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Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background Topical prostaglandin analogs (PGAs) are widely approved and preferred first-line options for glaucoma and elevated intraocular pressure (IOP). However, prostaglandin-associated periorbitopathy syndrome (PAPS) is now a well-recognized clinical and cosmetic concern for patients receiving PGAs, especially during long-term and unilateral therapy. PGA-associated periocular changes occur in a substantial proportion of patients, with older patients (>60 years) at greater risk of clinical presentation. PAPS may hinder long-term management of glaucoma, including treatment adherence, ophthalmic surgery outcomes, and reliable IOP measurements. Recommendation New therapeutic approaches may address this unmet clinical need. Omidenepag isopropyl (OMDI) is a novel, non-prostaglandin, selective EP2 receptor agonist in ongoing development, which provides a unique pharmacological mechanism of action. OMDI appears to provide IOP reductions comparable to PGAs, but without PAPS-related undesirable effects. OMDI may offer a suitable long-term option for patients who demonstrate decreased efficacy, or failure, of PGAs, plus patients with significant PAPS, while fulfilling international guidelines.

Radiotherapy efficacy is the result of radiation-mediated cytotoxicity coupled with stimulation of antitumor immune responses. We develop an in silico 3-dimensional agent-based model of diverse tumor-immune ecosystems (TIES) represented as anti- or pro-tumor immune phenotypes. We validate the model in 10,469 patients across 31 tumor types by demonstrating that clinically detected tumors have pro-tumor TIES. We then quantify the likelihood radiation induces antitumor TIES shifts toward immune-mediated tumor elimination by developing the individual Radiation Immune Score (iRIS). We show iRIS distribution across 31 tumor types is consistent with the clinical effectiveness of radiotherapy, and in combination with a molecular radiosensitivity index (RSI) combines to predict pan-cancer radiocurability. We show that iRIS correlates with local control and survival in a separate cohort of 59 lung cancer patients treated with radiation. In combination, iRIS and RSI predict radiation-induced TIES shifts in individual patients and identify candidates for radiation de-escalation and treatment escalation. This is the first clinically and biologically validated computational model to simulate and predict pan-cancer response and outcomes via the perturbation of the TIES by radiotherapy.

Purpose: In order for radiotherapy to enter the realm of personalized medicine it will be necessary to model and predict individual patient responses to radiotherapy. Methods and Materials: Here we model tumor dynamics as logistic growth and the effect of radiation as a reduction in the tumor carrying capacity, motivated by the impact of radiation on the tumor microenvironment. The model was assessed on weekly tumor volume data collected for two independent cohorts of head and neck cancer patients from XXXX1 and XXXX2 that received 66-70 Gy in standard daily fractions or with accelerated fractionation. To predict response to radiotherapy for individual patients, we developed a new forecasting framework that combined the learned tumor growth rate and carrying capacity reduction fraction (δ) distribution with weekly measurements of tumor volume reduction for a given test patient to estimate δ, which was used to predict patient-specific outcomes. Results: The model fit data from XXXX1 with high accuracy with patient-specific δ and a fixed tumor growth rate across all patients. The model fit data from an independent cohort from XXXX2 with comparable accuracy using the tumor growth rate learned from the XXXX1 cohort, demonstrating transferability of the growth rate. The forecasting framework predicted patient-specific outcomes with 76% sensitivity and 83% specificity for locoregional control and 68% sensitivity and 85% specificity for disease-free survival with the inclusion of four on-treatment tumor volume measurements. Conclusions: These results show that our simple mathematical model can describe a variety of tumor volume dynamics. Further, combining historically observed patient responses with a few patient-specific tumor volume measurements allows for the accurate prediction of patient outcomes, which may inform treatment adaptation and personalization.

Purpose Patients with recurrent glioblastoma (rGBM) have a poor prognosis. Epidermal growth factor receptor (EGFR) gene amplification is present in ~ 50% of glioblastomas (GBMs). Depatuxizumab mafodotin (depatux-m), formerly ABT-414, is an antibody–drug conjugate that preferentially binds cells with EGFR amplification, is internalized and releases a potent antimicrotubule agent, monomethyl auristatin F (MMAF). Here we report the safety, pharmacokinetics, and efficacy of depatux-m monotherapy at the recommended Phase 2 dose (RPTD) in patients with EGFR-amplified, rGBM. Methods M12-356 (NCT01800695) is an open-label study with three escalation and expansion cohorts. Sixty-six patients with EGFR-amplified, rGBM were treated with depatux-m monotherapy at 1.25 mg/kg intravenously every 2 weeks. Adults with measurable rGBM, who were bevacizumab-naïve, with EGFR amplification were eligible. Results Among 66 patients, median age was 58 years (range 35–80). All patients were previously treated with radiotherapy/temozolomide. The most common adverse events (AEs) were eye related (91%), including blurred vision (65%), dry eye (29%), keratitis, and photophobia (27% each). Grade 3/4 AEs occurred in 42% of all patients, and ocular Grade 3/4 AEs occurred in 33% of patients overall. One patient (2%) had a Grade 4 ocular AE. Ocular AEs were manageable and usually resolved once treatment with depatux-m ceased. The objective response rate was 6.8%, the 6-month progression-free survival rate was 28.8%, and the 6-month overall survival rate was 72.5%. Conclusion Depatux-m monotherapy displayed frequent but mostly Grade 1/2 ocular toxicities. A PFS6 of 28.8% was observed in this rGBM population, warranting further study. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3451-1) contains supplementary material, which is available to authorized users.

Introduction: Current medical therapy for glaucoma consists of topical agents that lower intraocular pressure (IOP). Prostaglandin F2α analogues, the most commonly used class of IOP-lowering drugs,...

