Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

In Vivo Simvastatin and Brain Radiation in a Model of HER2 + Inflammatory Breast Cancer Brain Metastasis.

Purpose: Inhibiting HMG-CoA reductase with simvastatin prevents breast cancer metastases in preclinical models and radiosensitizes monolayer and stem-like IBC cell lines in vitro . Given the extensive use of simvastatin worldwide and its expected penetration into the brain, we examined whether regulating cholesterol with simvastatin affected IBC3 HER2+ brain metastases. Methods and Materials: Breast cancer cell lines KPL4 and MDA-IBC3 were examined in vitro for DNA repair after radiation with or without statin treatment. Brain metastasis endpoints were examined in the MDA-IBC3 brain metastasis model after ex vivo exposure to lipoproteins and after tail vein injections with and without whole-brain radiotherapy (WBR) and oral statin exposure. Results: Ex vivo preculture of MDA-IBC3 cells with very low-density lipoprotein (vLDL) enhanced the growth of colonized lesions in the brain in vivo compared with control or high-density lipoprotein (HDL), and concurrent oral simvastatin/ WBR reduced the incidence of micrometastatic lesions evaluated 10 days after WBR. However, statin, with or without WBR, did not reduce the incidence, burden, or number of macrometastatic brain lesions evaluated 5 weeks after WBR. Conclusions: Although a role for cholesterol biosynthesis is demonstrated in DNA repair and response to whole brain radiation in this model, durable in vivo efficacy of concurrent whole brain irradiation and oral statin was not demonstrated.

Mt10 Vaccine Protects Diversity Outbred Mice from CVB3 Infection by Producing Virus-Specific Neutralizing Antibodies and Diverse Antibody Isotypes.

Group B coxsackieviruses (CVBs) cause a wide range of diseases in humans, but no vaccines are currently available to prevent these infections. Previously, we had demonstrated that a live attenuated CVB3 vaccine virus, Mutant 10 (Mt10), offers protection against multiple CVB serotypes as evaluated in various inbred mouse strains; however, the applicability of these findings to the outbred human population remains uncertain. To address this issue, we used Diversity Outbred (DO) mice, whose genome is derived from eight inbred mouse strains that may capture the level of genetic diversity of the outbred human population. To determine the efficacy of the Mt10 vaccine, we established the CVB3 infection model in the DO mice. We noted that CVB3 infection resulted mainly in pancreatitis, although viral RNA was detected in both the pancreas and heart. Histologically, the pancreatic lesions comprised of necrosis, post-necrotic atrophy, and lymphocyte infiltration. In evaluating the efficacy of the Mt10 vaccine, both male and female DO mice were completely protected in challenge studies with CVB3, and viral RNA was not detected in the heart or pancreas. Likewise, vaccine recipients of both sexes showed significant levels of virus-neutralizing antibodies. Furthermore, by using the CVB3 viral protein 1, virus-reactive antibodies were found to be diverse in the order of IgG2c, followed by IgG2a, IgG2b/IgG3, and IgG1. Together, the data suggest that the Mt10 vaccine virus can offer protection against CVB infections that may have translational significance.

MR-guided stereotactic radiation therapy for head and neck cancers.

