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Multiple myeloma is a progressive and incurable hematologic malignancy. It is predominantly a disease of older individuals, with a third of these patients considered to be elderly. In recent years, there has been a focus and emphasis on identifying and stratifying patients based on their functional status and frailty. There are several hallmark complications of the disease-hypercalcemia, renal insufficiency, anemia, bone pain-along with thromboembolism and compromised immunity that are common in patients with multiple myeloma. Due to the wide range of patient ages and functional status, there are, accordingly, different considerations for management of the above complications based on numerous factors, including frailty status. This review focuses on considerations and management of common complications of multiple myeloma in elderly patients. These include renal failure, skeletal complications, anemia, thromboembolism, and infectious complications.

Highlights • This feasibility study showed thyroid sparing in head and neck cancer patients. • Thyroid sparing with acceptable target volume coverage was possible with IMRT. • Average mean dose to thyroid was significantly reduced with thyroid optimization. • Thyroid optimized plans had relatively unchanged doses to surrounding OARs., Background Radiation-induced hypothyroidism is a common toxicity of head and neck radiation. Our re-planning study aimed to reduce thyroid dose while maintaining target coverage with IMRT. Methods We retrospectively identified patients with oral-cavity (n = 5) and oropharyngeal cancer (n = 5). Treatment plans were re-optimized with 45 Gy thyroid mean dose constraint, then we cropped the thyroid out of PTVs and further reduced thyroid dose. Target coverage was delivering 100% dose to ≥ 93% of PTV and 95% of dose to > 99% of PTV. Results Originally, average mean dose to thyroid was 5580 cGy. In model I, this dropped to 4325 cGy (p

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and has an overall five-year survival rate of less than twenty percent. For patients with unresectable disease, evolving liver-directed locoregional therapies provide efficacious treatment across the spectrum of disease stages and via a variety of catheter-directed and percutaneous techniques. Goals of locoregional therapies in HCC may include curative intent in early-stage disease, bridging or downstaging to surgical resection or transplantation for early or intermediate-stage disease, and local disease control and palliation in advanced-stage disease. This review explores the outcomes of chemoembolization, bland embolization, radioembolization, and percutaneous ablative therapies. Attention is also given to prognostic factors related to each of the respective techniques, as well as future directions of locoregional therapies for HCC.

Automated fare collection (AFC) systems such as smart cards are becoming increasingly popular among transit agencies worldwide. Two main configurations of AFC systems can be found, characterized by whether users are required to scan their cards at the beginning of their trips (i.e., entry-only system) or both at the beginning and end of their trips (i.e., entry–exit system). Recently, there has been growing interest in implementing the latter configuration in order to provide more equitable fare structures that charge users based on distance, while arguably providing more accurate data for an origin-destination analysis of users. Therefore, this study explores the spatial and temporal differences in transit users’ origin-destination estimations that are based on the two AFC system configurations. To achieve this goal, it uses AFC system data collected from GO Transit, the operator of the regional commuter rail and bus systems in the Greater Toronto and Hamilton Area (GTHA). A comprehensive model was developed which suggests that the entry–exit AFC system configuration helps in estimating about 14% more trips than an entry-only AFC system configuration; the latter uses a set of common assumptions that are normally employed by researchers in estimating users’ destinations. Spatial, temporal and mode related differences between the two system estimations were also found. This paper offers policy makers and planners a better understanding of the possible benefits/impacts of implementing entry–exit systems vs. entry-only systems on transit users’ origin-destination estimations.

The clinical management of melanoma patients has been rapidly evolving with the introduction of new targeted immuno-oncology (IO) therapeutics. The current diagnostic paradigms for melanoma patients begins with the histopathologic confirmation of melanoma, initial staging of disease burden with imaging and surgical approaches, treatment monitoring during systemic cytotoxic chemotherapy or IO therapeutics, restaging after completion of adjuvant systemic, surgical, and/or external radiation therapy, and the detection of recurrent malignancy/metastatic disease following therapy. New and evolving imaging approaches with positron-emission tomography (PET) imaging technologies, imaging methodologies, image reconstruction, and image analytics will likely continue to improve tumor detection, tumor characterization, and diagnostic confidence, enabling novel precision nuclear medicine practices for managing melanoma patients. This review will examine current concepts and challenges with existing PET imaging diagnostics for melanoma patients and introduce exciting new opportunities for PET in the current era of IO therapeutics.

Studies finding lower incidence rates of prostate cancer among men with diabetes have been primarily conducted in White non-Hispanic (WNH) populations. The purpose of this analysis is to compare the relationship between diabetes and prostate cancer among Black (BNH) and White non-Hispanic men. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data from 2011 to 2015 to compare incidence rates and tumor characteristics between BNH and WNH men by diabetes status. Age-adjusted incidence rates and corresponding rate ratios (RR) by diabetes status were calculated overall and by tumor grade, stage, and PSA level separately for BNH and WNH men. We used multivariable logistic regression to compare tumor characteristics among men with prostate cancer in the numerator, both within and across race/ethnic groups. Overall age-adjusted incidence rates were significantly lower in men with diabetes compared to those without among WNH men [RR = 0.88 95% Confidence Interval (CI) 0.86–0.90] but there was no difference in rates by diabetes status among BNH men (RR = 1.01 95% CI 0.96–1.07). Men with diabetes were less likely to be diagnosed with distant-staged tumors compared to those without diabetes in both race/ethnic groups but the magnitude of difference by diabetes status was greater in BNH [Odds Ratio (OR) = 0.52 95% CI 0.42–0.64] than WNH (OR = 0.88 95% CI 0.81–0.95) men (p-value for interaction

Smartphones with embedded Global Positioning System (GPS) technology provide an opportunity to passively collect individuals’ travel trajectory data, which can be utilized to identify critical aspe...

The household travel survey (HTS) is the most widely used passenger travel data collection method, and web-based HTS is currently the most dominant survey mode. However, there is a lack of proper u...