Background: Cancer care coordination across major academic medical centers and their networks is evolving rapidly, but the spectrum of organizational efforts has not been described. We conducted a mixed-methods survey of leading cancer centers and their networks to document care coordination and identify opportunities to improve geographically dispersed care. Methods: A mixed-methods survey was sent to 91 cancer centers in the United States and Canada. We analyzed the number and locations of network sites; access to electronic medical records (EMRs); clinical research support and participation at networks; use of patient navigators, care paths, and quality measures; and physician workforce. Responses were collected via Qualtrics software between September 2017 and December 2018. Results: Of the 69 responding cancer centers, 74% were NCI-designated. Eighty-seven percent of respondents were part of a matrix health system, and 13% were freestanding. Fifty-six reported having network sites. Forty-three respondents use navigators for disease-specific populations, and 24 use them for all patients. Thirty-five respondents use ≥1 types of care path. Fifty-seven percent of networks had complete, integrated access to their main center’s EMRs. Thirty-nine respondents said the main center provides funding for clinical research at networks, with 22 reporting the main center provides all funding. Thirty-five said the main center provided pharmacy support at the networks, with 15 indicating the main center provides 100% pharmacy support. Certification program participation varied extensively across networks. Conclusions: The data show academic cancer centers have extensive involvement in network cancer care, often extending into rural communities. Coordinating care through improved clinical trial access and greater use of patient navigation, care paths, coordinated EMRs, and quality measures is likely to improve patient outcomes. Although it is premature to draw firm conclusions, the survey results are appropriate for mapping next steps and data queries.

Introduction Cancer sequencing efforts have revealed that cancer is the most complex and heterogeneous disease that affects humans. However, radiation therapy (RT), one of the most common cancer treatments, is prescribed on the basis of an empirical one-size-fits-all approach. We propose that the field of radiation oncology is operating under an outdated null hypothesis: that all patients are biologically similar and should uniformly respond to the same dose of radiation. Methods We have previously developed the genomic-adjusted radiation dose, a method that accounts for biological heterogeneity and can be used to predict optimal RT dose for an individual patient. In this article, we use genomic-adjusted radiation dose to characterize the biological imprecision of one-size-fits-all RT dosing schemes that result in both over- and under-dosing for most patients treated with RT. To elucidate this inefficiency, and therefore the opportunity for improvement using a personalized dosing scheme, we develop a patient-specific competing hazards style mathematical model combining the canonical equations for tumor control probability and normal tissue complication probability. This model simultaneously optimizes tumor control and toxicity by personalizing RT dose using patient-specific genomics. Results Using data from two prospectively collected cohorts of patients with NSCLC, we validate the competing hazards model by revealing that it predicts the results of RTOG 0617. We report how the failure of RTOG 0617 can be explained by the biological imprecision of empirical uniform dose escalation which results in 80% of patients being overexposed to normal tissue toxicity without potential tumor control benefit. Conclusions Our data reveal a tapestry of radiosensitivity heterogeneity, provide a biological framework that explains the failure of empirical RT dose escalation, and quantify the opportunity to improve clinical outcomes in lung cancer by incorporating genomics into RT.

Background: The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and 18 F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACRT). Material and methods: An exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET. Results: The patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 vs. TRG 1–3; 91% accuracy in predicting TRG 0–1 vs. TRG 2–3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low vs. intermediate vs. high NAR scores. Conclusion: The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACRT. A larger cohort is warranted for further validation.

The increasing complexity of healthcare emphasizes the need for continued physician leadership and leadership training. This study aims to determine baseline attitudes toward the perceptions and utility of a leadership development curriculum (LDC) for radiation oncology (RO) residents. A novel longitudinal LDC was implemented for RO residents at our institution from 2018 to 2019. Prior to the curriculum, current and past residents in our institution's RO residency program were surveyed on their attitudes towards leadership in healthcare, emotional intelligence competencies, and leadership training interests. After the completion of the LDC, a post-curriculum survey was forwarded to current residents. The response rate was 84% (21 of 24) for the baseline survey and 90% (9 of 10) for the post-curriculum survey. Having a leadership training curriculum during residency was rated as extremely useful, with top training interests involving leading clinical teams, effective communication strategies, and conflict management. After the LDC, the residents reported high satisfaction with the curriculum and utilization of leadership training into their daily work. Our LDC demonstrates significant potential to engage trainees and improve their leadership skills at the graduate medical education level.

Introduction To develop a radiomic-based model to predict pathological complete response (pCR) and outcome following neoadjuvant chemoradiotherapy (NACRT) in oesophageal cancer. Methods We analysed 68 patients with oesophageal cancer treated with NACRT followed by esophagectomy, who had staging 18F-fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) and computed tomography (CT) scans performed at our institution. An in-house data-characterization algorithm was used to extract 3D-radiomic features from the segmented primary disease. Prediction models were constructed and internally validated. Composite feature, Fc = α * FPET + (1 - α) * FCT , 0 ≤ α ≤ 1, was constructed for each corresponding CT and PET feature. Loco-regional control (LRC), recurrence-free survival (RFS), metastasis-free survival (MFS) and overall survival (OS) were estimated by Kaplan-Meier analysis, and compared using log-rank test. Results Median follow-up was 59 months. pCR was achieved in 34 (50%) patients. Five-year RFS, LRC, MFS and OS were 67.1%, 88.5%, 75.6% and 57.6%, respectively. Tumour Regression Grade (TRG) 0-1 indicative of complete response or minimal residual disease was significantly associated with improved 5-year LRC [93.7% vs 71.8%; P = 0.020; HR 0.19, 95% CI 0.04-0.85]. Four separate pCR predictive models were built for CT alone, PET alone, CT+PET and composite. CT, PET and CT+PET models had AUC 0.73 ± 0.08, 0.66 ± 0.08 and 0.77 ± 0.07, respectively. The composite model resulted in an improvement of pCR predicting power with AUC 0.87 ± 0.06. Stratifying patients with a low versus high radiomic score showed clinically relevant improvement in 5-year LRC favouring low-score group (91.1% vs. 80%, 95% CI 0.09-1.77, P = 0.2). Conclusion The composite CT/PET radiomics model was highly predictive of pCR following NACRT. Validation in larger data sets is warranted to determine whether the model can predict clinical outcomes.

