Novel Functional Radiomics for Prediction of Cardiac Positron Emission Tomography Avidity in Lung Cancer Radiotherapy.

PURPOSE: Traditional methods of evaluating cardiotoxicity focus on radiation doses to the heart. Functional imaging has the potential to provide improved prediction for cardiotoxicity for patients with lung cancer. Fluorine-18 (18F) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging is routinely obtained in a standard cancer staging workup. This work aimed to develop a radiomics model predicting clinical cardiac assessment using 18F-FDG PET/CT scans before thoracic radiation therapy. METHODS: Pretreatment 18F-FDG PET/CT scans from three study populations (N = 100, N = 39, N = 70) were used, comprising two single-institutional protocols and one publicly available data set. A clinician (V.J.) classified the PET/CT scans per clinical cardiac guidelines as no uptake, diffuse uptake, or focal uptake. The heart was delineated, and 210 novel functional radiomics features were selected to classify cardiac FDG uptake patterns. Training data were divided into training (80%)/validation (20%) sets. Feature reduction was performed using the Wilcoxon test, hierarchical clustering, and recursive feature elimination. Ten-fold cross-validation was carried out for training, and the accuracy of the models to predict clinical cardiac assessment was reported. RESULTS: From 202 of 209 scans, cardiac FDG uptake was scored as no uptake (39.6%), diffuse uptake (25.3%), and focal uptake (35.1%), respectively. Sixty-two independent radiomics features were reduced to nine clinically pertinent features. The best model showed 93% predictive accuracy in the training data set and 80% and 92% predictive accuracy in two external validation data sets. CONCLUSION: This work used an extensive patient data set to develop a functional cardiac radiomic model from standard-of-care 18F-FDG PET/CT scans, showing good predictive accuracy. The radiomics model has the potential to provide an automated method to predict existing cardiac conditions and provide an early functional biomarker to identify patients at risk of developing cardiac complications after radiotherapy.

Contemporary evaluation of women and girls with abnormal uterine bleeding: FIGO Systems 1 and 2.

Abnormal uterine bleeding (AUB) is common, often debilitating, and may affect over 50% of reproductive-aged women and girls. Whereas AUB is a collection of symptoms that include intermenstrual bleeding and abnormalities in period duration, cycle length, and regularity, it is heavy menstrual bleeding (HMB) that is most contributory to iron deficiency and related anemia. It is apparent that AUB, in general, and HMB, in particular, remain underrecognized and underreported. FIGO created two systems for assessing and classifying AUB. FIGO System 1 defines the bleeding pattern using four primary descriptors: frequency, duration, regularity, and flow volume. FIGO System 2 provides a structured classification system of possible causes of AUB, using the acronym PALM-COEIN. "PALM" refers to structural causes of AUB (Polyp, Adenomyosis, Leiomyoma, Malignancy), and "COEI" refers to nonstructural causes (Coagulopathy, Ovulatory dysfunction, Endometrial, and Iatrogenic). The "N" is reserved for those entities that are currently not otherwise classified. Using FIGO System 1 as a gateway to FIGO System 2 streamlines the investigation of reproductive-aged women and girls with AUB. Understanding the pathogenesis of the FIGO System 2 "PALM-COEIN" causes helps interpret investigations and the onward management of AUB. Numerous evidence gaps exist concerning AUB; however, if researchers and trialists universally adopt FIGO Systems 1 and 2 for the assessment and diagnosis of AUB, clear translatable research findings can be applied globally.

Human development and reproduction in space-a European perspective.

This review summarises key aspects of the first reproductive and developmental systems Science Community White Paper, supported by the European Space Agency (ESA). Current knowledge regarding human development and reproduction in space is mapped to the roadmap. It acknowledges that sex and gender have implications on all physiological systems, however, gender identity falls outside the scope of the document included in the white paper collection supported by ESA. The ESA SciSpacE white papers on human developmental and reproductive functions in space aim to reflect on the implications of space travel on the male and female reproductive systems, including the hypothalamic-pituitary-gonadal (HPG) reproductive hormone axis, and considerations for conception, gestation and birth. Finally, parallels are drawn as to how this may impact society as a whole on Earth.