Neutrophil-to-lymphocyte ratio has been correlated with clinical outcomes in many cancers. We investigated whether the delta-NLR (ΔNLR) following radiation therapy (RT) could predict achieving surgical resection and the overall survival (OS) of patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC), and whether the splenic radiation dose impacted ΔNLR.101 patients with biopsy-proven BRPC or LAPC who received induction chemotherapy followed by RT were retrospectively enrolled. Following contouring of spleens, dose-volume histograms (DVHs) for splenic dosimetric parameters were calculated. Pre- and post-RT complete blood counts (CBC) within two weeks were recorded. Delta (Δ) values were calculated by subtracting the post-RT value from the pre-RT value. Cox regression survival analysis for pre and postradiation CBC values and OS was performed. Receiver operating curves (ROC) were generated and optimal cutoff points for highest sensitivity and specificity were identified. Kaplan-Meier curves for OS were generated.On univariate Cox regression analysis, the only significant CBC value associated with OS was ΔNLR (HR 1.06, CI 1.03-1.09, p 0.001). On multivariate analysis, ΔNLR, age, and completed resection all significantly predicted for worse OS (p 0.05). ΔNLR significantly predicted achieving surgical resection (p = 0.04) and the optimal cutoff point for ΔNLR was 2.5. Patients with ΔNLR 2.5 had significantly longer OS (log rank p = 0.046). Spleen radiation dose parameters were all significantly higher in patients with a ΔNLR ≥ 2.5. Optimal radiation cutoff points to predict a ΔNLR ≥ 2.5 were splenic Dmean of 308 cGy and V5 of 10.3%.Among patients with BRPC or LAPC who have received induction chemotherapy, elevated ΔNLR after RT significantly predicts worse OS and decreased odds of achieving resection. Furthermore, ΔNLR is correlated with higher splenic doses, suggesting the spleen may be an important organ at risk.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

The role of neoadjuvant therapy (NT) for ampullary carcinoma (AC) has not been clearly established.Patients who underwent pancreatoduodenectomy for AC between 2004 and 2016 were identified in the National Cancer Database. Overall survival (OS) was compared between those who received NT before resection and those who underwent surgery first (SF). Propensity score matching (PSM) was performed using age, pathologic T and N stage, and tumor differentiation.Among 8688 patients with AC, 175 (2.0%) received NT before surgery. While patients who received NT were younger (p = .022) and more likely to have nodal metastasis (43.3% vs. 35.1%, p .001), there was no difference in OS on univariate (43 vs. 33 months; hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.88-1.37, p = .401) or multivariate (HR: 1.09, 95% CI: 0.88-1.36, p = .416) analysis between groups. After PSM, there remained no difference in OS between NT or SF groups on univariate (37 vs. 32 months; HR: 1.20, 95% CI: 0.87-1.64, p = .350) or multivariate (HR: 0.99, 95% CI: 0.71-1.38, p = .943) analysis.NT followed by surgery was not associated with improved survival outcomes compared with SF among patients with localized AC. While NT is an acceptable alternative for patients with advanced disease, SF should remain the standard of care.

Purpose: Esophageal cancer is a deadly malignancy with a 5-year survival rate of only 5% to 20%, which has remained unchanged for decades. Esophageal cancer possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell-cycle checkpoint, which likely makes esophageal cancer cells highly reliant upon G2–M checkpoint for adaptation to DNA replication stress and DNA damage after radiation. We aim to explore whether targeting Wee1 kinase to abolish G2–M checkpoint sensitizes esophageal cancer cells to radiotherapy. Experimental Design: Cell viability was assessed by cytotoxicity and colony-forming assays, cell-cycle distribution was analyzed by flow cytometry, and mitotic catastrophe was assessed by immunofluorescence staining. Human esophageal cancer xenografts were generated to explore the radiosensitizing effect of AZD1775 in vivo. Results: The IC50 concentrations of AZD1775 on esophageal cancer cell lines were between 300 and 600 nmol/L. AZD1775 (100 nmol/L) as monotherapy did not alter the viability of esophageal cancer cells, but significantly radiosensitized esophageal cancer cells. AZD1775 significantly abrogated radiation-induced G2–M phase arrest and attenuation of p-CDK1-Y15. Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased γH2AX levels, and subsequently reduced survival after radiation. Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of esophageal cancer tumor xenografts. Conclusions: Abrogation of G2–M checkpoint by targeting Wee1 kinase with AZD1775 sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts. Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.

The NCCN Guidelines for Rectal Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with rectal cancer. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines. These updates include clarifying the definition of rectum and differentiating the rectum from the sigmoid colon; the total neoadjuvant therapy approach for localized rectal cancer; and biomarker-targeted therapy for metastatic colorectal cancer, with a focus on new treatment options for patients with BRAF V600E– or HER2 amplification–positive disease.

Aged cotton rats (Sigmodon hispidus) from an established breeding colony displayed signs of spontaneous exophthalmos. Of a total of 118 colony animals that were older than 6 mo of age, 37 (31%) displayed signs of exophthalmos. These rats were clinically healthy and had no other signs of disease. Ophthalmic exams, molecular and microbiologic testing, and histopa- thology were performed to determine the cause of the exophthalmos and to provide appropriate treatment. Environmental monitoring records were also reviewed for vivarium rooms in which the cotton rats were housed. Histopathology findings supported that the exophthalmos in these cotton rats was secondary to retro-orbital thrombosis associated with cardiomyopathy. The exophthalmic eyes were treated by either removal of the affected eye (enucleation) or surgical closure of the eyelids (temporary tarsorraphy). Enucleation of the exophthalmic eye was the best intervention for these aged cotton rats. These findings demonstrate the potential for a high incidence of ocular problems occurring secondary to cardiomyopathy in aged cotton rats. Enucleation as a therapeutic intervention for exophthalmic eyes in aged cotton rats prolongs the morbidity-free time span during which these aged animals can be used experimentally.