Serious infections owing to vancomycin-resistant enterococci have historically proven to be difficult clinical cases, requiring combination therapy and management of treatment-related toxicity. Despite the introduction of new antibiotics with activity against vancomycin-resistant enterococci to the therapeutic armamentarium, significant challenges remain. An understanding of the factors driving the emergence of resistance in vancomycin-resistant enterococci, the dynamics of gastrointestinal colonization and microbiota-mediated colonization resistance, and the mechanisms of resistance to the currently available therapeutics will permit clinicians to be better prepared to tackle these challenging hospital-associated pathogens.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.

BACKGROUND: We examine the prognostic implications of mid-course nodal response in oropharyngeal cancer (OPX) to radiation therapy. METHODS: In 44 patients with node-positive OPX undergoing concurrent chemoradiation, nodal volumes were measured on cone beam CTs from days 1, 10, 20, and 35. Nodal decrease (ND) was based on percent shrinkage from day 1. RESULTS: At a median follow-up of 17 months, the 2-year disease-free survival (DFS), locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS) were 87%, 92%, 89%, and 92%, respectively. Patients with ND ≥43% at D20 had improved LRC (100% vs 78.4%, P = .03) compared to D20 ND

Optimizing treatment for patients with low-grade gliomas should focus on the role of radiation and chemotherapy, as well as the prognostic impact of molecular diagnostics (1p/19q and IDH status). For anaplastic oligodendroglioma, focus should be placed on molecular markers (particularly 1p/19q status) and combination treatment with chemotherapy (temozolomide or PCV [procarbazine, lomustine, and vincristine]) and radiation. For patients with malignant glioblastomas, the role of methylguanine methyl-transferase (MGMT) methylation status has become increasingly important to treatment decisions. MGMT methylation status should be considered in elderly patients and/or those with low performance status (methylated patients benefit from temozolomide) and a hypofractionated radiation schedule should be used.

Purpose: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. Patients and Methods: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. Results: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32–0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5–22.2) vs. 5.6 (95% CI, 3.7–7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07–0.45; P < 0.0001). Conclusions: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM. See related commentary by Wick and Wagener, p. 1535

Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) who actively smoke during treatment have worse survival compared with never-smokers and former-smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response. We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers. Experimental Design: Tumor specimens were subjected to analysis of CD3, CD8, FOXP3, PD-1, PD-L1, and pancytokeratin by multiplex immunofluorescence, whole-exome sequencing, and RNA sequencing. Immune markers were measured in tumor core, tumor margin, and stroma. Results: Our data indicate that current smokers have significantly lower numbers of CD8+ cytotoxic T cells and PD-L1+ cells in the TIM compared with never- and former-smokers. While tumor mutation burden and mutant allele tumor heterogeneity score do not associate with smoking status, gene-set enrichment analyses reveal significant suppression of IFNα and IFNγ response pathways in current smokers. Gene expression of canonical IFN response chemokines, CXCL9, CXCL10, and CXCL11, are lower in current smokers than in former smokers, suggesting a mechanism for the decreased immune cell migration to tumor sites. Conclusions: These results suggest active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T cells, likely as a result of suppression of IFN response pathways. Our study highlights the importance of understanding the interaction between smoking and TIM in light of emerging immune modulators for cancer management.

Therapeutic advances for glioblastoma have been minimal over the past 2 decades. In light of the multitude of recent phase III trials that have failed to meet their primary endpoints following promising preclinical and early-phase programs, a Society for Neuro-Oncology Think Tank was held in November 2020 to prioritize areas for improvement in the conduct of glioblastoma clinical trials. Here, we review the literature, identify challenges related to clinical trial eligibility criteria and trial design in glioblastoma, and provide recommendations from the Think Tank. In addition, we provide a data-driven context with which to frame this discussion by analyzing key study design features of adult glioblastoma clinical trials listed on ClinicalTrials.gov as “recruiting” or “not yet recruiting” as of February 2021.

Swarm Intelligence (SI) is a biological phenomenon that enables social species to reach group decisions by converging as real-time systems. Studied in fish schools, bird flocks, and bee swarms, SI has been shown to greatly amplify group intelligence. Artificial Swarm Intelligence (ASI) is recently developed method that enables networked human groups, moderated by real-time swarming algorithms to achieve similar benefits. While ASI can significantly boost the accuracy of group forecasts, estimation, and decisions, the process can be brittle if a large majority supports an inaccurate view, even if their average confidence is low. Thus, a major focus of ASI research has been to increase resilience to low-confidence majorities. This paper introduces a new structure called a hyperswarm that enables a confident minority to more easily sway an unsure majority, enabling convergence on solutions that would otherwise be inaccessible. The approach involves dividing a population P into a set of overlapping subgroups (H1, H2 … HP) such that each member is only exposed to the real-time behaviors of their subgroup. And because each subgroup overlaps multiple other subgroups, interactions can quickly propagate across the full population. In this paper we simulate hyperswarm dynamics, showing that a confident minority can sway a less confident majority in real time, even when more than 65% of the participants initially harbor the majority view, so long as the minority has higher confidence. In addition, we derive theoretical guidelines to predict hyperswarm success based on population size, subgroup size, and confidence differential.

Background Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. Methods Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in the phase 1 clinical trial. Results PDX tumors exposed to different doses of adavosertib revealed intra- and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient’s response to adavosertib. Conclusions The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to preclinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice.