Spatiotemporal properties of glutamate input support direction selectivity in the dendrites of retinal starburst amacrine cells.

The asymmetric summation of kinetically distinct glutamate inputs across the dendrites of retinal 'starburst' amacrine cells is one of the several mechanisms that have been proposed to underlie their direction-selective properties, but experimentally verifying input kinetics has been a challenge. Here, we used two-photon glutamate sensor (iGluSnFR) imaging to directly measure the input kinetics across individual starburst dendrites. We found that signals measured from proximal dendrites were relatively sustained compared to those measured from distal dendrites. These differences were observed across a range of stimulus sizes and appeared to be shaped mainly by excitatory rather than inhibitory network interactions. Temporal deconvolution analysis suggests that the steady-state vesicle release rate was ~3 times larger at proximal sites compared to distal sites. Using a connectomics-inspired computational model, we demonstrate that input kinetics play an important role in shaping direction selectivity at low stimulus velocities. Taken together, these results provide direct support for the 'space-time wiring' model for direction selectivity.

Cerebral hemodynamic and metabolic dysregulation in the postradiation brain.

Technological advances in the delivery of radiation and other novel cancer therapies have significantly improved the 5-year survival rates over the last few decades. Although recent developments have helped to better manage the acute effects of radiation, the late effects such as impairment in cognition continue to remain of concern. Accruing data in the literature have implicated derangements in hemodynamic parameters and metabolic activity of the irradiated normal brain as predictive of cognitive impairment. Multiparametric imaging modalities have allowed us to precisely quantify functional and metabolic information, enhancing the anatomic and morphologic data provided by conventional MRI sequences, thereby contributing as noninvasive imaging-based biomarkers of radiation-induced brain injury. In this review, we have elaborated on the mechanisms of radiation-induced brain injury and discussed several novel imaging modalities, including MR spectroscopy, MR perfusion imaging, functional MR, SPECT, and PET that provide pathophysiological and functional insights into the postradiation brain, and its correlation with radiation dose as well as clinical neurocognitive outcomes. Additionally, we explored some innovative imaging modalities, such as quantitative blood oxygenation level-dependent imaging, susceptibility-based oxygenation measurement, and T2-based oxygenation measurement, that hold promise in delineating the potential mechanisms underlying deleterious neurocognitive changes seen in the postradiation setting. We aim that this comprehensive review of a range of imaging modalities will help elucidate the hemodynamic and metabolic injury mechanisms underlying cognitive impairment in the irradiated normal brain in order to optimize treatment regimens and improve the quality of life for these patients.

From menarche to menopause, heavy menstrual bleeding is the underrated compass in reproductive health.

Menstruation is defined as monthly uterine bleeding, regarded as a sign of reproductive health. When characterized by excessive bleeding (heavy menstrual bleeding [HMB]), it may act as a useful clinical marker for diagnosis of reproductive diseases. Endometrial and myometrial mechanisms underlying abnormal uterine bleeding (AUB), which includes HMB, have hormonal, cellular, and molecular aspects. Structural and nonstructural causes of AUB, presenting with HMB as the major symptom, result in iron depletion and consequent anemia. Heavy menstrual bleeding can be considered as a single entity to identify the possible underlying causes, which may be different to some extent to those of AUB, as a whole. Furthermore, the difficulties in defining HMB through objective methods do not allow the current epidemiological scenario on the prevalence of the symptom among reproductive-age women to be outlined. Moreover, the introduction of new diagnostic methods, including imaging technologies, entails a revision of the available figures on HMB in different age groups from menarche to menopause. In addition, a proper diagnostic algorithm for HMB should be implemented to adapt recommendations for clinical investigation when HMB is present.

Mapping the non-pregnant uterus cell-by-cell.

The endometrium is a dynamic, multicellular tissue that is constantly remodeled in response to regulating hormones. In a recent issue of Nature Genetics, Garcia-Alonso et al. delineate the unique genetic signatures of the endometrial cells. Their findings validate a three-dimensional epithelial organoid system for modeling endometrial glands ex utero.

