Citations

Problem definition: Coordinated care network (CCN) is a burgeoning paradigm where patients’ diagnosis and treatment plans are developed based on collaboration between multiple, colocated medical specialties to holistically address patients’ health needs. A primary performance metric for CCNs is how quickly patients can complete their itinerary of appointments at multiple medical services in the network. Rapid completion is critical to care delivery but also presents a major operational challenge. Because information about a patient’s condition and treatment options evolves over the course of the itinerary, care paths are not known a priori. Thus, appointments (except for the first one) cannot be reserved in advance, which may result in significant delays if capacity is not allocated properly. Methodology/results: We study capacity allocation for the patient’s first (root) appointment as the primary operational lever to achieve rapid itinerary completion in CCNs. We develop a novel queueing-based analytical framework to optimize this root appointment allocation, maximizing the proportion of patients completing care by prespecified deadlines. Our framework accounts for the complex interactions among all patients in the network through the blocking process, which contrasts with conventional siloed planning. We provide an exact characterization of the itinerary time and develop a mean-field approximation with convergence guarantees that permits tractable solutions for large-scale network problems. In a simulation case study of Mayo Clinic, our solution improves on-time completion from 60% under the current plan to more than 93%. Managerial implications: We demonstrate that root appointment allocation is a multifaceted problem and that ignoring any of those facets can lead to poor performance. Simultaneously accounting for all of these complexities makes manual template design or traditional optimization methods inadequate, highlighting the significance of our integrated approach. Supplemental Material: The online appendix is available at https://doi.org/10.1287/msom.2022.0649 .

PURPOSE International medical graduates (IMGs) are an essential component of the oncology workforce in the United States, comprising a third of all practicing oncologists and almost half of hematology/oncology fellows. In this article, we discuss the contributions of IMGs in the US oncology workforce, review unique challenges faced by IMGs, and propose potential solutions to overcome these challenges. METHODS ASCO's IMG Community of Practice was established with the mission to connect, mentor, guide, raise awareness, and overcome the challenges unique to IMGs interested in pursuing medical oncology in the United States. The content of this article is based on discussions at the IMG Community of Practice meetings at ASCO's 2023 and 2024 Annual Meetings. RESULTS IMGs bring an inherent diversity of thought and experience to the oncology workforce. They provide high-quality, culture- and language-concordant care to a diverse population of patients with cancer. However, IMGs in oncology face significant hardships throughout their careers, including visa-related restrictions, psychosocial and cultural struggles, as well as differential treatment while applying for residency and fellowship training, and early career positions. Greater awareness of these challenges among the members of the hematology/oncology community, along with institutional and individual efforts to support IMGs, is warranted. CONCLUSION We encourage oncology professionals and institutions to join our efforts in recognizing the unique paths of IMGs and providing support and advocacy to maximize the potential of IMGs in the US oncology workforce.

Abstract Accumulating evidence suggests dysregulated immune checkpoint (IC) signaling can exacerbate COVID-19 severity, but the role of these molecules in the pathogenesis of fatal COVID-19-related diffuse alveolar damage (DAD) remains elusive. Understanding how IC proteins influence acute lung injury due to COVID-19 can provide insights into potential therapeutic strategies to modulate immune responses and improve patient outcomes. Here, in a single-center autopsy cohort, we determined the cellular localization of ICs in lung tissue from cases of fatal COVID-19, DAD-comparators, and non-fibrotic controls by using immunohistochemistry, and investigated their association with clinical outcomes. We expanded our findings by performing analyses of publicly available single-cell RNA sequencing datasets from patients with fatal COVID-19 and non-fibrotic controls. We demonstrated the presence of protein-protein interaction networks of ICs in the lung cellular niche by performing transcriptomic profiling of lung tissue-derived RNA counts from patients with fatal COVID-19. Further, we leveraged data from the largest international, multi-center COVID-19 autopsy cohort and validated that, among patients with fatal COVID-19, those with higher PD-L1/CD274 expression in lung endothelial cells had more rapid clinical deterioration. Lastly, in a cohort of individuals with early COVID-19, IC plasma protein levels were elevated in those with persistent SARS-CoV-2 RNAemia and adverse clinical outcomes. Collectively, our data provide unique pathological insights into the role of IC dysregulation and differential disease severity in COVID-19.