We conducted an institutional study to compare the clinical and pathological efficacy between the neoadjuvant therapy (NAT)‐modified FOLFIRINOX (mFOLF) vs nanoparticle albumin–bound paclitaxel plus gemcitabine (nab‐P/G) for borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) patients who completed resection. The study retrospectively enrolled patients with pathologically confirmed BRPC or LAPC from 2010 to 2018 at our institution. The survival rates were determined by the Kaplan‐Meier method and log‐rank test was used to test differences. Cox's proportional hazard model was used to assess survival with respect to covariates. Seventy‐two patients who completed at least two cycles of neoadjuvant chemotherapy and surgical resection were included, with 52 (72.2%) patients receiving mFOLF and 20 (27.8%) receiving nab‐P/G. Patients treated with mFOLF had statistically higher rates of RECIST 1.1 partial or complete response (16/52 vs 1/20, P = .028). Additionally, mFOLF patients had greater pathological tumor size reduction, fewer positive lymph nodes, and higher treatment response grade compared to the nab‐P/G patients (all P, Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with poor survival rates. For borderline resectable or unresectable disease, intensive multi‐drug chemotherapy regimens with either modified FOLFIRINOX (mFOLF) or nab‐paclitaxel plus gemcitabine are preferred. We retrospectively compared these two chemotherapy regimens in patients who completed resection and found the mFOLF group had better overall clinical and pathological response rates. Randomized clinical trials are needed, and this study provides valuable information in the interim.

Wearable technologies for measuring digital and chemical physiology are pervading the consumer market and hold potential to reliably classify states of relevance to human performance including stress, sleep deprivation, and physical exertion. The ability to efficiently and accurately classify physiological states based on wearable devices is improving. However, the inherent variability of human behavior within and across individuals makes it challenging to predict how identified states influence human performance outcomes of relevance to military operations and other high-stakes domains. We describe a computational modeling approach to address this challenge, seeking to translate user states obtained from a variety of sources including wearable devices into relevant and actionable insights across the cognitive and physical domains. Three status predictors were considered: stress level, sleep status, and extent of physical exertion; these independent variables were used to predict three human performance outcomes: reaction time, executive function, and perceptuo-motor control. The approach provides a complete, conditional probabilistic model of the performance variables given the status predictors. Construction of the model leverages diverse raw data sources to estimate marginal probability density functions for each of six independent and dependent variables of interest using parametric modeling and maximum likelihood estimation. The joint distributions among variables were optimized using an adaptive LASSO approach based on the strength and directionality of conditional relationships (effect sizes) derived from meta-analyses of extant research. The model optimization process converged on solutions that maintain the integrity of the original marginal distributions and the directionality and robustness of conditional relationships. The modeling framework described provides a flexible and extensible solution for human performance prediction, affording efficient expansion with additional independent and dependent variables of interest, ingestion of new raw data, and extension to two- and three-way interactions among independent variables. Continuing work includes model expansion to multiple independent and dependent variables, real-time model stimulation by wearable devices, individualized and small-group prediction, and laboratory and field validation.

Background In patients with stage III melanoma, the use of adjuvant radiation therapy (RT) after lymph node dissection (LND) may be currently considered in selected high-risk patients to improve tumor control. Melanomas harbor BRAF mutations (BRAF+) in 40–50% of cases, the majority of which are on the V600E residue. This study sought to compare the clinical outcomes after RT between patients with BRAF+ and BRAF− melanoma. Methods This was a retrospective review of 105 Stage III melanoma patients treated at our institution with LND followed by adjuvant RT from 2006 to 2019. BRAF mutational status was determined on the primary skin or nodal tissue samples from all patients. We compared characteristics of the BRAF+ and BRAF− groups using Fisher’s exact test and Wilcoxon rank sum test and performed univariate and multivariate analysis using Kaplan–Meier estimates, log-rank tests, and Cox proportional hazards modeling with the clinical outcomes of local–regional lymph node control, distant metastasis-free survival (DMFS), recurrence-free survival (RFS), and overall survival (OS). Results Fifty-three (50%) patients harbored a BRAF mutation (92%, pV600E). BRAF+ patients were younger and had primary tumors more commonly found in the trunk vs head and neck compared to BRAF- patients (p BRAF + patients was 60% compared to 81% in the BRAF- patients (HR 4.5, 95% CI 1.3–15.5, p = 0.02). There were no significant differences in 5-year DMFS, RFS, and OS rates between the two BRAF patient groups. The presence of 4 or more positive LNs remained a significant prognostic factor for local–regional lymph node control, RFS, and OS in multivariate analysis. Conclusions Stage III melanoma patients with BRAF mutation treated with adjuvant RT had > 4 times increased risk of local recurrence or regional lymph node recurrence. These results could be useful for adjuvant RT consideration in lymph node positive melanoma patients and supports other data that BRAF mutation confers radiation resistance.

This paper presents a longitudinal analysis of activity generation behaviour in the Greater Toronto and Hamilton Area (GTHA) between 1996 and 2016 for various activity types: work, school, shopping, other. The analyses are conducted using the data from the five most recent Transportation Tomorrow Surveys. For work and school purposes, the population is divided into sub-categories considering occupational sectors and educational levels respectively. Further subdivision is made by treating first work/school activity of the day and subsequent work/school activities as distinct activity types. Considerable stability over time in the majority of the model parameters is found in all cases, indicating that both work/school and non-work/school activity episode generation in the GTHA has been very stable over the 20-year period analyzed. Year-specific models and joint models, within which the data are pooled across the years, return very similar results implying that robust joint models that exploit the full time-series of survey data available can be constructed. While first-trips to work and post-secondary schools in the day can be parametrically modelled with reasonable fits, second/subsequent work/school activities and non-work/school activities display considerable randomness in occurrence. Elementary and secondary school trips generally need only be modelled using average trip rates across the student population: parametric, utility-based models provide very little additional explanatory power. In addition, investigation of survey design biases shows that there is no significant survey design effect on activity/trip generation for the first work/school-related activities, however, the models reveal significant biases when the subsequent work/school-related activities and non-work/school activities are analyzed.