Purpose Review the second reported case of zonisamide induced angle closure. Case Report Patient presentation of ciliochoroidal effusion syndrome secondary to zonisamide. Conclusions Prompt recognition and management of ciliochoroidal effusion syndrome is paramount as newer sulfonamide medications are introduced.

Human-in-the-loop (HITL) AI may enable an ideal symbiosis of human experts and AI models, harnessing the advantages of both while at the same time overcoming their respective limitations. The purpose of this study was to investigate a novel collective intelligence technology designed to amplify the diagnostic accuracy of networked human groups by forming real-time systems modeled on biological swarms. Using small groups of radiologists, the swarm-based technology was applied to the diagnosis of pneumonia on chest radiographs and compared against human experts alone, as well as two state-of-the-art deep learning AI models. Our work demonstrates that both the swarm-based technology and deep-learning technology achieved superior diagnostic accuracy than the human experts alone. Our work further demonstrates that when used in combination, the swarm-based technology and deep-learning technology outperformed either method alone. The superior diagnostic accuracy of the combined HITL AI solution compared to radiologists and AI alone has broad implications for the surging clinical AI deployment and implementation strategies in future practice.

In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT).

Background: The presence of TILs has been correlated with clinical outcomes and response to therapy in breast cancer. However, evaluation of TILs in breast cancer has largely been based on pathologic examination of tumor samples. Here, we report the relationship between invasive breast cancer locoregional recurrence (LRR) and the presence of TILs estimated by transcriptomic analysis with the deconvolution algorithm CIBERSORT. Methods: Patients were identified from an IRB-approved prospective tissue collection protocol at one academic institution and two community hospitals. 526 primary breast tumor samples were identified and gene expression profiling was assessed with high density Affymetrix microarray chips. Proportions of 22 different TIL types in samples were inferred based on the CIBERSORT algorithm, which uses gene expression data to estimate TIL presence. TIL presence was determined by dichotomization at the level of the first quartile among all samples (>Q1=TIL presence). Patient characteristics and clinical outcomes were obtained by chart review. Time to event analysis was performed using Kaplan Meier (KM) estimates and the log-rank test. Associations between patient factors, tumor factors, TIL presence, and LRR were explored with univariable (UVA) and multivariable (MVA) analyses. Factors significant on UVA (p Results: 526 women with invasive breast cancer and available genomic profiling were retrospectively identified for analysis. Median age at diagnosis was 58 years. 70% of tumors were Stage I-II. 69% were luminal subtypes and 17% were triple negative. 37% received mastectomy, 25% received mastectomy + radiation, and 32% received breast conserving therapy. 64% received chemotherapy, and 62% received hormonal therapy. Median follow-up was 74.4 months. There were 61 LRRs. We found significant differences in time to LRR when comparing presence vs. no presence of resting memory CD4+ T-cells (RMCD4+) (p=0.01), activated natural killer cells (ANK) (p=0.003), and neutrophils (PMNs) (p=0.03). On UVA, factors associated with LRR were patient age at diagnosis (p=0.009), pathologic T stage (p=0.045), Estrogen receptor status (p=0.03), biologic subtype (p=0.01), lymphovascular invasion (LVI) (p=0.018), positive margins (p Conclusion: In this study of 526 women with invasive breast cancer, we identified that enrichment of certain TILs is associated with LRR. These results suggest genomic-based assays of TIL presence may be useful to predict LRR in invasive breast cancer. Citation Format: Liveringhouse CL, Grass GD, Figura NB, Mills MN, Purcell JD, Rosensweig SR, Blumencranz PW, Allen KG, Ahmed KA, Harrison LB, Torres-Roca JF, Robinson TJ, Diaz R. Locoregional recurrence in invasive breast cancer and association with tumor infiltrating leukocyte (TIL) presence [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-08-15.

Highlights • Soft tissue sarcomas have traditionally been treated with a one-size fits all approach, despite a wide range of histologies and clinical outcomes. • The radiosensitivity index has demonstrated that soft tissue sarcomas are in general radioresistant, however exhibit a wide range of radiosensitivity. • These differences in radiosensitivity are associated with decreased locoregional control in patients with radioresistant histologies. • Using the radiosensitivity index we identify specific histologies of soft tissue sarcoma that may be more radioresistant, and suggest a genomic-based radiation dosing framework., Background Soft-tissue sarcomas (STS) are heterogeneous with variable response to radiation therapy (RT). Utilizing the radiosensitivity index (RSI) we estimated the radiobiologic ratio of lethal to sublethal damage (α/β), genomic-adjusted radiation dose(GARD), and in-turn a biological effective radiation dose (BED). Methods Two independent cohorts of patients with soft-tissue sarcoma were identified. The first cohort included 217 genomically-profiled samples from our institutional prospective tissue collection protocol; RSI was calculated for these samples, which were then used to dichotomize the population as either highly radioresistant (HRR) or conventionally radioresistant (CRR). In addition, RSI was used to calculate α/β ratio and GARD, providing ideal dosing based on sarcoma genomic radiosensitivity. A second cohort comprising 399 non-metastatic-STS patients treated with neoadjuvant RT and surgery was used to validate our findings. Results Based on the RSI of the sample cohort, 84% would historically be considered radioresistant. We identified a HRR subset that had a significant difference in the RSI, and clinically a lower tumor response to radiation (2.4% vs. 19.4%), 5-year locoregional-control (76.5% vs. 90.8%), and lower estimated α/β (3.29 vs. 5.98), when compared to CRR sarcoma. Using GARD, the dose required to optimize outcome in the HRR subset is a BEDα/β=3.29 of 97 Gy. Conclusions We demonstrate that on a genomic scale, that although STS is radioresistant overall, they are heterogeneous in terms of radiosensitivity. We validated this clinically and estimated an α/β ratio and dosing that would optimize outcome, personalizing dose.