Uterine bleeding: how understanding endometrial physiology underpins menstrual health.

Menstruation is a physiological process that is typically uncomplicated. However, up to one third of women globally will be affected by abnormal uterine bleeding (AUB) at some point in their reproductive years. Menstruation (that is, endometrial shedding) is a fine balance between proliferation, decidualization, inflammation, hypoxia, apoptosis, haemostasis, vasoconstriction and, finally, repair and regeneration. An imbalance in any one of these processes can lead to the abnormal endometrial phenotype of AUB. Poor menstrual health has a negative impact on a person's physical, mental, social, emotional and financial well-being. On a global scale, iron deficiency and iron deficiency anaemia are closely linked with AUB, and are often under-reported and under-recognized. The International Federation of Gynecology and Obstetrics have produced standardized terminology and a classification system for the causes of AUB. This standardization will facilitate future research endeavours, diagnosis and clinical management. In a field where no new medications have been developed for over 20 years, emerging technologies are paving the way for a deeper understanding of the biology of the endometrium in health and disease, as well as opening up novel diagnostic and management avenues.

Gain control by sparse, ultra-slow glycinergic synapses.

In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ∼95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing α4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs.

Adult Pleomorphic Rhabdomyosarcomas: Assessing Outcomes Associated with Radiotherapy and Chemotherapy Use in the National Cancer Database.

PURPOSE: Practice patterns for treatment of localized adult pleomorphic rhabdomyosarcoma (PRMS) remain quite variable given its rarity. Current national guidelines recommend management similar to that of other high-grade soft tissue sarcomas (STS), which include surgery with perioperative radiation (RT) with or without chemotherapy. Using the National Cancer Database (NCDB), we assessed practice patterns and overall outcomes of patients with localized PRMS. Patients and Methods. Patients with stage II/III PRMS treated with surgical resection from 2004 to 2015 were identified from the NCDB. Predictors of RT and chemotherapy use were assessed using multivariable logistic regression analysis. The association of radiation and chemotherapy status on overall survival was assessed using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: Of 243 total patients, RT and chemotherapy were not uniformly utilized, with 44% receiving chemotherapy and in those who did not undergo amputation 62% receiving RT. In those who did not undergo amputation, RT was associated with improved survival on both univariate (HR: 0.49, 95% CI 0.32-0.73, P < 0.001) and multivariate analysis (HR: 0.40, 95% CI 0.26-0.62, P < 0.001), corresponding to greater 5-year overall survival (59% vs. 38%, P < 0.001). Chemotherapy was associated with a higher rate of 5-year overall survival (63% vs. 39%, P < 0.001). However, the survival benefit of chemotherapy did not reach statistical significance on multivariate analysis (HR: 0.65, 95% CI 0.41-1.03, P=0.064). Notable predictors of omission of RT included female gender (OR: 0.40, 95% CI 0.22-0.74, P < 0.01) and age ≥ 70 (OR: 0.55, 95% CI 0.30-1.00, P=0.05). Correspondingly, factors associated with omission of chemotherapy included age ≥70 (OR: 0.17, 95% CI 0.08-0.39, P < 0.001). CONCLUSIONS: A significant proportion of patients with localized adult PRMS are not receiving RT. Likewise, use of chemotherapy was heterogeneous. Our findings note potential benefits and underutilization of RT, for which further investigation is warranted.

Definitive Local Therapy Is Associated with Improved Survival in Metastatic Soft Tissue Sarcomas.