A previous study found evidence that a breast cancer risk prediction model preferentially selected for less aggressive tumors in Swedish women. In the US, the Gail model has been widely used and was used for entry criteria in two large breast cancer prevention trials. We assessed if higher risk levels from the Gail model were associated with less aggressive tumor characteristics and if risk levels were predictive of mortality and survival. We used questionnaire data from women in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial to calculate Gail risk levels (low

Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.From the Drugs@FDA, clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

The technology around generating efficient and sustainable energy is rapidly evolving; hydrogen and fuel cells are versatile examples within a portfolio of options. This article provides an overview of the early-stage materials R&D in hydrogen and fuel cells at the US Department of Energy (DOE) Fuel Cell Technologies Office within the Office of Energy Efficiency & Renewable Energy. The article highlights technology status and progress toward achieving DOE targets, discusses R&D needs and challenges, and provides specific examples where advanced materials research is relevant to addressing those challenges. For broader context, materials R&D advances are discussed in the context of DOE’s H2@Scale initiative, which is enabling innovations to generate cost-competitive hydrogen as an energy carrier, enabling renewables, as well as nuclear, fossil fuels, and the grid, to enhance the economics of both baseload power plants and intermittent solar and wind, enhancing resiliency and avoiding curtailment.

In 2013, the US Preventive Services Task Force recommended low-dose computed tomography screening for smokers at high risk of lung cancer; however, use remains low. Efforts to promote lung cancer screening need to consider how receptive this population is to preventive healthcare and cancer screening. In addition, because of demonstrated heterogeneity in behaviors by smoking status, interventions may need to differ among eligible high-risk subgroups. To assess the engagement of high-risk smokers in other preventive healthcare behaviors, we examined healthcare use, including non-lung cancer screening, and healthcare provider discussions regarding screening by eligibility for lung cancer screening. We used the 2015 National Health Interview Survey to assess smoking history, healthcare use, cancer screening, vaccinations, and healthcare provider discussions regarding non-lung cancer screening. We calculated weighted prevalence estimates and prevalence ratios comparing eligible and ineligible current and former smokers to never smokers. Eligible current and former smokers had significantly different healthcare utilization and screening concordance compared to never smokers and to each other. Compared to never smokers, eligible current smokers were significantly less likely to be concordant with breast, colorectal, and cervical cancer screening while eligible former smokers were only less likely to be concordant with breast cancer screening. Eligible current smokers were less likely to report physician discussions about non-lung screening tests. Provider discussions about screening and engagement in preventive healthcare differed among current and former smokers eligible for lung cancer screening. Intervention efforts to increase lung cancer screening levels will likely need to differ as well.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract that has increased in incidence across recent years. Often diagnosed at an advanced stage, outcomes for SBA are worse on average than for other related malignancies, including colorectal cancer. Due to the rarity of this disease, few studies have been done to direct optimal treatment, although recent data have shown that SBA responds to treatment differently than colorectal cancer, necessitating a separate approach to treatment. The NCCN Guidelines for Small Bowel Adenocarcinoma were created to establish an evidence-based standard of care for patients with SBA. These guidelines provide recommendations on the workup of suspected SBA, primary treatment options, adjuvant treatment, surveillance, and systemic therapy for metastatic disease. Additionally, principles of imaging and endoscopy, pathologic review, surgery, radiation therapy, and survivorship are described.

Objective The purpose of the study was to test the ability of oculomotor, vestibular, and reaction time (OVRT) metrics to serve as a concussion assessment or diagnostic tool for general clinical use. Setting and participants Patients with concussion were high school-aged athletes clinically diagnosed in a hospital setting with a sports-related concussion (n = 50). Control subjects were previously recruited male and female high school student athletes from 3 local high schools (n = 170). Design Video-oculography was used to acquire eye movement metrics during OVRT tasks, combined with other measures. Measures were compared between groups, and a subset was incorporated into linear regression models that could serve as indicators of concussion. Measures The OVRT test battery included multiple metrics of saccades, smooth pursuit tracking, nystagmoid movements, vestibular function, and reaction time latencies. Results Some OVRT metrics were significantly different between groups. Linear regression models distinguished control subjects from concussion subjects with high accuracy. Metrics included changes in smooth pursuit tracking, increased reaction time and reduced saccade velocity in a complex motor task, and decreased optokinetic nystagmus (OKN) gain. In addition, optokinetic gain was reduced and more variable in subjects assessed 22 or more days after injury. Conclusion These results indicate that OVRT tests can be used as a reliable adjunctive tool in the assessment of concussion and that OKN results appear to be associated with a prolonged expression of concussion symptoms.

Next-generation X-ray imaging missions require fast, low-noise detectors that can survive the harsh environment of space without significant loss of performance. As part of a detector development effort toward a mission such as Lynx, we report on the effects of proton exposure on the spectral performance, dark current and charge transfer efficiency of a back illuminated MIT Lincoln Laboratory CCID93. The CCD has 8 micron pixels and can be clocked with 2.5MHz pixel speeds with CMOS compatible voltage swings. The 40 MeV proton dose is chosen to represent typical on orbit exposure. Variations with charge injection, temperature, and clocking speed are explored. These results are compared with those of the front illuminated version of the same device.

We describe an implementation of a broad-band soft X-ray polarimeter, substantially based on previous designs. The Globe-Orbiting Soft X-ray Polarimeter (GOSoX) is a SmallSat. As in a related mission concept the PiSoX Polarimeter, the grating arrangement is designed optimally for the purpose of polarimetry matching the dispersion of a spectrometer to a laterally graded multilayer (LGML). For GOSoX, the optics are lightweight Si mirrors in a one-bounce parabolic configuration. The instrument covers the wavelength range from 31 A to 75 A (165 - 400 eV). Upon satellite rotation, the intensities of the dispersed spectra, after reflection and polarizing by the LGMLs, give the three Stokes parameters needed to determine a source's linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe the potential scientific return and the proposed mission concept following the results of a JPL Team X concept study.