The most challenging complication associated with Factor VIII (FVIII) replacement therapy is the development of neutralizing anti-drug antibodies, or inhibitors, which occur in 23-35% of severe (FVIII level via neonatal Fc receptor (FcRn) binding, other Fc-mediated interactions, including engagement with Fc gamma receptors (FcγR), may have immunological consequences. Several case reports and retrospective analyses suggest that rFVIIIFc offers superior outcomes with respect to ITI compared to other FVIII products. Previously we and others demonstrated rFVIIIFc interactions with activating FcγRIIIA/CD16. Here, we investigated if rFVIIIFc activates natural killer (NK) cells via CD16. We demonstrated rFVIIIFc signaling via CD16 independent of Von Willebrand Factor (VWF):FVIII complex formation. We established that rFVIIIFc potently activated NK cells in a CD16-dependent fashion resulting in IFNγ secretion and cytolytic perforin and granzyme B release. We also demonstrated an association between rFVIIIFc-mediated NK cell IFNγ secretion levels and the high-affinity (158V) CD16 genotype. Furthermore, we show that rFVIIIFc-activated CD16+ NK cells were able to lyse a B-cell clone (BO2C11) bearing an anti-FVIII B-cell receptor in an antibody-dependent cellular cytotoxicity (ADCC) assay. These in vitro findings provide an underlying molecular mechanism that may help explain clinical case reports and retrospective studies suggesting rFVIIIFc may be more effective in tolerizing HA patients with anti-FVIII inhibitors compared to FVIII not linked to Fc. Our in vitro findings suggest a potential use of Fc-fusion proteins acting via NK cells to target antigen-specific B-cells, in the management of unwanted immune responses directed against immunogenic self-antigens or therapeutic protein products.

Purpose/Objective(s) As current radiotherapy (RT) treatment schedules are not personalized for individual patients, with the prescribed dose being uniform for particular subtypes and stages of cancer, despite highly variable responses between patients, we performed an in silico trial to determine optimal personalized RT dose for head and neck cancer patients in order to minimize excess dose with the objective of minimizing toxicity and improving QOL without sacrificing tumor control. Materials/Methods Weekly tumor volume data were collected from two cancer centers for n = 39 head and neck cancer patients that received 66-70 Gy in 2-2.12 Gy daily fractions or with accelerated fractionation. Clinical outcome data, i.e., locoregional control (LRC) and disease-free survival (DFS), were also collected. Tumor volume reduction was connected to LRC by means of a volume reduction threshold associated with LRC. Due to limited patient numbers, the in silico trial was performed in an iterative leave-one-out fashion as follows: (1) a simple 2 parameter model of tumor growth and response to RT was calibrated to tumor volume data from 38 patients, (2) the calibrated model parameters were combined with the left-out patient's tumor volume data from weeks 1-4 of RT to simulate tumor volumes forward sampling from a patient-specific distribution of radiosensitivity parameters, (3) minimum cumulative radiation dose required for local tumor control was estimated by calculating the dose at which > 95% the simulated tumor volume trajectories were below the volume reduction threshold associated with LRC. Results The optimal minimum radiation dose required for LRC was calculated for each patient. We found that 87% of the patients (34/39) received a higher total dose than estimated as necessary by our model with an average overdose of 37 Gy/patient, while the remaining patients were estimated to have received too little dose, with an average underdose of 47 Gy/patient. Notably, our results showed that the current one-size-fits-all approach results in no patient receiving their optimal RT dose. Conclusion Here we show a method to determine a personalized minimum RT dose to achieve LRC. Such simulations and estimates may allow radiation oncologists to identify candidates for dose de-escalation, dose escalation, or additional concurrent treatments, such as chemotherapy.

Drug development suffers from a lack of predictive and human-relevant in vitro models. Organ-on-chip (OOC) technology provides advanced culture capabilities to generate physiologically appropriate, human-based tissue in vitro, therefore providing a route to a predictive in vitro model. However, OOC technologies are often created at the expense of throughput, industry-standard form factors, and compatibility with state-of-the-art data collection tools. Here we present an OOC platform with advanced culture capabilities supporting a variety of human tissue models including liver, vascular, gastrointestinal, and kidney. The platform has 96 devices per industry standard plate and compatibility with contemporary high-throughput data collection tools. Specifically, we demonstrate programmable flow control over two physiologically relevant flow regimes: perfusion flow that enhances hepatic tissue function and high-shear stress flow that aligns endothelial monolayers. In addition, we integrate electrical sensors, demonstrating quantification of barrier function of primary gut colon tissue in real-time. We utilize optical access to the tissues to directly quantify renal active transport and oxygen consumption via integrated oxygen sensors. Finally, we leverage the compatibility and throughput of the platform to screen all 96 devices using high content screening (HCS) and evaluate gene expression using RNA sequencing (RNA-seq). By combining these capabilities in one platform, physiologically-relevant tissues can be generated and measured, accelerating optimization of an in vitro model, and ultimately increasing predictive accuracy of in vitro drug screening.

Since its inaugural issue nearly half a century ago, Antimicrobial Agents and Chemotherapy has served as a premier source for reports on scientific and clinical advances in the field of antimicrobial chemotherapy. As a follow-up to the previous “History of Antimicrobial Agents and Chemotherapy from 1972 to 1998” written by George A. Jacoby (Antimicrob Agents Chemother 43:999–1002, 1999, https://doi.org/10.1128/AAC.43.5.999 ), we herein highlight the further evolution of this comprehensive and authoritative journal in response to changing science, demographics, and information technology.