Background: Definitive local therapy is often utilized in patients with metastatic soft tissue sarcomas (STS) to reduce morbidity associated with local tumor progression. We hypothesize that it is associated with improved overall survival (OS). Methods: Patients with newly diagnosed metastatic STS treated with chemotherapy were identified from the National Cancer Database and dichotomized into cohorts: 1. definitive local therapy (defined as either definitive dose radiotherapy, definitive surgery, or surgery with perioperative radiotherapy) or 2. conservative therapy (defined as systemic therapy with or without palliative therapy). The association between definitive local therapy and OS, and factors associated with the receipt of definitive local therapy were assessed. Results: Total of 4180 patients were identified. Compared with the conservative therapy, receipt of any definitive local therapy was associated with improved OS (median 17.9 vs. 10.1 months). The survival benefit remained on multivariate analyses and propensity-score matched analyses, with a stepwise improvement with surgery and combined modality local therapy, specifically radiotherapy (HR: 0.77; p < 0.001), surgery (HR: 0.67; p < 0.001), and combined surgery and radiotherapy (HR: 0.42; p < 0.001). Conclusions: Analysis of a large national cancer registry of patients with metastatic STS suggests that chemotherapy plus definitive local therapy is associated with a significant survival benefit compared to the standard chemotherapy alone.

Radiotherapy Remains Underused in the Treatment of Soft-Tissue Sarcomas: Disparities in Practice Patterns in the United States.

BACKGROUND: Practice patterns of radiation therapy (RT) use for soft-tissue sarcoma (STS) remain quite variable, despite clinical practice guidelines recommending the addition of RT to surgery for patients with high-grade STS, particularly for larger tumors. Using the National Cancer Database (NCDB), we assessed patterns of overall RT use, neoadjuvant versus adjuvant treatment, and specific RT modalities in this population. PATIENTS AND METHODS: Patients aged ≥18 years with stage II/III STS in 2004 through 2015 were identified from the NCDB. Patterns of care were assessed using multivariable logistic regression analysis. RESULTS: Of 27,426 total patients, 11,654 (42%) were treated with surgery alone versus 15,772 (58%) with RT in addition to surgery, with no overall increase in RT use over the study period. Notable clinical predictors of receipt of RT included tumor size (>5 cm), grade III, and tumors arising in the extremities. Conversely, female sex, older age (≥70 years), Black race, noncommercial insurance coverage, farther distance to treatment, and poor performance status were negative predictors of RT use. Of those receiving RT, 27% were treated with neoadjuvant RT and 73% with adjuvant RT. The proportion of those receiving neoadjuvant RT increased over time. Relevant factors associated with neoadjuvant RT included treatment at academic centers, larger tumor size, and extremity tumors. Of those who received RT with a modality specified as either intensity-modulated RT (IMRT) or 3D conformal RT (3DCRT), 61% were treated with IMRT and 39% with 3DCRT. The proportion of patients treated with IMRT increased over time. Relevant factors associated with IMRT use included treatment at academic centers, commercial insurance coverage, and larger and nonextremity tumors. CONCLUSIONS: Although use of neoadjuvant RT and IMRT has increased over time, a significant number of patients with STS are not receiving adjuvant or neoadjuvant RT. Our findings also note potential sociodemographic disparities and highlight the concern that not all patients with STS are being equally considered for RT.

Impact of Tumor-Infiltrating Lymphocytes on Overall Survival in Merkel Cell Carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin. As the clinical course can be variable, prognostic markers are needed to better stratify patients. Prior literature, composed of small series with limited sample size, has demonstrated that tumor-infiltrating lymphocytes (TILs) are an important prognostic marker in MCC. To validate these findings on a population level, we sought to analyze and report the prognostic value of TILs in a large national data set. MATERIALS AND METHODS: A retrospective observational cohort study was conducted of patients with nonmetastatic MCC from 2010 to 2015 using the National Cancer Database. Individual variables trending toward significance using a univariable analysis were included in a multivariable Cox proportional hazards model to assess their independent effect on overall survival (OS). TILs were subclassified into none, nonbrisk, and brisk and the survival analysis was performed. Propensity score-weighted multivariable analysis (PS MVA) was performed to adjust for additional confounding. RESULTS: A total of 2,182 patients met inclusion criteria: 611 (28.0%) were identified as having TILs present, and 1,571 (72.0%) had TILs absent in the tumor. On MVA, subdivision of TIL status into nonbrisk (hazard ratio [HR], 0.750; 95% confidence interval [CI], 0.602-0.933) and brisk (HR, 0.499; 95% CI, 0.338-0.735) was associated with incrementally improved OS compared with no TILs. The association of nonbrisk and brisk TILs with improved OS was retained on PS MVA (Nonbrisk: HR, 0.720; 95% CI, 0.550-0.944; Brisk: HR, 0.483; 95% CI, 0.286-0.814). CONCLUSION: The presence of nonbrisk and brisk TILs is associated with incrementally improved OS in patients with nonmetastatic MCC in a large national data set. This pathologic feature can aid with risk stratification, estimation of prognosis, and, importantly, decision-making with respect to treatment intensification in high-risk patients. IMPLICATIONS FOR PRACTICE: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy with variable clinical course. Prognostic markers are needed to better risk stratify patients. We present the largest retrospective observational cohort study of patients with nonmetastatic MCC using the National Cancer Database. Our analysis demonstrates an association between increasing degrees of tumor-infiltrating lymphocytes and incrementally improved survival. These conclusions improve pathologic risk stratification, and decision-making with respect to treatment intensification. Intensification may include adjuvant radiation therapy to the primary site after wide excision despite small tumor size, to the nodal basin in sentinel lymph node-negative patients, or offering closer follow-up.

