 3078.52 (0.17) per 10,000 population, indicating a more homogenous distribution of COVID-19 burden, whereas in Vermont the median case count per neighborhood (CV) is 810.98 (0.84) per 10,000 population. We also find that correlations between features of the neighborhood social environment and burden vary in magnitude and direction by state. CONCLUSIONS: Our findings underscore the importance that local contexts may play when addressing the long-term social and economic fallout communities will face from COVID-19.

A lack of data on the geographic location of COVID-19 cases in the U.S has limited our ability to examine how COVID-19 burden has been distributed across neighborhoods within U.S. states. It may be that certain neighborhoods have borne a disproportionate burden of COVID-19 and are more likely to experience greater long-term social and economic consequences from the pandemic. We used data from 21 states to examine the distribution of COVID-19 cases across neighborhoods and states in the U.S. We find that the distribution of COVID-19 varies widely both within neighborhoods in a state, and between states. We also find that the features of the neighborhood social environment that are correlated with neighborhood COVID-19 burden vary by state. Our findings show that the local neighborhood may play an important role in addressing long-term social and economic consequences from COVID-19.

The association between incarceration and housing insecurity and advanced immune age during late life.

Emerging evidence suggests that psychosocial stress ages the immune system. Accordingly, immune aging may be an important potential mechanism linking psychosocial stress to aging-related decline and disease. Incarceration and housing insecurity represent severe and complex experiences of a multitude of psychosocial stressors, including discrimination, violence, and poverty. In this study, we investigated the association between incarceration and/or housing insecurity and advanced immune age in adults aged 55 and older. Our sample was derived from the Health and Retirement Survey (HRS), with n = 7003 individuals with valid housing insecurity data and n = 7523 with valid incarceration data. From 2016 Venous Blood Study data, we assessed immune aging using a comprehensive set of immune markers including inflammatory markers (IL-6, CRP, s-TNFR1), markers of viral control (CMV IgG antibodies), and ratios of T cell phenotypes (CD8+:CD4+, CD+ Memory: Naïve, CD4+ Memory: Naïve, CD8+ Memory: Naïve ratios). We found that both incarceration and housing insecurity were strongly associated with more advanced immune aging as indicated by increased inflammation, reduced viral control, and reduction in naïve T cells relative to memory T cells. Given that those who experienced incarceration, housing insecurity, and/or are racialized minorities were less likely to be included in this study, our results likely underestimated these associations. Despite these limitations, our study provided strong evidence that experiencing incarceration and/or housing insecurity may accelerate the aging of the immune system.

Dosimetric impact of applicator displacement on three-dimensional image-guided high-dose-rate brachytherapy treatments for cervical cancer.

Purpose: To determine the dosimetric impact of brachytherapy applicator displacement during intracavitary (IC) and combined intracavitary/interstitial (IC/IS) high-dose-rate brachytherapy in the treatment of cervical cancer. Material and methods: Data from 27 consecutively treated patients undergoing IC or IC/IS high-dose-rate brachytherapy with tandem and ovoid-based applicators at a single academic medical center were analyzed. Virtual applicator displacements (a single shift of whole applicator with tandem/ovoid/associated needles) of 0 (clinical position), 2, 5, 7, and 10 mm in the inferior direction were modeled on treatment planning CT or MRI scans, with maintaining the same dwell times. Radiation dose to target volumes (D90 of high-risk clinical target volume) and organs at risk (OARs) (D0.1cc, D1cc, and D2cc of bladder, rectum, and sigmoid) were calculated for each virtual applicator shift, and significance of displacements was assessed using general linear model and Kruskal-Wallis test. Results: Mean dose to high-risk clinical target volume (HR-CTV) D90 was 95.7%, 88.9%, 84.6%, and 77.1% of the prescribed dose in clinical position with displacements of 2, 5, 7, and 10 mm, respectively. Rectal D2cc significantly increased by 28% and 44% at displacement of 7 mm and 10 mm, respectively. IC/IS cases showed relatively greater dosimetric differences than IC cases, with HR-CTV D90 doses of 94.4%, 85.8%, 80.4%, and 72.4% at virtual displacements of 2, 5, 7, and 10 mm, respectively. Conclusions: Applicator displacements of 5 mm or greater result in statistically significant and clinically meaningful decreases in radiation dose to HR-CTV during 3-dimensional high-dose-rate brachytherapy treatment planning, with corresponding increase in radiation dose to the rectum. IC/IS applicator displacements lead to relatively greater differences than those of IC applicators.