Approximately 1.7% of the US population has chronic hepatitis C virus (HCV) infection, but among adults born between 1945 and 1965 prevalence increases to 3.25%, and this birth cohort accounts for almost 75% of the total burden of HCV.1 2 The availability of effective direct-acting antiviral (DAA) therapy for HCV makes screening, linkage to care and treatment a national priority. The Centers for Disease Control and Prevention (CDC) and US Preventative Services Task Force (USPSTF) have recommended one-time HCV screening for persons born between 1945 and 1965,2 3 yet only 14%–17% of this cohort has been screened for HCV.4 5 To improve adherence to HCV screening recommendations for patients hospitalised at our medical centre, the Division of Infectious Diseases (ID) at the University of Vermont Medical Center (UVMMC) undertook a quality improvement (QI) initiative to screen patients born between 1945 and 1965 who were seen by the ID Consultation Service. UVMMC is a 562-bed academic medical centre affiliated with the Robert Larner MD College of Medicine at the University of Vermont (UVM) and serves over 1 million patients in Vermont and New York State. Recognising that the baseline prevalence rate of HCV is 1.45% of adults in Vermont and 1.49% in New York,1 we hypothesised that screening hospitalised patients seen by the ID Consultation Service would increase screening rates, identify undiagnosed HCV infections and link patients to care. We developed a protocol to identify patients born between 1945 and 1965 seen by the ID Consultation Service, perform HCV screening and link patients to outpatient care. All patients receiving a consult were being treated for conditions unrelated to HCV (eg, osteomyelitis, endocarditis, urinary tract infections). ID physicians …

Background Echinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans, most often reported in Europe and Asia. Only 1 previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in western and central Canada. Methods We used immunohistochemical testing with the monoclonal antibody Em2G11 and a species-specific enzyme-linked immunosorbent assay affinity-purified antigen Em2, as well as COX1 gene sequencing. Results Using pathology, immunohistochemical staining, specific immunodiagnostic testing, and COX1 gene sequencing, we were able to definitively identify E. multilocularis as the causative agent of our patient’s liver and lung lesions, which clustered most closely with the European haplotype. Conclusions We have identified the first case of a European haplotype E. multilocularis in the United States and the first case of this parasitic infection east of the Mississippi River. Given the identification of this haplotype in Canada, this appears to be an emerging infectious disease in North America.

This study explores the repeated use of glucarpidase following HD-MTX in patients with CNSL. HD-MTX requires aggressive hydration and inpatient monitoring to prevent toxicity. Glucarpidase 50 units(u)/kg for delayed MTX clearance results in a reduction of systemic MTX levels without crossing the blood brain barrier. This study explores the use of 1000 or 2000 units of glucarpidase following repeated cycles of MTX 3–8 g/m2. Eligible adult patients had isolated CNSL, CrCl ≥ 60 mL/min, and KPS ≥ 50. Rituximab with MTX was administered for eight cycles. Glucarpidase was given 24 hours after each MTX infusion. MTX concentrations were monitored in serum and cerebrospinal fluid (CSF). Twelve patients enrolled to date and data are available for 50 doses of MTX (3 g/m2 (20), 6 g/m2 (21), 8 g/m2 (9)). Glucarpidase 1000u (14) or 2000u (36) resulted in at least a 95% reduction in serum MTX levels within 15 minutes following 49/50 doses. A 93% decrease was seen with the remaining dose. Glucarpidase was not detected in the CSF of 7 patients analyzed. Potentially cytotoxic MTX concentrations (10–6 M) were observed in CSF 1 hour (7/7) and 6 hours (4/7) after glucarpidase administration. Radiographic responses are evaluable in 9 patients: complete response (5), partial response (2), stable disease (1), and progressive disease (1). No grade 3 events were attributed to glucarpidase; one grade 4 event of anaphylaxis occurred. Anti-glucarpidase antibodies were detected in 2/5 patients analyzed. In summary, administration of low-dose glucarpidase 24 hours after MTX 3–8 g/m2 results in a reproducible rapid reduction in serum MTX levels in non-renally impaired patients. CSF MTX levels remain therapeutic and clinical response expected from MTX-based therapy does not appear compromised. Anti-glucarpidase antibodies may develop though significance remains unclear. Study is ongoing. Future directions will explore glucarpidase use for reduction of inpatient stay with HD-MTX.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Emergence of the COVID-19 crisis has catalyzed rapid paradigm shifts throughout medicine. Even after the initial wave of the virus subsides, a wholesale return to the prior status quo is not prudent. As a specialty that values the proper application of new technology, radiation oncology should strive to be at the forefront of harnessing telehealth as an important tool to further optimize patient care. We remain cognizant that telehealth cannot and should not be a comprehensive replacement for in-person patient visits because it is not a one for one replacement, dependent on the intention of the visit and patient preference. However, we envision the opportunity for the virtual patient “room” where multidisciplinary care may take place from every specialty. How we adapt is not an inevitability, but instead, an opportunity to shape the ideal image of our new normal through the choices that we make. We have made great strides toward genuine multidisciplinary patient-centered care, but the continued use of telehealth and virtual visits can bring us closer to optimally arranging the spokes of the provider team members around the central hub of the patient as we progress down the road through treatment.

Background The aim of this study was to assess the impact on quality of life from informing patients with cancer of their diagnosis and disease status. Method We searched the follow databases, PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), PsycINFO, WEB OF SCIENCE, Embase, CBM (Chinese Biomedical Literature database), WANFANG database (Chinese Medicine Premier), and CNKI (China National Knowledge Infrastructure), using the following terms: neoplasm, cancer, tumor, tumor, carcinoma, disclosure, truth telling, breaking bad news, knowledge, knowing, awareness, quality of life, QOL. Pairs of reviewers independently screened documents and extracted the data, and the meta-analysis was performed using Revman 5.0 software. Results Eleven thousand seven hundred forty records retrieved from the databases and 23 studies were included in the final analysis. A meta-analysis revealed that there were no differences in either the general quality of life and symptoms of fatigue, pain, dyspnea, insomnia, appetite loss, and diarrhea, between informed and uniformed cancer patients (P > 0.05). There were also no differences found between the patient groups in physical function, role function, cognitive activity, and emotional function (P > 0.05). In terms of vitality, patients who were completely informed about their diagnosis showed higher vitality than uniformed patients. Uninformed patients seemed to have lower social function scores. Between partly informed and uninformed cancer patients, no differences were found in their general quality of life, function domains, and disease-related symptoms (P > 0.05). Conclusion Informing cancer patients of their diagnosis may not have a detrimental effect on their quality of life. Trial registration CRD42017060073 .