Purpose: MR-guided radiotherapy (MRgRT) has the advantage of utilizing high soft tissue contrast imaging to track daily changes in target and critical organs throughout the entire radiation treatment course. Head and neck (HN) stereotactic body radiation therapy (SBRT) has been increasingly used to treat localized lesions within a shorter timeframe. The purpose of this study is to examine the dosimetric difference between the step-and-shot intensity modulated radiation therapy (IMRT) plans on Elekta Unity and our clinical volumetric modulated arc therapy (VMAT) plans on Varian TrueBeam for HN SBRT. Method: Fourteen patients treated on TrueBeam sTx with VMAT treatment plans were re-planned in the Monaco treatment planning system for Elekta Unity MR-Linac (MRL). The plan qualities, including target coverage, conformity, homogeneity, nearby critical organ doses, gradient index and low dose bath volume, were compared between VMAT and Monaco IMRT plans. Additionally, we evaluated the Unity adaptive plans of adapt-to-position (ATP) and adapt-to-shape (ATS) workflows using simulated setup errors for five patients and assessed the outcomes of our treated patients. Results: Monaco IMRT plans achieved comparable results to VMAT plans in terms of target coverage, uniformity and homogeneity, with slightly higher target maximum and mean doses. The critical organ doses in Monaco IMRT plans all met clinical goals; however, the mean doses and low dose bath volumes were higher than in VMAT plans. The adaptive plans demonstrated that the ATP workflow may result in degraded target coverage and OAR doses for HN SBRT, while the ATS workflow can maintain the plan quality. Conclusion: The use of Monaco treatment planning and online adaptation can achieve dosimetric results comparable to VMAT plans, with the additional benefits of real-time tracking of target volume and nearby critical structures. This offers the potential to treat aggressive and variable tumors in HN SBRT and improve local control and treatment toxicity.

Investigation into Cardiac Myhc-α 334-352-Specific TCR Transgenic Mice Reveals a Role for Cytotoxic CD4 T Cells in the Development of Cardiac Autoimmunity.

Myocarditis is one of the major causes of heart failure in children and young adults and can lead to dilated cardiomyopathy. Lymphocytic myocarditis could result from autoreactive CD4+ and CD8+ T cells, but defining antigen specificity in disease pathogenesis is challenging. To address this issue, we generated T cell receptor (TCR) transgenic (Tg) C57BL/6J mice specific to cardiac myosin heavy chain (Myhc)-α 334-352 and found that Myhc-α-specific TCRs were expressed in both CD4+ and CD8+ T cells. To investigate if the phenotype is more pronounced in a myocarditis-susceptible genetic background, we backcrossed with A/J mice. At the fourth generation of backcrossing, we observed that Tg T cells from naïve mice responded to Myhc-α 334-352, as evaluated by proliferation assay and carboxyfluorescein succinimidyl ester staining. The T cell responses included significant production of mainly pro-inflammatory cytokines, namely interferon (IFN)-γ, interleukin-17, and granulocyte macrophage-colony stimulating factor. While the naïve Tg mice had isolated myocardial lesions, immunization with Myhc-α 334-352 led to mild myocarditis, suggesting that further backcrossing to increase the percentage of A/J genome close to 99.99% might show a more severe disease phenotype. Further investigations led us to note that CD4+ T cells displayed the phenotype of cytotoxic T cells (CTLs) akin to those of conventional CD8+ CTLs, as determined by the expression of CD107a, IFN-γ, granzyme B natural killer cell receptor (NKG)2A, NKG2D, cytotoxic and regulatory T cell molecules, and eomesodermin. Taken together, the transgenic system described in this report may be a helpful tool to distinguish the roles of cytotoxic cardiac antigen-specific CD4+ T cells vs. those of CD8+ T cells in the pathogenesis of myocarditis.

Patterns of failure for recurrent head and neck squamous cell carcinoma treated with salvage surgery and postoperative IMRT reirradiation.