XRISM is an X-ray astronomical mission by the JAXA, NASA, ESA and other international participants, that is planned for launch in 2022 (Japanese fiscal year), to quickly restore high-resolution X-ray spectroscopy of astrophysical objects. To enhance the scientific outputs of the mission, the Science Operations Team (SOT) is structured independently from the instrument teams and the Mission Operations Team. The responsibilities of the SOT are divided into four categories: 1) guest observer program and data distributions, 2) distribution of analysis software and the calibration database, 3) guest observer support activities, and 4) performance verification and optimization activities. As the first step, lessons on the science operations learned from past Japanese X-ray missions are reviewed, and 15 kinds of lessons are identified. Among them, a) the importance of early preparation of the operations from the ground stage, b) construction of an independent team for science operations separate from the instrument development, and c) operations with well-defined duties by appointed members are recognized as key lessons. Then, the team structure and the task division between the mission and science operations are defined; the tasks are shared among Japan, US, and Europe and are performed by three centers, the SOC, SDC, and ESAC, respectively. The SOC is designed to perform tasks close to the spacecraft operations, such as spacecraft planning, quick-look health checks, pre-pipeline processing, etc., and the SDC covers tasks regarding data calibration processing, maintenance of analysis tools, etc. The data-archive and user-support activities are covered both by the SOC and SDC. Finally, the science-operations tasks and tools are defined and prepared before launch., Comment: 42 pages, 7 figures, 8 table, Accepted for Publication in JATIS (SPIE)

Here we introduce a new reconstruction technique for two-dimensional Bragg scattering tomography (BST), based on the Radon transform models of Webber and Miller [Inverse Probl. Imaging 15, 683 (2021).10.3934/ipi.2021010]. Our method uses a combination of ideas from multibang control and microlocal analysis to construct an objective function which can regularize the BST artifacts; specifically the boundary artifacts due to sharp cutoff in sinogram space (as observed in [arXiv preprint, arXiv:2007.00208 (2020)]), and artifacts arising from approximations made in constructing the model used for inversion. We then test our algorithm in a variety of Monte Carlo (MC) simulated examples of practical interest in airport baggage screening and threat detection. The data used in our studies is generated with a novel Monte-Carlo code presented here. The model, which is available from the authors upon request, captures both the Bragg scatter effects described by BST as well as beam attenuation and Compton scatter.

Perioperative pain management is an important consideration in early recovery and patient satisfaction following laparoscopic donor nephrectomy. Transmuscular quadratus lumborum block has been described to reduce pain and opioid usage following several abdominal surgeries. In this prospective single‐blind randomized controlled trial, we compared 52 patients who adhered to our institutional donor nephrectomy Early Recovery After Surgery pathway, which includes a laparoscopic‐guided transversus abdominus plane block, to 40 patients who additionally received a transmuscular quadratus lumborum block with liposomal bupivacaine. Compared to control patients, those who received the block spent longer in the operating room prior to the surgical start (65.4 vs. 51.6 min, P

Background Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the importance of completing multimodality therapy, the purpose of this qualitative study was to characterize physician perspectives on barriers and facilitators to delivering NT. Methods A purposive sample of surgical, medical, and radiation oncologists participated in semi-structured interviews. Interviews were transcribed and coded by 3 independent researchers, iteratively identifying themes until saturation was achieved. Results Participants (n = 27) were heterogeneous in specialty, years of experience, practice setting, gender, and geography. The most commonly cited advantage of NT was the ability to downstage patients. The most commonly cited barriers included lack of access and limited evidence. Patient preference for immediate surgery was frequently cited as a barrier, but most participants felt that patients eventually understood the treatment recommendation after informed discussion. Recommendations to enhance the delivery of NT included improved patient education, communication, and better evidence. Conclusion In this qualitative study, indications for, barriers to, and opportunities to improve the delivery of NT for localized PDAC were identified. These results highlight the need for better evidence and protocol standardization for NT as well as methods of improving care coordination, communication, and education to improve patient-centered outcomes.

Background: The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly among the elderly (age ≥65 years). We sought to compare patterns of care for the treatment of SCCA in elderly versus nonelderly patients. Methods: Data for patients with stages I–III SCCA diagnosed from 2004 through 2015 were obtained from the National Cancer Database. Patients were categorized as having received standard-of-care (SOC) chemoradiation (CRT) with multiagent chemotherapy, non-SOC therapy, palliative therapy, or no treatment. Differences in treatment groups were tested using the chi-square test. We used logistic regression to identify predictors of SOC CRT and multiagent versus single-agent chemotherapy in patients receiving CRT. Propensity score matching was used to compare overall survival (OS) in elderly patients receiving multiagent versus single-agent chemotherapy for those receiving CRT. Results: We identified 9,156 elderly and 17,640 nonelderly patients. A lower proportion of elderly versus nonelderly patients (54.5% vs 65.0%; PPP1.5-fold increase in the likelihood of elderly patients receiving single-agent chemotherapy (odds ratio, 1.52; 95% CI, 1.39–1.66) in multivariate analysis. After propensity score matching, 3-year OS was higher in elderly patients who received CRT with multiagent versus single-agent chemotherapy (77.1% vs 67.5%; hazard ratio, 0.78; 95% CI, 0.68–0.89; P=.0002). Conclusions: In this comprehensive study of patients with stages I–III SCCA, elderly patients were less likely than nonelderly patients to receive SOC CRT. The low proportion of elderly patients receiving SOC CRT with multiagent chemotherapy for localized anal cancer suggests that the optimal treatment approach for this vulnerable population remains undefined.