Background Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody–drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM. Methods M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5–1.5 mg/kg) on days 1 and 15, and TMZ (150–200 mg/m2) on days 1–5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve. Results There were 60 patients, median age 56 years (range, 20–79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%. Conclusions Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).

IN BRIEF Hispanic patients with type 2 diabetes have poorer glycemic control and are at higher risk of severe diabetes complications and mortality than non-Hispanic white patients. This post hoc analysis investigated the safety and efficacy of insulin degludec versus insulin glargine 100 units/mL (glargine U100) in the Hispanic patient subpopulation from the SWITCH 2 trial. In Hispanic patients, hypoglycemia was consistently lower and nocturnal hypoglycemia was significantly lower with degludec versus glargine U100 at similar levels of glycemic control. Overall, results in Hispanic patients in SWITCH 2 were consistent with those in non-Hispanic patients.

BackgroundBrain tumors can present as focal neurologic deficits (reflecting the tumor location) or generalized symptoms due to increased intracranial pressure. Occasionally, brain tumors can be found incidentally in asymptomatic patients or in patients with unrelated symptoms who undergo brain imaging. The term incidentaloma is used to refer to these imaging abnormalities.ObjectiveThe object of this study was to examine the prevalence and correlates of asymptomatic glioma in a large epidemiological study of brain tumors.MethodsThe analysis was based on a large series of patients with glioma (N = 1989) enrolled in a multicenter clinic-based epidemiologic study between 2005 and 2017. Patients were considered asymptomatic from the tumor, and thus as having an incidentally detected glioma (IDG), if the tumor was diagnosed during workup of injury or unrelated medical condition.ResultsA total of 32 of 1989 (1.6%) patients were asymptomatic at diagnosis. The leading indication for brain imaging in IDG was non-workplace injuries followed by medical workup for unrelated conditions. IDG was more prevalent in patients younger than 50 years of age (2.6% vs 1.0%). IDG was also more common in patients with low grade gliomas (4.7% for WHO grade II and 1.5% for WHO grade III) vs glioblastomas (0.6% in WHO grade IV).ConclusionThe present data suggest that gliomas may be found incidentally, especially among low grade gliomas. Studies of IDG may be useful as a proxy for early detection of tumor as a means to improve patient survival.

Radiotherapy is a pillar of cancer care and augments the response to immunotherapies. However, little is known regarding the relationships between the tumor immune ecosystem (TIES) and intrinsic radiosensitivity, and a pressing question in oncology is how to optimize radiotherapy to improve patient responses to immune therapies. To address this challenge, we profiled over 10,000 primary tumors for their metrics of radiosensitivity and immune cell infiltrate (ICI), and applied a new integrated in silico model that mimics the dynamic relationships between tumor growth, ICI flux and the response to radiation. We then validated this model with a separate cohort of 59 lung cancer patients treated with radiotherapy. These analyses explain radiation response based on its effect on the TIES and quantifies the likelihood that radiation can promote a shift to anti-tumor immunity. Dynamic modeling of the relationship between tumor radiosensitivity and the TIES may provide opportunity to personalize combined radiation and immunotherapy approaches.

Background Studies suggest treatment outcomes may vary between high (HVC)‐ and low‐volume centers (LVC). Radiation therapy (RT) for head and neck cancer (HNC) requires weeks of treatment, the inconvenience of which may influence a patient's choice for treatment location. We hypothesized that receipt of RT for HNC at a HVC would influence outcomes compared to patients evaluated at a HVC, but who chose to receive RT at a LVC. Methods From 1998 to 2011, 1930 HNC patients were evaluated at a HVC and then treated with RT at either a HVC or LVC. Time‐to‐event outcomes and treatment factors were compared. Results Median follow‐up was 34 months. RT was delivered at a HVC for 1368 (71%) patients and at a LVC in 562 (29%). Patients were more likely to choose HVC‐RT if they resided in the HVC's county or required definitive RT (all P

The acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.

Standard of care radiotherapy (RT) doses have been developed as a one-size-fits all approach designed to maximize tumor control rates across a population. Although this has led to high control rates for head and neck cancer with 66–70 Gy, this is done without considering patient heterogeneity. We present a framework to estimate a personalized RT dose for individual patients, based on pre- and early on-treatment tumor volume dynamics—a dynamics-adapted radiotherapy dose (DDARD). We also present the results of an in silico trial of this dose personalization using retrospective data from a combined cohort of n = 39 head and neck cancer patients from the Moffitt and MD Anderson Cancer Centers that received 66–70 Gy RT in 2–2.12 Gy weekday fractions. This trial was repeated constraining DDARD between (54, 82) Gy to test more moderate dose adjustment. DDARD was estimated to range from 8 to 186 Gy, and our in silico trial estimated that 77% of patients treated with standard of care were overdosed by an average dose of 39 Gy, and 23% underdosed by an average dose of 32 Gy. The in silico trial with constrained dose adjustment estimated that locoregional control could be improved by &gt, 10%. We demonstrated the feasibility of using early treatment tumor volume dynamics to inform dose personalization and stratification for dose escalation and de-escalation. These results demonstrate the potential to both de-escalate most patients, while still improving population-level control rates.