Purpose/Objectives: The purpose of this study was to evaluate patterns of locoregional recurrence (LRR) after surgical salvage and adjuvant reirradiation with IMRT for recurrent head and neck squamous cell cancer (HNSCC). Materials/Methods: Patterns of LRR for 61 patients treated consecutively between 2003 and 2014 who received post-operative IMRT reirradiation to ≥ 60 Gy for recurrent HNSCC were determined by 2 methods: 1) physician classification via visual comparison of post-radiotherapy imaging to reirradiation plans; and 2) using deformable image registration (DIR). Those without evaluable CT planning image data were excluded. All recurrences were verified by biopsy or radiological progression. Failures were defined as in-field, marginal, or out-of-field. Logistic regression analyses were performed to identify predictors for LRR. Results: A total of 55 patients were eligible for analysis and 23 (42 %) had documented LRR after reirradiation. Location of recurrent disease prior to salvage surgery (lymphatic vs. mucosal) was the most significant predictor of LRR after post-operative reirradiation with salvage rate of 67 % for lymphatic vs. 33 % for mucosal sites (p = 0.037). Physician classification of LRR yielded 14 (61 %) in-field failures, 3 (13 %) marginal failures, and 6 (26 %) out-of-field failures, while DIR yielded 10 (44 %) in-field failures, 4 (17 %) marginal failures, and 9 (39 %) out-of-field failures. Most failures (57 %) occurred within the original site of recurrence or first echelon lymphatic drainage. Of patients who had a free flap placed during salvage surgery, 56 % of failures occurred within 1 cm of the surgical flap. Conclusion: Our study highlights the role of DIR in enhancing the accuracy and consistency of POF analysis. Compared to traditional visual inspection, DIR reduces interobserver variability and provides more nuanced insights into dose-specific and spatial parameters of locoregional recurrences. Additionally, the study identifies the location of the initial recurrence as a key predictor of subsequent locoregional recurrence after salvage surgery and re-IMRT.

Adaptive frequency-domain filtering for neural signal preprocessing.

Electrical interference from various sources is a common issue for experimental extracellular electrophysiology recordings collected using multi-electrode array neural recording systems. This interference deteriorates the signal-to-noise ratio (SNR) of the raw electrophysiology signals and hampers the accuracy of data post-processing using techniques such as spike-sorting. Traditional signal processing methods to digitally remove electrical interference during post-processing include bandpass filtering to limit the signal to the relevant spectral range of the biological data, e.g., the spikes band (300 Hz - 7 kHz), targeted notch filtering to remove power line interference from standard alternating current mains electricity and common reference removal to minimize noise common to all electrodes. These methods require a priori knowledge of the frequency of the interfering signal source to address the unique electromagnetic interference environment of each experimental setup. We discuss an adaptive method for automatically removing narrow-band electrical interference through a spectral peak detection and removal (SPDR) step that can be applied during post-processing of the recorded data, based on the intuition that tall, narrowband signals localized in the signal spectrum correspond to interference, rather than the activity of neurons. A spectral peak prominence (SPP) threshold is used to detect these peaks in the frequency domain, which will then be removed via notch filtering. We applied this method to simulated waveforms and also experimental electrophysiology data collected from cerebral organoids to demonstrate its effectiveness for removing unwanted interference without significantly distorting the neural signals. We discuss that proper selection of the SPP threshold is required to avoid over-filtering, which can result in distortion of the electrophysiology data. We also compare the firing-rate activity in the filtered electrophysiology with fluorescence calcium imaging, a secondary cellular activity marker, to quantify signal distortion and provide bounds on SNR-based optimization of the SPP threshold. The adaptive filtering technique demonstrated in this paper is a powerful method that can automatically detect and remove interband interference in recorded neural signals, potentially enabling data collection in more naturalistic settings where external interference signals are difficult to eliminate.

Transgenic Mice Expressing Functional TCRs Specific to Cardiac Myhc-α 334-352 on Both CD4 and CD8 T Cells Are Resistant to the Development of Myocarditis on C57BL/6 Genetic Background.

Myocarditis is a predominant cause of congestive heart failure and sudden death in children and young adolescents that can lead to dilated cardiomyopathy. Lymphocytic myocarditis mediated by T cells can result from the recognition of cardiac antigens that may involve CD4 or CD8 T cells or both. In this report, we describe the generation of T cell receptor (TCR) transgenic mice on a C57BL/6 genetic background specific to cardiac myosin heavy chain (Myhc)-α 334-352 and make the following observations: First, we verified that Myhc-α 334-352 was immunogenic in wild-type C57BL/6 mice and induced antigen-specific CD4 T cell responses despite being a poor binder of IAb; however, the immunized animals developed only mild myocarditis. Second, TCRs specific to Myhc-α 334-352 in transgenic mice were expressed in both CD4 and CD8 T cells, suggesting that the expression of epitope-specific TCR is common to both cell types. Third, although T cells from naïve transgenic mice did not respond to Myhc-α 334-352, both CD4 and CD8 T cells from animals immunized with Myhc-α 334-352 responded to the peptide, indicating that antigen priming is necessary to break tolerance. Fourth, although the transgenic T cells could produce significant amounts of interferon-γ and interleukin-17, the immunized animals developed only mild disease, indicating that other soluble factors might be necessary for developing severe myocarditis. Alternatively, the C57BL/6 genetic background might be a major contributing factor for resistance to the development of myocarditis. Taken together, our model permits the determination of the roles of both CD4 and CD8 T cells to understand the disease-resistance mechanisms of myocarditis in a single transgenic system antigen-specifically.