Purpose/Objective(s) Radiation treatment planning for meningioma conventionally involves MRI contrast enhanced images to define residual tumor. However, the gross tumor volume may be difficult to delineate for patients with a meningioma in the skull base, sagittal sinus, or post resection. Advanced PET imaging using 68(GA)DOTATATE PET, which has been shown to be more sensitive and specific than MRI imaging, can be used for target volume delineation in these circumstances. We hypothesize that 68(GA)DOTATATE PET scan-based treatment planning will lead to differences in radiation treatment volumes and will be more precise compared to standard MRI alone. Materials/Methods Our study evaluated retrospective, deidentified, and blinded gross tumor volume (GTV) contour delineation of 5 CNS specialists (3 neuroradiologists, 2 CNS radiation oncologists) for 26 patients diagnosed with a meningioma who received both a 68(GA)DOTATATE PET and an MRI for radiation treatment planning. Both the MRI and the PET-based GTV were non-sequentially contoured by each physician for each patient. We defined a significant difference in volume delineation if there was > 100% difference in contoured volume found for 80% of physicians or more when comparing MRI and PET. A PET only lesion was defined as any lesion not seen on MRI but delineated on PET imaging by at least 80% of physicians. This lesion would need to be non-adjacent to the MRI based contours for the same patient. Results The mean volume of MRI based contours was 12.5 ccs (range 0.55-62 ccs). The mean volume for PET directed contours was 13.7 ccs (range 0.24-94 ccs). We found 15/26 (58%) patients had at least a 100% difference in volume between PET and MRI for 80% of physician contours. 8/26 (31%) patients had new non-adjacent areas contoured on PET that were not contoured by these physicians on the corresponding MRI. These new areas would not have been in the traditional MRI based volumes. Conclusion We found a significant difference in PET based volumes with 58% showing major differences in volume and 31% showing new areas not seen on MRI. This has major implications on tumor control. Our study supports that 68(GA)DOTATATE PET imaging can help radiation oncologist be more precise with radiation treatment volumes. Utilization of 68(GA)DOTATATE PET may find undetected areas of disease which in turn can improve local control and progression free survival. 68(GA)DOTATATE PET guided treatment planning should be studied prospectively.

As contact dimensions continue to shrink to support scaling, local CD variation (LCDU) becomes a critical driver of electrical variation and defectivity. Continued logic scaling is highly dependent on middle of line (MOL), which further amplifies the need for LCDU improvement. LCDU improvement will be critical to improving edge placement error (EPE). The same concepts can also be applied to back end of line (BEOL) vias. Since lithography tools are unable to consistently print contacts below 20 nm, it is typically necessary to shrink through etch. There are various etch techniques we can use to shrink contact dimensions each having different impacts on LCDU and defectivity. In this study we explore the impacts of various shrink methods to optimize LCDU and defect density. In this study a simple patterning stack of SiN + OPL + ARC + resist is used to simulate contact patterning. Various etch chambers and shrink techniques are used to reach a target CD range and LCDU and defect density are evaluated. The chambers evaluated include TEL’s conductor etcher and TEL’s dielectric etcher. LCDU data is collected using CDSEM. Defect density is evaluated using various etch techniques. Etch techniques such as deposition on resist, ARC and OPL, descum steps, pulsing and quasi atomic layer etch are explored. Multiple types of deposition techniques are used including selective deposition and cyclic deposition and trim. These techniques are optimized to be sensitive to open area and correct for local CD variations. On wafer LCDU performance of

Gate all around stacked nanosheet FET’s have emerged as the next technology to FinFET’s for beyond 7-nm scaling. With EUV technology integrated into manufacturing at 7nm, there is great interest to enable EUV direct print patterning for nanosheet technology in the FEOL. While sheet and gate pitches expected for the beyond 7nm node fall within the EUV direct print regime (>40nm), it is unclear if direct print solutions can meet device performance requirements at technology critical sheet widths and gate lengths. Here, we demonstrate electrical performance of nanosheet FET’s with 20 – 80 nm wide sheets with 40-150 nm pitch gates patterned with single expose EUV. We compare results against a benchmark double patterning process towards meeting variability, device and critical dimension targets. We also explore the limits of process and material knobs - resists, illuminations and etch chemistries with the specific goal of reducing LER/LWR and towards shrink for further scaling. Our results demonstrate crossover points between direct print EUV and double patterning processes for nanosheet technology and identify relevant design guidelines and focus areas to successfully enable EUV for the FEOL in nanosheets.

OBJECTIVE To compare intraocular pressure readings from three different tonometers, the Tono-Pen AVIA® (TP), TonoVet® (TV) and TonoVet Plus® (TV+) and to determine how measurements from each tonometer are affected by central corneal thickness (CCT). ANIMALS Ninety dogs. PROCEDURES Normal dogs and dogs with ocular disease were selected for study inclusion. Central corneal thickness measurements were gathered with the Pachette 4 ultrasonic pachymeter, and IOP measurements were gathered with the three tonometers in random order. ANOVA or Wilcoxon tests were utilized for overall group comparisons. Linear regression analyses were utilized to determine the association between IOP and CCT. RESULTS When comparing tonometers to each other, for all dogs, readings from the TV+were significantly different compared to the TV (p =

PURPOSE: Prior studies show that many patients receiving palliative cancer therapies misperceive likelihood of cure. Patients’ understanding of treatment benefits and risks beyond cure is unknown. We explore patient perceptions of palliative treatment in the novel therapeutic era. METHODS: We surveyed patients with advanced solid cancers and their oncologists regarding benefits and risks of palliative therapies. We assessed perceived likelihood of tumor response, survival benefit, symptom palliation, and side effects. We used generalized estimating equations to calculate least squares means of misperception (patient-assessed minus physician-assessed likelihood of benefit), accounting for clustering by physician, and compared the degree of misperception by participant characteristics. RESULTS: Of the 119 patients enrolled, median age was 65 years (range, 59-73 years), 55% were male, and 56% had prior treatment. Treatments included chemotherapy (60%), immunotherapy (24%), and targeted therapy (15%). Compared with their oncologists, patients overestimate curability (median misperception, 20%; interquartile range [IQR], 0 to 60), chances of tumor response (median, 20%; IQR, 0 to 40), symptom palliation (median, 10%; IQR, −10 to 30), and survival benefit (median, 20%; IQR, 0 to 40). Toxicity was relatively accurately estimated (median, 0.5%; IQR, −20 to 20). Immunotherapy was associated with higher risk of misperception of tumor response and toxicity. Misperceptions of tumor response and curability did not correlate (r = 0.13, P = .15). CONCLUSION: Compared with their oncologists, patients overestimated chances of tumor response, symptom palliation, and survival benefit, but accurately perceived likelihood of toxicity. There was no strong correlation between perception of curability and other goals of therapy. Communication focused on treatment goals alongside risks may reduce misperceptions and facilitate informed choices by patients.

