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Representative images of tumors from patients who received radiation treatment.

Supplementary Figure from A Phase 1/2 Trial Combining Avelumab and Trabectedin for Advanced Liposarcoma and Leiomyosarcoma

PDA tumor slice culture platform utilized for multimodal analysis before and after ex vivo immune modulation

TCR overlap analysis

Purpose:Pancreatic ductal adenocarcinoma (PDA) is rarely cured, and single-agent immune checkpoint inhibition has not demonstrated clinical benefit despite the presence of large numbers of CD8+ T cells. We hypothesized that tumor-infiltrating CD8+ T cells harbor latent antitumor activity that can be reactivated using combination immunotherapy.Experimental Design:Preserved human PDA specimens were analyzed using multiplex IHC (mIHC) and T-cell receptor (TCR) sequencing. Fresh tumor was treated in organotypic slice culture to test the effects of combination PD-1 and CXCR4 blockade. Slices were analyzed using IHC, flow cytometry, and live fluorescent microscopy to assess tumor kill, in addition to T-cell expansion and mobilization.Results:mIHC demonstrated fewer CD8+ T cells in juxtatumoral stroma containing carcinoma cells than in stroma devoid of them. Using TCR sequencing, we found clonal expansion in each tumor; high-frequency clones had multiple DNA rearrangements coding for the same amino acid binding sequence, which suggests response to common tumor antigens. Treatment of fresh human PDA slices with combination PD-1 and CXCR4 blockade led to increased tumor cell death concomitant with lymphocyte expansion. Live microscopy after combination therapy demonstrated CD8+ T-cell migration into the juxtatumoral compartment and rapid increase in tumor cell apoptosis.Conclusions:Endogenous tumor-reactive T cells are present within the human PDA tumor microenvironment and can be reactivated by combined blockade of PD-1 and CXCR4. This provides a new basis for the rational selection of combination immunotherapy for PDA.See related commentary by Medina and Miller, p. 3747

Device performance

Clinical Trial Design

Increased phosphorylation of PDGFR� and downstream effectors in an undifferentiated pleomorphic sarcoma displaying a lack of apoptotic response to microdosed doxorubicin.

Combination immunotherapy tumor slice culture experiment replicates

Introduction: Although federal laws require equal access to public transportation for people with disabilities, access barriers persist. Lack of sharing accessibility information on public transportation websites restricts people with disabilities from making transportation plans and effectively using public transportation systems. This project aims to document information provided about public transportation systems accessibility and share this information using an open data platform. Methods: We reviewed the top twenty-six public transportation systems in the United States based on federal funding in fiscal year 2020. Information about accessibility was abstracted from the webpages of each public transportation system by two independent reviewers from February-March 2022. Informed by universal design principles, public transportation systems were scored across six dimensions: facility accessibility (0-22 points), vehicle accessibility (0-11 points), inclusive policies (0-12 points), rider accommodations (0-9 points), paratransit services (0-6 points), and website accessibility (0-2 points). Total scores were calculated as the sum of each dimension and ranged from 0-62 points. Data and findings were publicly disseminated (https://disabilityhealth.jhu.edu/tract-dashboard/). Results: The average overall accessibility information score was 31.9 (SD=6.2) out of 62 possible points. Mean scores were 8.4 (SD=2.9) for facility accessibility, 4.5 (SD=2.1) for vehicle accessibility, 7.8 (SD=1.6) for inclusive policies, 4.9 (SD=1.6) for rider accommodations, 4.5 (SD=2.0) for paratransit services, and 1.8 (SD=0.4) for website accessibility. Eleven public transportation systems (42%) received the maximum score for paratransit services and 20 (77%) received the maximum score for website accessibility. No public transportation system received the maximum score for any of the other dimensions. Conclusions: Using a novel scoring system, we found significant variation in the accessibility information presented on public transportation system websites. Websites are a primary mode where users obtain objective information about public transportation systems and are therefore important platforms for communication. Absence of accessibility information creates barriers for the disability community and restricts equal access to public transportation.