The knowns and unknowns of cardiac autoimmunity in viral myocarditis.

Myocarditis can result from various infectious and non-infectious causes that can lead to dilated cardiomyopathy (DCM) and heart failure. Among the infectious causes, viruses are commonly suspected. But the challenge is our inability to demonstrate infectious viral particles during clinical presentations, partly because by that point, the viruses would have damaged the tissues and be cleared by the immune system. Therefore, viral signatures such as viral nucleic acids and virus-reactive antibodies may be the only readouts pointing to viruses as potential primary triggers of DCM. Thus, it becomes hard to explain persistent inflammatory infiltrates that might occur in individuals affected with chronic myocarditis/DCM manifesting myocardial dysfunctions. In these circumstances, autoimmunity is suspected, and antibodies to various autoantigens have been demonstrated, suggesting that immune therapies to suppress the autoimmune responses may be necessary. From this perspective, we endeavoured to determine whether or not the known viral causes are associated with development of autoimmune responses to cardiac antigens that include both cardiotropic and non-cardiotropic viruses. If so, what their nature and significance are in developing chronic myocarditis resulting from viruses as primary triggers.

Addition of Metastasis-Directed Therapy to Intermittent Hormone Therapy for Oligometastatic Prostate Cancer: The EXTEND Phase 2 Randomized Clinical Trial.

Importance: Despite evidence demonstrating an overall survival benefit with up-front hormone therapy in addition to established synergy between hormone therapy and radiation, the addition of metastasis-directed therapy (MDT) to hormone therapy for oligometastatic prostate cancer, to date, has not been evaluated in a randomized clinical trial. Objective: To determine in men with oligometastatic prostate cancer whether the addition of MDT to intermittent hormone therapy improves oncologic outcomes and preserves time with eugonadal testosterone compared with intermittent hormone therapy alone. Design, Setting, Participants: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a phase 2, basket randomized clinical trial for multiple solid tumors testing the addition of MDT to standard-of-care systemic therapy. Men aged 18 years or older with oligometastatic prostate cancer who had 5 or fewer metastases and were treated with hormone therapy for 2 or more months were enrolled to the prostate intermittent hormone therapy basket at multicenter tertiary cancer centers from September 2018 to November 2020. The cutoff date for the primary analysis was January 7, 2022. Interventions: Patients were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. Main Outcomes and Measures: The primary end point was disease progression, defined as death or radiographic, clinical, or biochemical progression. A key predefined secondary end point was eugonadal progression-free survival (PFS), defined as the time from achieving a eugonadal testosterone level (≥150 ng/dL; to convert to nanomoles per liter, multiply by 0.0347) until progression. Exploratory measures included quality of life and systemic immune evaluation using flow cytometry and T-cell receptor sequencing. Results: The study included 87 men (median age, 67 years [IQR, 63-72 years]). Median follow-up was 22.0 months (range, 11.6-39.2 months). Progression-free survival was improved in the combined therapy arm (median not reached) compared with the hormone therapy only arm (median, 15.8 months; 95% CI, 13.6-21.2 months) (hazard ratio, 0.25; 95% CI, 0.12-0.55; P < .001). Eugonadal PFS was also improved with MDT (median not reached) compared with the hormone therapy only (6.1 months; 95% CI, 3.7 months to not estimable) (hazard ratio, 0.32; 95% CI, 0.11-0.91; P = .03). Flow cytometry and T-cell receptor sequencing demonstrated increased markers of T-cell activation, proliferation, and clonal expansion limited to the combined therapy arm. Conclusions and Relevance: In this randomized clinical trial, PFS and eugonadal PFS were significantly improved with combination treatment compared with hormone treatment only in men with oligometastatic prostate cancer. Combination of MDT with intermittent hormone therapy may allow for excellent disease control while facilitating prolonged eugonadal testosterone intervals. Trial Registration: ClinicalTrials.gov Identifier: NCT03599765.