Higher Dose Volumes May Be Better for Evaluating Radiation Pneumonitis in Lung Proton Therapy Patients Compared With Traditional Photon-Based Dose Constraints.

PURPOSE: The dosimetric parameters used clinically to reduce the likelihood of radiation pneumonitis (RP) for lung cancer radiation therapy have traditionally been V20Gy ≤ 30% to 35% and mean lung dose ≤ 20 to 23 Gy; however, these parameters are derived based on studies from photon therapy. The purpose of this study is to evaluate whether such dosimetric predictors for RP are applicable for locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with proton therapy. METHODS AND MATERIALS: In the study, 160 (78 photon, 82 proton) patients with LA-NSCLC treated with chemoradiotherapy between 2011 and 2016 were retrospectively identified. Forty (20 photon, 20 proton) patients exhibited grade ≥2 RP after therapy. Dose volume histograms for the uninvolved lung were extracted for each patient. The percent lung volumes receiving above various dose levels were obtained in addition to V20Gy and Dmean. These dosimetric parameters and patient characteristics were evaluated with univariate and multivariate logistic regression tests. Receiver operating characteristic curves were generated to obtain the optimal dosimetric constraints through analyzing RP and non-RP sensitivity and specificity values. RESULTS: The multivariate analysis showed V40Gy and Dmean to be statistically significant for proton and photon patients, respectively. V35Gy to V50Gy were strongly correlated to V40Gy for proton patients. Based on the receiver operating characteristic curves, V35Gy to V50Gy had the highest area under the curve compared with other dose levels for proton patients. A potential dosimetric constraint for RP predictor in proton patients is V40Gy ≤ 23%. CONCLUSIONS: In addition to V20Gy and Dmean, the lung volume receiving higher doses, such as V40Gy, may be used as an additional indicator for RP in LA-NSCLC patients treated with proton therapy.

Predicted Secondary Malignancies following Proton versus Photon Radiation for Oropharyngeal Cancers.

PURPOSE: There has been a recent epidemic of human papillomavirus (HPV)-positive oropharyngeal cancer, accounting for 70% to 80% of diagnosed cases. These patients have an overall favorable prognosis and are typically treated with a combination of surgery, chemotherapy, and radiation. Because these patients live longer, they are at risk of secondary malignant neoplasms (SMNs) associated with radiation therapy. Therefore, we assessed the predicted risk of SMNs after adjuvant radiation therapy with intensity-modulated proton therapy (IMPT) compared with intensity modulated photon radiation therapy (IMRT) in patients with HPV- positive oropharyngeal cancers after complete resection. MATERIALS AND METHODS: Thirteen consecutive patients with HPV-positive oropharyngeal cancers treated with postoperative radiation alone were selected. All patients were treated with pencil beam scanning IMPT to a total dose of 60 Gy in 2 Gy fractions. The IMRT plans were generated for clinical backup and were used for comparative purposes. The SMN risk was calculated based on an organ equivalent dose model for the linear-exponential dose-response curve. RESULTS: Median age of the patient cohort was 63 years (range, 47-73 years). There was no difference in target coverage between IMPT and IMRT plans. We noted significant reductions in mean mandible, contralateral parotid, lung and skin organ equivalent doses with IMPT compared with IMRT plans (P < .001). Additionally, a significant decrease in the risk of SMNs with IMPT was observed for all the evaluated organs. Per our analysis, for patients with oropharyngeal cancers diagnosed at a national median age of 54 years with an average life expectancy of 27 years (per national Social Security data), 4 excess SMNs per 100 patients could be avoided by treating them with IMPT versus IMRT. CONCLUSIONS: Treatment with IMPT can achieve comparable target dose coverage while significantly reducing the dose to healthy organs, which can lead to fewer predicted SMNs compared with IMRT.