Impact of bowel space contouring variability on radiation dose and volume assessments in treatment planning for gynaecologic cancers.

INTRODUCTION: Correlations between radiation dose/volume measures and small bowel (SB) toxicity are inconsistent in the medical literature. We assessed the impact of inter-provider variation in bowel bag contouring technique on estimates of radiation dose received by the SB during pelvic radiotherapy. METHODS: Ten radiation oncologists contoured rectum, bladder and bowel bags on treatment planning computed tomography (CT) scans of two patients receiving adjuvant radiation for endometrial cancer. A radiation plan was generated for each patient and used to determine the radiation dose/volume for each organ. Kappa statistics were applied to assess the inter-provider contouring agreement, and Levene test evaluated the homogeneity of variance for radiation dose/volume metrics, including the V45Gy (cm3 ). RESULTS: The bowel bag showed greater variation in radiation dose/volume estimates compared to the bladder and rectum. The V45Gy ranged from 163 to 384 cm3 for data set A and 109 to 409 cm3 for dataset B. Kappa values were 0.82/0.83, 0.92/0.92 and 0.94/0.86 for the bowel bag, rectum, and bladder on data sets A/B, demonstrating lower inter-provider agreement for bowel bag compared with bladder and rectum. CONCLUSION: Inter-provider contouring variability is more significant for the bowel bag than the rectum and bladder, with an associated greater variability in dose and volume estimates during radiation planning.

State Variation in Neighborhood COVID-19 Burden: Findings from the COVID Neighborhood Project.

A lack of fine, spatially-resolute case data for the U.S. has prevented the examination of how COVID-19 burden has been distributed across neighborhoods, a known geographic unit of both risk and resilience, and is hampering efforts to identify and mitigate the long-term fallout from COVID-19 in vulnerable communities. Using spatially-referenced data from 21 states at the ZIP code or census tract level, we documented how the distribution of COVID-19 at the neighborhood-level varies significantly within and between states. The median case count per neighborhood (IQR) in Oregon was 3,608 (2,487) per 100,000 population, indicating a more homogenous distribution of COVID-19 burden, whereas in Vermont the median case count per neighborhood (IQR) was 8,142 (11,031) per 100,000. We also found that the association between features of the neighborhood social environment and burden varied in magnitude and direction by state. Our findings underscore the importance of local contexts when addressing the long-term social and economic fallout communities will face from COVID-19.

Neoadjuvant Radiotherapy Facility Type Affects Anastomotic Complications After Esophagectomy.

BACKGROUND: Esophagectomy is a complex oncologic surgery that results in lower perioperative morbidity and mortality when performed in high-volume hospitals by experienced surgeons; however, limited data exists evaluating the importance of neoadjuvant radiotherapy delivery at high- versus low-volume centers. We sought to compare postoperative toxicity among patients treated with preoperative radiotherapy delivered at an academic medical center (AMC) versus community medical centers (CMC). METHODS: Consecutive patients undergoing esophagectomy for locally advanced esophageal or gastroesophageal junction (GEJ) cancer at an academic medical center between 2008 and 2018 were reviewed. Associations between patient factors and treatment-related toxicities were calculated in univariate (UVA) and multivariable analyses (MVA). RESULTS: One hundred forty-seven consecutive patients were identified: 89 CMC and 58 AMC. Median follow-up was 30 months (0.33-124 months). Most patients were male (86%) with adenocarcinoma (90%) located in the distal esophagus or GEJ (95%). Median radiation dose was 50.4 Gy between groups. Radiotherapy at CMCs resulted in higher rates of re-operation after esophagectomy (18% vs 7%, p = 0.055) and increased rates of anastomotic leak (38% vs 17%, p < 0.01). On MVA, radiation at a CMC remained predictive of anastomotic leak (OR 6.13, p < 0.01). CONCLUSION: Esophageal cancer patients receiving preoperative radiotherapy had higher rates of anastomotic leaks when radiotherapy was completed at a community medical center versus academic medical center. Explanations for these differences are uncertain but further exploratory analyses regarding dosimetry and radiation field size are warranted.