Vaccines against Group B Coxsackieviruses and Their Importance.

The group B coxsackieviruses (CVBs) exist in six serotypes (CVB1 to CVB6). Disease associations have been reported for most serotypes, and multiple serotypes can cause similar diseases. For example, CVB1, CVB3, and CVB5 are generally implicated in the causation of myocarditis, whereas CVB1 and CVB4 could accelerate the development of type 1 diabetes (T1D). Yet, no vaccines against these viruses are currently available. In this review, we have analyzed the attributes of experimentally tested vaccines and discussed their merits and demerits or limitations, as well as their impact in preventing infections, most importantly myocarditis and T1D.

2D optical confinement in an etchless stratified trench waveguide.

We demonstrate novel trapezoidal and rectangular stratified trench optical waveguide designs that feature low-loss two-dimensional confinement of guided optical modes that can be realized in continuous polymer thin film layers formed in a trench mold. The design is based on geometrical bends in a thin film core to enable two-dimensional confinement of light in the transverse plane, without any variation in the core thickness. Incidentally, the waveguide design would completely obviate the need for etching the waveguide core, avoiding the scattering loss due to the etched sidewall roughness. This new design exhibits an intrinsic leakage loss due to coupling of light out of the trench, which can be minimized by choosing an appropriate waveguide geometry. Finite-difference eigenmode simulation demonstrates a low intrinsic leakage loss of less than 0.15 dB/cm. We discuss the principle of operation of these stratified trench waveguides and present the design and numerical simulations of a specific realization of this waveguide geometry. The design considerations and tradeoffs in propagation loss and confinement compared with traditional ridge waveguides are discussed.

Optimizing Preventive Adjuvant Linac-Based (OPAL) Radiation: A Phase 2 Trial of Daily Partial Breast Irradiation.

PURPOSE: Evidence supports use of partial-breast irradiation (PBI) in the management of early breast cancer, but the optimal dose-fractionation remains unsettled. METHODS AND MATERIALS: We conducted a phase 2 clinical trial (OPAL trial) to evaluate a novel PBI dosing schedule of 35 Gy in 10 daily fractions. Patients with close (<2 mm) margins also received a boost of 9 Gy in 3 fractions. Eligible patients underwent margin-negative lumpectomy for ductal carcinoma in situ or estrogen receptor-positive invasive breast cancer, up to 3 cm, pTis-T2 N0. The primary outcome was any grade ≥2 toxic effect occurring from the start of radiation through 6 months of follow-up. Secondary outcomes included patient-reported cosmesis, breast pain, and functional status, measured using the Breast Cancer Treatment Outcomes Scale, and physician-reported cosmesis, measured using the Radiation Therapy and Oncology Group scale. The Cochran-Armitage trend test and multivariable mixed-effects longitudinal growth curve models compared outcomes for the OPAL study population with those for a control group of similar patients treated with whole-breast irradiation (WBI) plus boost. RESULTS: All 149 patients enrolled on the OPAL trial received the prescribed dose, and 17.4% received boost. The median age was 64 years; 83.2% were White, and 73.8% were overweight or obese. With median follow-up of 2.0 years, 1 patient (0.7%) experienced in-breast recurrence. Prevalence of the primary toxicity outcome was 17.4% (26 of 149 patients) in the OPAL trial compared with 72.7% (128 of 176 patients) in the control WBI-plus-boost cohort (P < .001). In longitudinal multivariable analysis, treatment on the OPAL trial was associated with improved patient-reported cosmesis (P < .001), functional status (P = .004), breast pain (P = .004), and physician-reported cosmesis (P < .001). CONCLUSIONS: Treatment with daily PBI was associated with substantial reduction in early toxicity and improved patient- and physician-reported outcomes compared with WBI plus boost. Daily external-beam partial-breast irradiation with 13 or fewer fractions merits further prospective evaluation.