Men with prostate cancer have high cause-specific survival, and most deaths are from other causes. This study aimed to investigate other and all-cause mortality in a large cancer screening cohort.From the PLCO (Prostate, Lung, Colorectal and Ovarian) Cancer Screening Trial cohort, we selected men diagnosed with prostate cancer from 1994-2014. We examined other and all-cause survival by prostate cancer risk level, defined as the D'Amico categories for localized disease (low, intermediate and high risk) plus nonlocalized disease. We developed 3 Cox proportional hazards models to assess the relationship between risk level and survival. Model I controlled for age, race, study arm and diagnosis year. Model II additionally controlled for other demographic and medical history factors. Model III additionally controlled for initial treatment.Of 76,672 men in PLCO and 10,859 prostate cancer cases, 9,248 (85.2%) had known prostate cancer risk level (mean±SD age 70.4±6.2 years). Median followup time from diagnosis was 10.8 years (IQR 6.8-15.0). Of 3,318 deaths 81% were from other causes. Compared to the low risk group, other-cause mortality HRs were 1.13 (95% CI 1.04-1.23), 1.35 (95% CI 1.21-1.50) and 1.63 (95% CI 1.35-1.97) for intermediate risk, high risk and advanced disease, respectively, in model II. Model III HRs were similar to model II except for advanced disease, where the HR decreased to 1.35.Other-cause survival was greater in lower vs higher risk disease, even after controlling for lifestyle characteristics and comorbidities. Further research is needed to identify factors contributing to this higher other-cause mortality to help mitigate the risk.

We describe a new implementation of a broad-band soft X-ray polarimeter, substantially based on a previous design. This implementation, the Pioneer Soft X-ray Polarimeter (PiSoX) is a SmallSat, designed for NASA’s call for Astrophysics Pioneers, small missions that could be CubeSats, balloon experiments, or SmallSats. As in REDSoX, the grating arrangement is designed optimally for the purpose of polarimetry with broad-band focussing optics by matching the dispersion of the spectrometer channels to laterally graded multilayers (LGMLs). The system can achieve polarization modulation factors over 90%. For PiSoX, the optics are lightweight Si mirrors in a one-bounce parabolic configuration. High efficiency, blazed gratings from opposite sectors are oriented to disperse to a LGML forming a channel covering the wavelength range from 35 A to 75 A (165 - 350 eV). Upon satellite rotation, the intensities of the dispersed spectra, after reflection and polarizing by the LGMLs, give the three Stokes parameters needed to determine a source’s linear polarization fraction and orientation. The design can be extended to higher energies as LGMLs are developed further. We describe examples of the potential scientific return from instruments based on this design.

Several high-throughput, high-resolution X-ray mission concepts now under study, including Lynx, a flagship, and AXIS, a probe, require large-format imaging detectors with performance at least as good as the best current generation devices but with much higher readout rates. We are investigating the potential of new CCD detector technology developed at MIT Lincoln Laboratory for meeting the needs of these missions. This technology features low-voltage charge transfer and fast, low-noise amplifiers. Deployed in a multiple output sensor architecture with low-power (application-specific integrated circuit) signal processing, this technology offers an attractive path to the high frame rates and low power consumption required. This approach is one of three candidates selected for development for Lynx, and it has also been included in the AXIS baseline. Here we report recent progress in developing this technology, with a focus on two characteristics critical to good low-energy response: read noise and charge packet size. We have measured read noise below 4 electrons, RMS (the Lynx requirement) at pixel rates up to 2.5 MHz in both front- and back-illuminated test devices, with transfer clock levels of ±1.5 V. We have also exploited the 8 µm pixel size of test detectors to measure the spatial extent of X-ray induced charge packets as a function of detector bias. We infer a root-mean-square radius 4 µm for charge packets originating at the entrance window of a 50 μm thick back-illuminated detector under high-bias (-20 V) conditions. We note that the high pixel ’aspect ratio’ (thickness : pixel size ≈ 6 : 1) of our test devices is similar to that expected for Lynx and AXIS detectors, and discuss implications of our charge cloud size measurements for noise requirements for these missions

The XRISM is the astronomical mission to perform the high-resolution X-ray spectroscopy of astrophysical objects using the micro-calorimeter array. In order to enhance the scientific outputs of the mission, the science operations team (SOT) is structured with responsibilities of the spacecraft planning, data processing and distributions, development and maintenance of analyses software and calibration database, and users’ supports. The operation concepts are established based on lessons learned from past X-ray missions. The SOT consists of the Science Operations Center at JAXA and the Science Data Center at NASA. Details of science operations plan and preparation status on SOC are summarized.

Next-generation X-ray imaging missions require fast, low-noise detectors that can survive the harsh environment of space without significant loss of performance. As part of a detector development effort toward a mission such as Lynx, we report on the effects of proton exposure on the spectral performance, dark current and charge transfer effciency of an MIT Lincoln Lab CCID93. The CCD has 8 micron pixels and can be clocked with 2.5MHz pixel speeds with CMOS compatible voltage swings. The 40 MeV proton dose is chosen to represent typical on orbit exposure. Variations with charge injection, temperature, and clocking speed are explored.

The X-Ray Imaging and Spectroscopy Mission, XRISM, is scheduled to launch in 2022, with the goal of building on the brief successes of the ASTRO-H (Hitomi) mission, and recovering the prime science objective to solve outstanding astrophysical questions using high resolution X-ray spectroscopy. The XRISM Science Operations Team (SOT), consists of the JAXA-led Science Operations Center (SOC) and NASA-led Science Data Center (SDC) that work together to optimize the scientific output from the Resolve high-resolution spectrometer and the Xtend wide-field imager through planning and scheduling observations, processing and distribution of data, development and distribution of software tools and the calibration database (CaldB), user support, and support of ground and in-flight calibration. Here, we summarize the roles and responsibilities of the SDC, and the current status and future plans, covering scheduling software, software and CalDB production and release, data transmission and processing pipeline, and simulation and other post-pipeline analysis tools. Resolve poses particular challenges due to its unprecedented combination of high spectral resolution and throughput, broad spectral coverage, and relatively small field-of-view and large pixel-size; and, we highlight those challenges.