Ultrastructural localization of glutamate delta 1 (GluD1) receptor immunoreactivity in the mouse and monkey striatum.

The glutamate receptor delta 1 (GluD1) is strongly expressed in the striatum. Knockout of GluD1 expression in striatal neurons elicits cognitive deficits and disrupts the thalamostriatal system in mice. To understand the potential role of GluD1 in the primate striatum, we compared the cellular and subcellular localization of striatal GluD1 immunoreactivity (GluD1-IR) in mice and monkeys. In both species, striatal GluD1-IR displayed a patchy pattern of distribution in register with the striosome/matrix compartmentation, but in an opposite fashion. While GluD1 was more heavily expressed in the striosomes than the matrix in the monkey caudate nucleus, the opposite was found in the mouse striatum. At the electron microscopic level, GluD1-IR was preferentially expressed in dendritic shafts (47.9 ± 1.2%), followed by glia (37.7 ± 2.5%), and dendritic spines (14.3 ± 2.6%) in the matrix of the mouse striatum. This pattern was not statistically different from the labeling in the striosome and matrix compartments of the monkey caudate nucleus, with the exception of a small amount of GluD1-positive unmyelinated axons and axon terminals in the primate striatum. Immunogold staining revealed synaptic and perisynaptic GluD1 labeling at putative axo-dendritic and axo-spinous glutamatergic synapses, and intracellular labeling on the surface of mitochondria. Confocal microscopy showed that GluD1 is preferentially colocalized with thalamic over cortical terminals in both the striosome and matrix compartments. These data provide the anatomical substrate for a deeper understanding of GluD1 regulation of striatal glutamatergic synapses, but also suggest possible extrasynaptic, glial, and mitochondrial GluD1 functions.

On the absolute configurational stability of bromonium and chloronium ions.

Halonium ions have long been established as the critical intermediates in halogenation and halofunctionalization of alkenes. Although these workhorse reactions have been extensively studied mechanistically and employed synthetically, the paucity of enantioselective variants is striking. A central problem in the development of catalytic enantioselective halofunctionalizations is the reversible formation of halonium ions and the facile olefin-to-olefin transfer. In this report, configurationally defined and enantiomerically enriched bromonium and chloronium ions are generated (by solvolysis of enantiomerically enriched precursors) and shown to be intercepted intermolecularly with high enantio- and diastereospecificity by various nucleophiles. Most importantly, the stereospecificity of capture is not significantly eroded in the presence of olefins.

The impact of skeletal muscle abnormalities on tolerance to adjuvant chemotherapy and radiation and outcome in patients with endometrial cancer.

INTRODUCTION: Skeletal muscle abnormalities, such as low skeletal muscle mass, measured by skeletal muscle index (SMI), and low skeletal muscle quality, measured by skeletal muscle density (SMD), are associated with poor prognosis in cancer. There has been little investigation of their impact on tolerance to radiation therapy and overall outcome in gynaecologic cancers. We examined the effect of low SMI and SMD on treatment tolerance and survival outcomes in patients with endometrial cancer receiving pelvic radiation. METHODS: Stage IB-IVA patients with endometrial cancer treated at one institution between 2007 and 2017 were reviewed. All patients received hysterectomy and pelvic radiation. SMI was based on the cross-sectional area of skeletal muscle at the L3 vertebral body. SMD was expressed as the mean radiation attenuation in Hounsfield units (HUs) at the same vertebral level. RESULTS: Sixty-four patients met criteria for analysis. Forty-four per cent had low SMI (<41 cm2 /m2 ), 80% had low SMD (mean < 33 HU if BMI> 25 and mean < 41 HU if BMI < 25), and 33% had both. Patients with both features were less likely to complete planned chemotherapy (p = 0.01); this was consistent on multivariate analysis. Radiation treatments were well-tolerated regardless of SMI or SMD. On survival analysis, having both low SMI and low SMD was associated with poorer outcomes compared with having either individual factor (p = 0.04). CONCLUSION: Large percentages of patients with endometrial cancer have low skeletal muscle mass and density. Low skeletal muscle measures predict for poor tolerance to chemotherapy in this patient population. Compliance with adjuvant radiation is high, regardless of SMI and SMD.