Temporal characterization of acute pain and toxicity kinetics during radiation therapy for head and neck cancer. A retrospective study.

Objectives: Pain during Radiation Therapy (RT) for oral cavity/oropharyngeal cancer (OC/OPC) is a clinical challenge due to its multifactorial etiology and variable management. The objective of this study was to define complex pain profiles through temporal characterization of pain descriptors, physiologic state, and RT-induced toxicities for pain trajectories understanding. Materials and methods: Using an electronic health record registry, 351 OC/OPC patients treated with RT from 2013 to 2021 were included. Weekly numeric scale pain scores, pain descriptors, vital signs, physician-reported toxicities, and analgesics were analyzed using linear mixed effect models and Spearman's correlation. Area under the pain curve (AUCpain) was calculated to measure pain burden over time. Results: Median pain scores increased from 0 during the weekly visit (WSV)-1 to 5 during WSV-7. By WSV-7, 60% and 74% of patients reported mouth and throat pain, respectively, with a median pain score of 5. Soreness and burning pain peaked during WSV-6/7 (51%). Median AUCpain was 16% (IQR (9.3-23)), and AUCpain significantly varied based on gender, tumor site, surgery, drug use history, and pre-RT pain. A temporal increase in mucositis and dermatitis, declining mean bodyweight (-7.1%; P < 0.001) and mean arterial pressure (MAP) 6.8 mmHg; P < 0.001 were detected. Pulse rate was positively associated while weight and MAP were negatively associated with pain over time (P < 0.001). Conclusion: This study provides insight on in-depth characterization and associations between dynamic pain, physiologic, and toxicity kinetics. Our findings support further needs of optimized pain control through temporal data-driven clinical decision support systems for acute pain management.

Cardiac myosin-specific autoimmune T cells contribute to immune-checkpoint-inhibitor-associated myocarditis.

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis.

CMU Array: A 3D nanoprinted, fully customizable high-density microelectrode array platform.

Microelectrode arrays provide the means to record electrophysiological activity critical to brain research. Despite its fundamental role, there are no means to customize electrode layouts to address specific experimental or clinical needs. Moreover, current electrodes demonstrate substantial limitations in coverage, fragility, and expense. Using a 3D nanoparticle printing approach that overcomes these limitations, we demonstrate the first in vivo recordings from electrodes that make use of the flexibility of the 3D printing process. The customizable and physically robust 3D multi-electrode devices feature high electrode densities (2600 channels/cm2 of footprint) with minimal gross tissue damage and excellent signal-to-noise ratio. This fabrication methodology also allows flexible reconfiguration consisting of different individual shank lengths and layouts, with low overall channel impedances. This is achieved, in part, via custom 3D printed multilayer circuit boards, a fabrication advancement itself that can support several biomedical device possibilities. This effective device design enables both targeted and large-scale recording of electrical signals throughout the brain.

PhIP-Seq Reveals Autoantibodies for Ubiquitously Expressed Antigens in Viral Myocarditis.