Enterococci, one of the most common causes of hospital-associated infections, are responsible for substantial morbidity and mortality. Enterococcus faecalis, the more common and virulent species, causes serious high-inoculum infections, namely infective endocarditis, that are associated with cardiac surgery and mortality rates that remained unchanged for the last 30 years. The best cures for these infections are observed with combination antibiotic therapy; however, optimal treatment has not been fully elucidated. It is the purpose of this review to highlight treatment options and their limitations, and provide direction for future investigative efforts to aid in the treatment of these severe infections. While ampicillin plus ceftriaxone has emerged as a preferred treatment option, mortality rates continue to be high, and from a safety standpoint, ceftriaxone, unlike other cephalosporins, promotes colonization with vancomycin resistant-enterococci due to high biliary concentrations. More research is needed to improve patient outcomes from this high-mortality disease.

Gliomas are the most common type of malignant primary brain tumor and few risk factors have been linked to their development. Handedness has been associated with several pathologic neurological conditions such as schizophrenia, autism, and epilepsy, but few studies have evaluated a connection between handedness and risk of glioma. In this study, we examined the relationship between handedness and glioma risk in a large case-control study (1,849 glioma cases and 1,354 healthy controls) and a prospective cohort study (326,475 subjects with 375 incident gliomas). In the case-control study, we found a significant inverse association between left handedness and glioma risk, with left-handed persons exhibiting a 35% reduction in the risk of developing glioma (Odds Ratio (OR)=0.65, 95% Confidence Interval (CI): 0.51, 0.83) after adjustment for age, gender, race, education, and state of residence; similar inverse associations were observed for GBM (OR=0.69, 95% CI: 0.52, 0.91), and non-GBM (OR=0.59, 95% CI: 0.42, 0.82) subgroups. The association was consistent in both males and females, and across age strata, and was observed in both glioblastoma and in lower grade tumors. In the prospective cohort study, we found no association between handedness and glioma risk (Hazards Ratio=0.92, 95% CI: 0.67, 1.28) adjusting for age, gender, and race. Further studies on this association may help to elucidate mechanisms of pathogenesis in glioma.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

Purpose: Our purpose was to characterize the clinical influences, genetic risk factors, and gene mechanisms contributing to persistent cisplatin-induced peripheral neuropathy (CisIPN) in testicular cancer survivors (TCSs). Experimental Design: TCS given cisplatin-based therapy completed the validated EORTC QLQ-CIPN20 questionnaire. An ordinal CisIPN phenotype was derived, and associations with age, smoking, excess drinking, hypertension, body mass index, diabetes, hypercholesterolemia, cumulative cisplatin dose, and self-reported health were examined for 680 TCS. Genotyping was performed on the Illumina HumanOmniExpressExome chip. Following quality control and imputation, 5.1 million SNPs in 680 genetically European TCS formed the input set. GWAS and PrediXcan were used to identify genetic variation and genetically determined gene expression traits, respectively, contributing to CisIPN. We evaluated two independent datasets for replication: Vanderbilt's electronic health database (BioVU) and the CALGB 90401 trial. Results: Eight sensory items formed a subscale with good internal consistency (Cronbach α = 0.88). Variables significantly associated with CisIPN included age at diagnosis (OR per year, 1.06; P = 2 × 10−9), smoking (OR, 1.54; P = 0.004), excess drinking (OR, 1.83; P = 0.007), and hypertension (OR, 1.61; P = 0.03). CisIPN was correlated with lower self-reported health (OR, 0.56; P = 2.6 × 10−9) and weight gain adjusted for years since treatment (OR per Δkg/m2, 1.05; P = 0.004). PrediXcan identified lower expressions of MIDN and RPRD1B, and higher THEM5 expression as associated with CisIPN (P value for each < 5 × 10−6) with replication of RPRD1B meeting significance criteria (Fisher combined P = 0.0089). Conclusions: CisIPN is associated with age, modifiable risk factors, and genetically determined expression level of RPRD1B. Further study of implicated genes could elucidate the pathophysiologic underpinnings of CisIPN. Clin Cancer Res; 23(19); 5757–68. ©2017 AACR.

Purpose: Radiation therapy (RT) is associated with high stress levels. The role of music therapy (MT) for patients receiving RT is not well described. This study evaluates the impact of MT on anxiety and distress during simulation in patients with newly diagnosed head and neck or breast cancer. Methods and Materials: This institutional review board–approved randomized trial of MT versus no MT at the time of simulation included the pre–State-Trait Anxiety Inventory (STAI-S Anxiety) questionnaire and Symptom Distress Thermometer (SDT). Patients randomized to MT received a consultation with a music therapist, during which music of the patients’ choice to be played during simulation was selected. The no-MT patients did not receive the MT consultation, nor did they hear prerecorded music during simulation. Subsequent to the simulation, all patients repeated the STAI-S Anxiety questionnaire and the SDT. Results: Of the 78 patients enrolled (39 in MT group and 39 in no-MT group), 38 had breast cancer and 40 had head and neck cancer. The male-female ratio was 27:51. The overall mean pre- and post-simulation STAI-S scores were 38.7 (range, 20–60) and 35.2 (range, 20–72), respectively. The overall mean pre- and post-simulation SDT scores were 3.2 (range, 0–10) and 2.5 (range, 0–10), respectively. The MT group had mean pre- and post-simulation STAI-S scores of 39.1 and 31.0, respectively (P, Summary Music therapy’s capacity to address anxiety in cancer patients has not been well described. This institutional review board–approved study evaluated a protocolized music therapy intervention’s impact on anxiety and distress experienced by patients undergoing computed tomography simulation. The intervention significantly reduced anxiety and distress in patients with newly diagnosed head and neck or breast cancer, with a greater effect in subgroups with higher baseline levels of anxiety and distress. Continued research on music therapy’s effects in radiation oncology is warranted.