The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth.

The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras(v12), resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.

Visceral adipose ratio as a novel predictor for acute bowel toxicity in patients receiving pelvic radiation: Preliminary dosimetric analysis and clinical validation.

INTRODUCTION: During radiation treatment planning, the small bowel (SB) is often contoured as a 'bowel bag' encompassing the entire peritoneal space that may be occupied by SB. This method incorporates large volumes of visceral adipose, potentially resulting in misleading estimates of radiation dose to the SB. We evaluated the relative volume of adipose within the peritoneal space and applied this as a correction factor to standard bowel bag dosimetric measures, hypothesizing that corrected SB measures would better correlate with acute toxicity. METHODS: Eighteen consecutive patients receiving pelvic radiation for gynaecologic cancers over a 1-year period at an academic medical centre were included. Bowel function was assessed with the Expanded Prostate Index Composite (EPIC) questionnaire. Bowel bags were contoured on simulation computed tomography (CT) scans. Adipose was auto-contoured using previously published Hounsfield Unit criteria and used to create an adipose correction factor (ACF). The ACF was applied to V45 cc and V40% volumes to create adipose corrected measures (AC-V45 cc and AC-V40%). Correlations between EPIC scores and dosimetric measures were assessed using Spearman coefficients. RESULTS: V45 cc and V40% did not correlate with overall EPIC bowel domain score; however, AC-V40% did show a significant correlation (P = 0.02). Correlations of V45 cc and V40% with the bowel bother subdomain of EPIC were both significantly improved by applying the ACF (P = 0.02 for AC-V45 cc; P < 0.01 for AC-V40%). CONCLUSIONS: Adipose corrected bowel bag dosimetric constraints correlate better with acute bowel toxicity than current standard practice. Longer follow-up is needed to determine if similar findings are seen with late toxicity.

The impact of sarcopenia on tolerance of radiation and outcome in patients with head and neck cancer receiving chemoradiation.

BACKGROUND AND PURPOSE: Sarcopenia is a predictor of poor prognosis in cancer patients. One potential mechanism for worse outcomes in sarcopenic patients is worse tolerance to treatment; this has not been investigated with regard to radiation treatment. We reviewed our institutional experience of head and neck cancer patients receiving concurrent chemoradiation and assessed outcomes with respect to sarcopenia. MATERIALS AND METHODS: Patients treated between 2012 and 2016 were reviewed. Sarcopenia was assessed from radiation planning computed tomography (CT) scans using muscles at the C3 vertebral body using previously published methods. Survival was calculated using the Kaplan-Meier method. Association between patient factors and outcome was calculated in univariate and multivariate analyses. RESULTS: Two hundred and forty-six patients were included. Fifty-eight percent met criteria for sarcopenia. Thirty-seven percent experienced chemotherapy delays of >1 week and 14% had radiation treatment breaks >1 week. On multivariate analysis, concurrent smoking (HR 3.85, p < 0.01) and sarcopenia (HR 2.15, p = 0.01) were associated with chemotherapy toxicity and age >65 years (HR 2.94, p < 0.01) and sarcopenia (HR 2.99, p = 0.04) were associated with prolonged radiation breaks. Sarcopenia was associated with worse overall survival (HR 1.83, p = 0.03) and progression-free survival (HR 1.65, p = 0.03) in the overall cohort. When analyzed separately, sarcopenia was not associated with outcomes in p16-positive oropharynx cancers. CONCLUSION: Sarcopenic patients receiving concurrent chemoradiation are more likely to require radiation treatment breaks and suffer chemotherapy toxicity than their non-sarcopenic counterparts. This may contribute to worse survival outcomes in head and neck cancer, with the exception of p16-positive oropharyngeal cancer.