Enteroviruses such as group B coxsackieviruses (CVB) are commonly suspected as causes of myocarditis that can lead to dilated cardiomyopathy (DCM), and the mouse model of CVB3 myocarditis is routinely used to understand DCM pathogenesis. Mechanistically, autoimmunity is suspected due to the presence of autoantibodies for select antigens. However, their role continues to be enigmatic, which also raises the question of whether the breadth of autoantibodies is sufficiently characterized. Here, we attempted to comprehensively analyze the autoantibody repertoire using Phage ImmunoPrecipitation Sequencing (PhIP-Seq), a versatile and high-throughput platform, in the mouse model of CVB3 myocarditis. First, PhIP-Seq analysis using the VirScan library revealed antibody reactivity only to CVB3 in the infected group but not in controls, thus validating the technique in this model. Second, using the mouse peptide library, we detected autoantibodies to 32 peptides from 25 proteins in infected animals that are ubiquitously expressed and have not been previously reported. Third, by using ELISA as a secondary assay, we confirmed antibody reactivity in sera from CVB3-infected animals to cytochrome c oxidase assembly factor 4 homolog (COA4) and phosphoinositide-3-kinase adaptor protein 1 (PIK3AP1), indicating the specificity of antibody detection by PhIP-Seq technology. Fourth, we noted similar antibody reactivity patterns in CVB3 and CVB4 infections, suggesting that the COA4- and PIK3AP1-reactive antibodies could be common to multiple CVB infections. The specificity of the autoantibodies was affirmed with influenza-infected animals that showed no reactivity to any of the antigens tested. Taken together, our data suggest that the autoantibodies identified by PhIP-Seq may have relevance to CVB pathogenesis, with a possibility that similar reactivity could be expected in human DCM patients.

Adhering to Eat and Exercise Status During Radiotherapy for Oropharyngeal Cancer for Prevention and Mitigation of Radiotherapy-Associated Dysphagia.

Importance: Previously published work reported independent benefit of maintenance of oral intake (eat) and swallowing exercise adherence (exercise) during radiotherapy (RT) on diet and functional outcomes. The current study seeks to validate the authors' previously published findings in a large contemporary cohort of patients with oropharynx cancer (OPC) and address limitations of the prior retrospective study using prospective, validated outcome measures. Objective: To examine the longitudinal association of oral intake and swallowing exercise using validated, clinician-graded and patient-reported outcomes. Design, Setting, and Participants: Secondary analysis of a prospective OPC registry including patients who underwent primary RT/chemoradiotherapy (CRT) or primary transoral robotic surgery plus RT/CRT for OPC at a single-institution comprehensive cancer center. Exposures: Adherence to speech pathology swallowing intervention during RT coded as (1) eat: oral intake at end of RT (nothing by mouth [NPO]; partial oral intake [PO], with feeding tube [FT] supplement; full PO); and (2) exercise: swallowing exercise adherence (nonadherent vs partial/full adherence). Main Outcomes and Measures: Feeding tube and diet (Performance Status Scale for Head and Neck Cancer) patient-reported swallowing-related quality of life (MD Anderson Dysphagia Inventory; MDADI) and clinician-graded dysphagia severity grade (videofluoroscopic Dynamic Imaging Grade of Swallowing Toxicity; DIGEST) were collected at baseline, 3 to 6 months, and 18 to 24 months post-RT. Results: A total of 595 patients (mean [SD] age, 65 [10] years; 532 [89%] male) who underwent primary RT (111 of 595 [19%]), CRT (434 of 595 [73%]), or primary transoral robotic surgery plus RT/CRT (50 of 595 [8%]) were included in this cohort study. At the end of RT, 55 (9%) patients were NPO, 115 (19%) were partial PO, 425 (71%) were full PO, and 340 (57%) reported exercise adherence. After multivariate adjustment, subacute return to solid diet and FT were independently associated with oral intake (odds ratio [OR], 2.0; 95% CI, 1.0-4.1; OR, 0.1; 95% CI, 0.0-0.2, respectively) and exercise (OR, 2.9; 95% CI, 1.9-4.5; OR, 0.3; 95% CI, 0.1-0.5, respectively). Subacute MDADI (ß = 6.5; 95% CI, 1.8-11.2), FT duration (days; ß = -123.4; 95% CI, -148.5 to -98.4), and less severe dysphagia per DIGEST (OR, 0.6; 95% CI, 0.3-1.0) were independently associated with oral intake, while exercise was independently associated with less severe laryngeal penetration/aspiration per DIGEST-safety (OR, 0.7; 95% CI, 0.4-1.0). DIGEST grade associations with oral intake were not preserved long-term; however, exercise was associated with a higher likelihood of solid diet intake and better swallow safety per DIGEST. Conclusions and Relevance: The findings of this cohort study extend the authors' previously published findings that oral intake and swallowing exercise during RT are associated with favorable functional outcomes, now demonstrated with broader domains of function using validated measures. Patterns of benefit differed in this study. Specifically, better subacute recovery of swallow-related quality of life and less severe dysphagia were found among patients who maintained oral intake independent of exercise adherence, and shorter FT utilization and better long-term diet and swallowing safety were found among those who exercised independent of oral intake.