Place is a social determinant of health, as recently evidenced by COVID-19. Previous literature surrounding health disparities in the United States often fails to acknowledge the role of structural racism on place-based health disparities for historically marginalized communities (i.e., Black and African American communities, Hispanic/Latinx communities, Indigenous communities [i.e., First Nations, Native American, Alaskan Native, and Native Hawaiian], and Pacific Islanders). This narrative review summarizes the intersection between structural racism and place as contributors to COVID-19 health disparities.This narrative review accounts for the unique place-based health care experiences influenced by structural racism, including health systems and services and physical environment. We searched online databases for peer-reviewed and governmental sources, published in English between 2000 and 2021, related to place-based U.S. health inequities in historically marginalized communities. We then narrate the link between the historical trajectory of structural racism and current COVID-19 health outcomes for historically marginalized communities.Structural racism has infrequently been named as a contributor to place as a social determinant of health. This narrative review details how place is intricately intertwined with the results of structural racism, focusing on one's access to health systems and services and physical environment, including the outdoor air and drinking water. The role of place, health disparities, and structural racism has been starkly displayed during the COVID-19 pandemic, where historically marginalized communities have been subject to greater rates of COVID-19 incidence and mortality.As COVID-19 becomes endemic, it is crucial to understand how place-based inequities and structural racism contributed to the COVID-19 racial disparities in incidence and mortality. Addressing structurally racist place-based health inequities through anti-racist policy strategies is one way to move the United States toward achieving health equity.

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3–specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3–specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

OBJECTIVE To 1) determine current intravenous (IV) acetaminophen use in pediatric inpatients; and 2) determine the association between opioid medication duration when used with or without IV acetaminophen. METHODS A retrospective analysis of pediatric inpatients exposed to IV acetaminophen from January 2011 to June 2016, using the national database Health Facts. RESULTS Eighteen thousand one hundred ninety-seven (2.0%) of 893,293 pediatric inpatients received IV acetaminophen for a median of 14 doses per patient (IQR, 8–56). A greater proportion of IV acetaminophen patients were admitted to the intensive care unit (ICU) (14.8% vs 5.1%, p < 0.0001), received positive pressure ventilation (2.0% vs 1.5%, p < 0.0001), had a higher hospital mortality rate (0.9% vs 0.3%, p < 0.0001), and were operative (35.5% vs 12.8%, p < 0.001) than those not receiving IV acetaminophen. The most common operations associated with IV acetaminophen use were musculoskeletal and digestive system operations. Prescription of IV acetaminophen increased over time, both in prescription rates and number of per patient doses. Of the 18,197 patients prescribed IV acetaminophen, 16,241 (89.2%) also were prescribed opioids during their hospitalization. A multivariate analysis revealed patients prescribed both IV acetaminophen and opioids had a 54.8% increase in opioid duration as compared with patients who received opioids alone. CONCLUSIONS This is the first study to assess IV acetaminophen prescription practices for pediatric inpatients. Intravenous acetaminophen prescription was greater in the non-operative pediatric inpatient population than operative patients. Intravenous acetaminophen prescription was associated with an increase in opioid duration as compared with patients who received opioids alone, suggesting that it is commonly used to supplement opioids for pain relief.

Entrepreneurship involves cooperative efforts in which multiple stakeholders and resources are brought together to develop a valuable product or service. Accordingly, one key process through which entrepreneurs make progress exploiting their opportunities is by identifying, selecting, enrolling, and coordinating a network of stakeholders. However, although there is a widespread realization that bringing new ventures to life requires multiple stakeholders, precious little academic research has taken a holistic approach to stakeholder engagement. In this special issue we: (a) suggest that stakeholder theory provides a novel lens for viewing the critical entrepreneurial behavior of engaging stakeholders—and taking shared responsibility for an unmet opportunity, (b) describe the intriguing articles that encompass this special issue, and (c) offer our thoughts on directions for future research at the intersection of stakeholder theory and entrepreneurship.