29 Background: International Medical Graduates (IMGs) comprise over one-third of internal medicine (IM) trainees and practicing oncologists in the United States. We aimed to examine challenges faced by IM IMG residents in pursuing hematology-oncology (HO) fellowship positions. Methods: We conducted a pilot survey using SurveyPluto to assess demographics and evaluate visa related challenges amongst ACGME residents interested in HO. The survey was disseminated through the ASCO IMG Community of Practice (CoP), the Heme-Onc Fellows Mentorship Empowerment (H.O.M.E) group and the IMG Oncologists social media homepage (@IMG_Oncologists). Results: A total of 59 IMG residents completed the survey (20% PGY-1, 36% PGY-2 and 44% PGY-3). The majority of trainees (88%) were from community or university-affiliated community programs. J-1 visa was the most common visa type (67.8%). The visa process was rated as difficult or very difficult by 36% of trainees. Annual visa renewal was required by 51% trainees and 55.9% reported visa related impact on plans for research grant applications (Table). The greatest challenges associated with visa status were disruption of travel plans and inability to unite with family (35.6%); obtaining documentation from home country (33.9%); visa renewal (28.8%) and lack of clarity in visa instructions (27.1%). Among resources that respondents wanted better access to, IMG networking groups (81.4%), legal/financial aids (47.5%), institutional visa seminars (45.8%) and flexibility from their program to visit family overseas (45.8%) were identified as priorities. Conclusions: Visa related barriers pose significant challenges to IMGs interested in HO. Policy changes, advocacy work and additional resources could be beneficial for future IMG oncologists. Challenges associated with visa status for hematology/oncology aspirants. Greatest visa related barriers during training % of respondents (n=59) Documentation from home country 33.9% Disruption in travel plans/ inability to unite with family 35.6% Lack of clarity in renewal instructions/ renewal process post document procurement 55.9% Ability to secure grant affected by visa 22% Non-monetary grant aspects affected by visa 13.6% Did not pursue grants due to visa 20.3% Desired resources during residency Institutional visa seminars 45.8% IMG network groups 81.4% Program flexibility to visit family overseas/ legal and financial aids 45.8%/47.5%

Abstract Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

Abstract Maturation of the secondary antibody repertoire requires class‐switch recombination (CSR), which switches IgM to other immunoglobulins (Igs), and somatic hypermutation, which promotes the production of high‐affinity antibodies. Following immune response or infection within the body, activation of T cell‐dependent and T cell‐independent antigens triggers the activation of activation‐induced cytidine deaminase, initiating the CSR process. CSR has the capacity to modify the functional properties of antibodies, thereby contributing to the adaptive immune response in the organism. Ig CSR defects, characterized by an abnormal relative frequency of Ig isotypes, represent a rare form of primary immunodeficiency. Elucidating the molecular basis of Ig diversification is essential for a better understanding of diseases related to Ig CSR defects and could provide clues for clinical diagnosis and therapeutic approaches. Here, we review the most recent insights on the diversification of five Ig isotypes and choose several classic diseases, including hyper‐IgM syndrome, Waldenström macroglobulinemia, hyper‐IgD syndrome, selective IgA deficiency, hyper‐IgE syndrome, multiple myeloma, and Burkitt lymphoma, to illustrate the mechanism of Ig CSR deficiency. The investigation into the underlying mechanism of Ig CSR holds significant potential for the advancement of increasingly precise diagnostic and therapeutic approaches.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

8555 Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), with historically poor outcome. Excellent response of metastatic PSC to immunotherapy was previously reported, but its outcome compared with other NSCLCs is unknown in the immunotherapy era. Methods: NCDB was queried for stage IV NSCLC diagnosed from 2016 to 2020. Patients who were treated with chemotherapy only or immunotherapy only in the first course of treatment were included. Log-rank was used for survival analysis and adjusted by cox regression for age, gender, race, academic/integrated center, insurance, and comorbidity. Results: A total of 37,617 patients were identified, including 201 PSCs and 37,416 other NSCLCs. Pleomorphic (54%) was the most common PSC subtype. There was significant interaction between the survival effect of treatment and histology (interaction p = 0.024). When treated with immunotherapy alone, no significant difference was found between PSC and other NSCLCs (median survival 11.4 vs 12.4 months, logrank p = 0.56, HR 1.02, 95% CI 0.81 – 1.30). However, when treated with chemotherapy alone, PSC remained significantly associated with worse survival (median survival 4.5 vs. 8.5 months, logrank p <0.001, HR 0.67, 95% CI 0.54 – 0.83). Among PSC subtypes, spindle/giant cell PSCs were more likely to benefit from immunotherapy alone than pleomorphic PSCs (interaction p = 0.005), when compared with chemotherapy (Spindle/giant cell subtype: HR 0.24, 95% CI 0.14 – 0.42; Pleomorphic subtype: HR 0.60, 95% CI 0.37 – 0.99). Conclusions: Compared with other NSCLCs, PSC may not be associated with worse survival when treated with immunotherapy alone as it was when treated with chemotherapy. Distinct PSC subtypes may respond differently to immunotherapy and warrants further research. [Table: see text]

Abstract BACKGROUND One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration. METHODS/RESULTS Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. CONCLUSIONS Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.