Definitive Local Consolidative Therapy for Oligometastatic Solid Tumors: Results From the Lead-in Phase of the Randomized Basket Trial EXTEND.

PURPOSE: The benefit of local consolidative therapy (LCT) for oligometastasis across histologies remains uncertain. EXTernal beam radiation to Eliminate Nominal metastatic Disease (EXTEND; NCT03599765) is a randomized phase 2 basket trial evaluating the effectiveness of LCT for oligometastatic solid tumors. We report here the prospective results of the single-arm "lead-in" phase intended to identify histologies most likely to accrue to histology-specific endpoints in the randomized phase. METHODS AND MATERIALS: Eligible histologies included colorectal, sarcoma, lung, head and neck, ovarian, renal, melanoma, pancreatic, prostate, cervix/uterine, breast, and hepatobiliary. Patients received LCT to all sites of active metastatic disease and primary/regional disease (as applicable) plus standard-of-care systemic therapy or observation. The primary endpoint in EXTEND was progression-free survival (PFS), and the primary endpoint of the lead-phase was histology-specific accrual feasibility. Adverse events were graded by Common Terminology Criteria for Adverse Events version 4.0. RESULTS: From August 2018 through January 2019, 50 patients were enrolled and 49 received definitive LCT. Prostate, breast, and kidney were the highest enrolling histologies and identified for independent accrual in the randomization phase. Most patients (73%) had 1 or 2 metastases, most often in lung or bone (79%), and received ablative radiation (62%). Median follow-up for censored patients was 38 months (range, 16-42 months). Median PFS was 13 months (95% confidence interval, 9-24), 3-year overall survival rate was 73% (95% confidence interval, 57%-83%), and local control rate was 98% (93 of 95 tumors). Two patients (4%) had Common Terminology Criteria for Adverse Events grade 3 toxic effects related to LCT; no patient had grade 4 or 5 toxic effects. CONCLUSIONS: The prospective lead-in phase of the EXTEND basket trial demonstrated feasible accrual, encouraging PFS, and low rates of severe toxic effects at mature follow-up. The randomized phase is ongoing with histology-based baskets that will provide histology-specific evidence for LCT in oligometastatic disease.

Unilateral Radiation Therapy for Tonsillar Cancer: Treatment Outcomes in the Era of Human Papillomavirus, Positron-Emission Tomography, and Intensity Modulated Radiation Therapy.

PURPOSE: The goal of this study was to evaluate disease, survival, and toxic effects after unilateral radiation therapy treatment for tonsillar cancer. METHODS AND MATERIALS: A retrospective study was performed of patients treated at our institution within the period from 2000 to 2018. Summary statistics were used to assess the cohort by patient characteristics and treatments delivered. The Kaplan-Meier method was used to determine survival outcomes. RESULTS: The cohort comprised 403 patients, including 343 (85%) with clinical and/or radiographic evidence of ipsilateral cervical nodal disease and 181 (45%) with multiple involved nodes. Human papillomavirus was detected in 294 (73%) tumors. Median follow-up time was 5.8 years. Disease relapse was infrequent with local recurrence in 9 (2%) patients, neck recurrence in 13 (3%) patients, and recurrence in the unirradiated contralateral neck in 9 (2%) patients. Five- and 10-year overall survival rates were 94% and 89%, respectively. Gastrostomy tubes were needed in 32 (9%) patients, and no patient had a feeding tube 6 months after therapy. CONCLUSIONS: For patients with well-lateralized tonsillar tumors and no clinically evident adenopathy of the contralateral neck, unilateral radiation therapy offers favorable rates of disease outcomes and a relatively low toxicity profile.