Gynecologic Risk Mitigation Considerations for Long-Duration Spaceflight.

INTRODUCTION: As NASA and its international partners, as well as the commercial spaceflight industry, prepare for missions of increasing duration and venturing outside of low-Earth orbit, mitigation of medical risk is of high priority. Gynecologic considerations constitute one facet of medical risk for female astronauts. This manuscript will review the preflight, in-flight, and postflight clinical evaluation, management, and prevention considerations for reducing gynecologic and reproductive risks in female astronauts.METHODS: Relevant gynecological articles from databases including Ovid, Medline, Web of Science, various medical libraries, and NASA archives were evaluated for this review. In particular, articles addressing preventive measures or management of conditions in resource-limited environments were evaluated for applicability to future long-duration exploration spaceflight.RESULTS: Topics including abnormal uterine bleeding, anemia, bone mineral density, ovarian cysts, venous thromboembolism, contraception, fertility, and health maintenance were reviewed. Prevention and treatment strategies are discussed with a focus on management options that consider limitations of onboard medical capabilities.DISCUSSION: Long-duration exploration spaceflight will introduce new challenges for maintenance of gynecological and reproductive health. The impact of the space environment outside of low-Earth orbit on gynecological concerns remains unknown, with factors such as increased particle radiation exposure adding complexity and potential risk. While the most effective means of minimizing the impact of gynecologic or reproductive pathology for female astronauts is screening and prevention, gynecological concerns can arise unpredictably as they do on Earth. Careful consideration of gynecological risks and potential adverse events during spaceflight is a critical component to risk analysis and preventive medicine for future exploration missions.Steller JG, Blue RS, Burns R, Bayuse TM, Antonsen EL, Jain V, Blackwell MM, Jennings RT. Gynecologic risk mitigation considerations for long-duration spaceflight. Aerosp Med Hum Perform. 2020; 91(7):543-564.

Updating Photon-Based Normal Tissue Complication Probability Models for Pneumonitis in Patients With Lung Cancer Treated With Proton Beam Therapy.

PURPOSE: No validated models for predicting the risk of radiation pneumonitis (RP) with proton beam therapy (PBT) currently exist. Our goal was to externally validate and recalibrate multiple established photon-based normal tissue complication probability models for RP in a cohort with locally advanced nonsmall cell lung cancer treated with contemporary doses of chemoradiation using PBT. METHODS AND MATERIALS: The external validation cohort consisted of 99 consecutive patients with locally advanced nonsmall cell lung cancer treated with chemoradiation using PBT. RP was retrospectively scored at 3 and 6 months posttreatment. We evaluated the performance of the photon Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) pneumonitis model, the QUANTEC model adjusted for clinical risk factors, and the newer Netherlands updated QUANTEC model. A closed testing procedure was performed to test the need for model updating, either by recalibration-in-the-large (re-estimation of intercept), recalibration (re-estimation of intercept/slope), or model revision (re-estimation of all coefficients). RESULTS: There were 21 events (21%) of ≥grade 2 RP. The closed testing procedure on the PBT data set did not detect major deviations between the models and the data and recommended adjustment of the intercept only for the photon-based Netherlands updated QUANTEC model (intercept update: -1.2). However, an update of the slope and revision of the model coefficients were not recommended by the closed testing procedure, as the deviations were not significant within the power of the data. CONCLUSIONS: The similarity between the dose-response relationship for PBT and photons for normal tissue complications has been an assumption until now. We demonstrate that the preexisting, widely used photon based models fit our PBT data well with minor modifications. These now-validated and updated normal tissue complication probability models can aid in individualizing selection of the most optimal treatment technique for a particular patient.