Space-based X-ray detectors are subject to significant fluxes of charged particles in orbit, notably energetic cosmic ray protons, contributing a significant background. We develop novel machine learning algorithms to detect charged particle events in next-generation X-ray CCDs and DEPFET detectors, with initial studies focusing on the Athena Wide Field Imager (WFI) DEPFET detector. We train and test a prototype convolutional neural network algorithm and find that charged particle and X-ray events are identified with a high degree of accuracy, exploiting correlations between pixels to improve performance over existing event detection algorithms. 99 per cent of frames containing a cosmic ray are identified and the neural network is able to correctly identify up to 40 per cent of the cosmic rays that are missed by current event classification criteria, showing potential to significantly reduce the instrumental background, and unlock the full scientific potential of future X-ray missions such as Athena, Lynx and AXIS., Proceedings of the SPIE, Astronomical Telescopes and Instrumentation, Space Telescopes and Instrumentation 2020: Ultraviolet to Gamma Ray

The optimal treatment for stage I squamous cell carcinoma of the anus (SCCA) remains undefined. Recently, wide local excision alone was found to have comparable survival to those treated with chemoradiation (CRT). Given that local excision may be sufficient for the treatment of stage I SCCA, we hypothesized that radiation therapy (RT) alone, compared to CRT would result in equivalent overall survival (OS) in this population. We identified non-surgically treated patients with stage I SCCA from the National Cancer Database from 2004&ndash, 2015. We included only patients treated either with CRT (45&ndash, 59.4 Gy with chemotherapy initiated within 14 days of RT) or RT alone (45&ndash, 59.4 Gy with no chemotherapy). The primary endpoint was OS between CRT and RT patients. Propensity-score matched (PSM) analysis was performed to determine the effect of concurrent chemotherapy on OS using a Cox proportional hazards model with robust standard error to account for clustering in matched pairs. We identified 3552 stage I patients treated with CRT and 287 treated with RT. Compared to patients treated with CRT, those that received RT were more likely to be &ge, 70 years old (33.1% vs. 19.7%, p &lt, 0.001) and less likely to be female (63.1% vs. 71.0%, p &lt, 0.001). The proportion of patients with a Charlson-Deyo score of 0 was similar in both groups (80.8% RT vs. 82.7% CRT, p = 0.164). The PSM cohort consisted of 287 pairs of patients with median follow-up 48.3 months (interquartile range, 24.4&ndash, 85.1 months) and 151 deaths (86 RT, 65 CRT). CRT was associated with a 31% reduction in the risk of death (HR = 0.69, 95% CI 0.50&ndash, 0.95, p = 0.023). We found that CRT was associated with improved OS, compared to RT alone, in patients with non-surgically treated stage I SCCA. These data suggest that de-intensification of therapy in stage I SCCA must be used with caution. However, given the retrospective nature of the data, prospective trials are required.

Radiation-induced cardiovascular disease, including coronary artery disease, is a well-known sequela of radiation therapy and represents a significant source of morbidity and mortality for cancer survivors. This review examines current literature and guidelines to care for this growing population of cancer survivors. The development of radiation-induced ischemic heart disease following radiation can lead even to early cardiotoxicities, inclusive of coronary artery disease, which limit cancer treatment outcomes. These coronary lesions tend to be diffuse, complex, and proximal. Early detection with multimodality imaging and targeted intervention is required to minimize these risks. Early awareness, detection, and management of radiation-induced cardiovascular disease are paramount as cancer survivorship continues to grow.

Background: The heterogeneity of the breast tumor microenvironment (TME) may contribute to the lack of durable responses to immune checkpoint blockade (ICB), however, mouse models to test this are currently lacking. Proper choice and use of pre-clinical models are necessary for rigorous, pre-clinical studies to rapidly move laboratory findings into the clinic to treat patients. Methods: To elucidate how tumor latency and the heterogeneity of the TME contributes to ICB resistance, we performed comprehensive characterization of the TME using quantitative flow-cytometry and RNA expression analysis (NanoString) utilizing three distinct breast cancer models, all derived from the same autochthonous model. Tumor cells were obtained from the commonly used MMTV-PyMT murine breast cancer model and 1E6, 1E5 or 1E4 cells were either immediately injected into the mammary fat pad of FVB/NJ wild type mice or frozen (i.e. the tumor inoculation derived from the MMTV-PyMT tumors were never cultured). We then correlated the immunophenotyping to the efficacy observed from ICB. Results: These studies reveal that the number of cells used to generate syngeneic tumors significantly influences tumor latency, the infiltrating leukocyte population and response to ICB. The 4 models had vastly different TMEs which correlated to responses to ICB. Compared to the autochthonous model, all three syngeneic models had significantly more tumor infiltrating lymphocytes (TILs; CD3 + , CD4 + , and CD8 + ) and higher proportions of PD-L1 positive myeloid cells, whereas the MMTV-PyMT model had the highest frequency of myeloid cells out of total leukocytes. Increased TILs correlated with response to anti-PD-L1 and anti-CTLA-4 therapy; but tumor cell PD-L1expression and T-cell PD-1 expression did not. Conclusions: Here we have identified ICB-sensitive and resistant breast cancer models, generated from the same tumor cell inoculum. These models represent an opportunity to further interrogate the TME for breast cancer treatment and provide novel insights into therapeutic combinations and response to ICB. We believe this work serves as an important resource for the field to inform proper mouse model selection for pre-clinical studies.

Although the development of effective combined chemoradiation regimens for esophageal cancers has resulted in statistically significant survival benefits, the majority of patients treated with curative intent develop locoregional and/or distant relapse. Further improvements in disease control and survival will require the development of individualized therapy based on the knowledge of host and tumor genomics and potentially harnessing the host immune system. Although there are a number of gene targets that are amplified and proteins that are overexpressed in esophageal cancers, attempts to target several of these have not proven successful in unselected patients. Herein, we review our current state of knowledge regarding the molecular pathways implicated in esophageal carcinoma, and the available agents for targeting these pathways that may rationally be combined with standard chemoradiation, with the hope that this commentary will guide future efforts of novel combinations of therapy.