Potential Venous Thromboembolism Risk in Female Astronauts.

BACKGROUND: Whether the unique environment of space affects astronaut risk of venous thromboembolism (VTE) is not known. On Earth, it is known that use of combined oral contraceptives (COCs) doubles the risk of VTE. Since some female astronauts choose to use COCs, this retrospective study examined known risk factors associated with VTE risk to determine whether the available data suggested elevated VTE risk in female astronauts.METHODS: Longitudinal health data were requested for female astronauts who flew short and long duration missions between 2000 and 2014. Pre- and postflight hematological and biochemical blood markers were available and evaluated. Astronauts' postflight measurements were compared to clinically relevant terrestrial high risk levels to determine any trend toward increased risk for VTE following spaceflight. Secondarily, a comparison of pre- and postflight changes was made, as well as an assessment of COC impact.RESULTS: A total of 38 astronaut-flights were included in this study and no VTE events were found. Analysis of potential VTE risk factors showed no evidence suggesting elevated VTE risk in female astronauts associated with spaceflight, regardless of contraceptive use.DISCUSSION: Arguably, all astronauts encounter many physiological stressors during spaceflight missions, but women using the combined contraceptive pill add a known risk factor for VTE. The risk factors analyzed within this study showed no trend toward an increased risk of VTE for female astronauts. This study provides an evidence base supporting the safety of COC use by female astronauts and also reinforces the importance of healthy lifestyle on VTE risk reduction.Jain V, Ploutz-Snyder R, Young M, Charvat JM, Wotring VE. Potential venous thromboembolism risk in female astronauts. Aerosp Med Hum Perform. 2020; 91(5):432-439.

Association of Age with Efficacy of Immunotherapy in Metastatic Melanoma.

Management of melanoma has been revolutionized by the use of immune checkpoint inhibitors. Immune system changes associated with aging may affect the efficacy of immune-based therapies. Using the National Cancer Database, we evaluated the impact of age on the receipt and efficacy of modern immunotherapies in patients with metastatic melanoma. We identified 11,944 patients from 2011-2015, of whom 25% received immunotherapy. Older (≥60 years), compared with younger, patients were less likely to receive immunotherapy (odds ratio, 0.69; 95% confidence interval [CI], 0.61-0.78; p < .001). Immunotherapy was associated with a survival benefit in both younger and older patients (<60 years: hazard ratio [HR], 0.64; 95% CI, 0.57-0.72; p < .001; ≥60 years: HR, 0.55; 95% CI, 0.50-0.60; p < .001). Importantly, there was a statistically significant interaction between age and survival with immunotherapy, where a greater benefit was observed for older patients (pinteraction = 0.013). Further work studying the age-related response to immunotherapy is warranted.

The functional organization of excitation and inhibition in the dendrites of mouse direction-selective ganglion cells.

Recent studies indicate that the precise timing and location of excitation and inhibition (E/I) within active dendritic trees can significantly impact neuronal function. How synaptic inputs are functionally organized at the subcellular level in intact circuits remains unclear. To address this issue, we took advantage of the retinal direction-selective ganglion cell circuit, where directionally tuned inhibition is known to shape non-directional excitatory signals. We combined two-photon calcium imaging with genetic, pharmacological, and single-cell ablation methods to examine the extent to which inhibition 'vetoes' excitation at the level of individual dendrites of direction-selective ganglion cells. We demonstrate that inhibition shapes direction selectivity independently within small dendritic segments (<10µm) with remarkable accuracy. The data suggest that the parallel processing schemes proposed for direction encoding could be more fine-grained than previously envisioned.