Citations

Abstract There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT.

Background: Refractory angina(Ang) effects 150 –250,000 pts in the US alone. These individuals have exhausted options for revasc and continue to have lifestyle limiting ang despite optimal medical Rx. Pre-clinical studies provided evidence that human CD34+ cells(CD34) can stimulate new blood vessel formation in ischemic myocardium(Myo), improving perfusion and function. We performed a phase 2 study of intraMyo injection of autologous CD34 in pts with CCS Class 3 and 4 Ang to obtain evidence for feasibility, safety and bioactivity. Methods: A phase 2 randomized, double-blind, placebo-controlled clinical trial was performed at 26 centers in the United States. There were 3 treatment groups: placebo, low dose (1×10^5 CD34/kg body wt) and high dose (5×10^5 CD34/kg). All pts underwent mobilization with GCSF 5 mcg/kg/day SC for 5 d, followed by apheresis on d5 to collect mononuclear cells. On day 6 CD34 were purified from the collected cells using the Isolex 300i device. After lot release testing, CD34 were injected endocardially at 10 locations in the ischemic Myo using the Myostar catheter following NOGA mapping. Placebo injections consisted of identical volumes of the diluent only. Results: A total of 167 pts were randomized and completed the injection procedure and 162 completed the 6 mo evaluation. The mean age of subjects was 61.0±8.9, there were 22 female and 145 male subjects. Trop was elevated in 26 pts at baseline and in 71 at some point following GCSF or injection. At 6 mo CD34 treated pts showed more reduction in ang frequency (−8.6 placebo vs 14.2 low dose) and improved ETT time (+69 sec placebo vs. +138 low dose). At 12m CD34 treated continue to show more reduction in angina (−8.2 placebo vs. −15.0 low dose) and improved ETT (+58 sec placebo vs. + 139 sec low dose). For key endpoints the high dose group results were inferior to low dose. The 12m data set has been locked and is being analyzed and the results of the completed analysis will be presented. Conclusions: Autologous CD34 cell therapy was associated with improved exercise tolerance and reduced angina in no-option pts with intractable angina. Ongoing analysis will determine endpoints, sample size and suitability of this therapy for a phase III study in no-option pts with refractory angina.

Abstract Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease arising from the maladaptive differentiation of lung stem cells into bronchial epithelial cells rather than into alveolar type 1 (AT1) cells, which are responsible for gas exchange. Here, we report that healthy lungs maintain their stem cells through tonic Hippo and β-catenin signaling, which promote Yap/Taz degradation and allow for low level expression of the Wnt target gene Myc. Inactivation of upstream activators of the Hippo pathway in lung stem cells inhibits this tonic β-catenin signaling and Myc expression and promotes their Taz mediated differentiation into AT1 cells. Vice versa, increased Myc in collaboration with Yap promotes the differentiation of lung stem cells along the basal and myoepithelial like lineages allowing them to invade and bronchiolize the lung parenchyma in a process reminiscent of submucosal gland development. Our findings indicate that stem cells exhibiting the highest Myc levels become supercompetitors that drive remodeling, whereas loser cells with lower Myc levels terminally differentiate into AT1 cells.

Abstract Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

Abstract Background Since 2009, inflammatory bowel disease (IBD) specialists have utilized “IBD LIVE,” a weekly live video conference with a global audience, to discuss the multidisciplinary management of their most challenging cases. While most cases presented were confirmed IBD, a substantial number were diseases that mimic IBD. We have categorized all IBD LIVE cases and identified “IBD-mimics” with consequent clinical management implications. Methods Cases have been recorded/archived since May 2018; we reviewed all 371 cases from May 2018–February 2023. IBD-mimics were analyzed/categorized according to their diagnostic and therapeutic workup. Results Confirmed IBD cases made up 82.5% (306/371; 193 Crohn’s disease, 107 ulcerative colitis, and 6 IBD-unclassified). Sixty-five (17.5%) cases were found to be mimics, most commonly medication-induced (n = 8) or vasculitis (n = 7). The evaluations that ultimately resulted in correct diagnosis included additional endoscopic biopsies (n = 13, 21%), surgical exploration/pathology (n = 10, 16.5%), biopsies from outside the GI tract (n = 10, 16.5%), genetic/laboratory testing (n = 8, 13%), extensive review of patient history (n = 8, 13%), imaging (n = 5, 8%), balloon enteroscopy (n = 5, 8%), and capsule endoscopy (n = 2, 3%). Twenty-five patients (25/65, 38%) were treated with biologics for presumed IBD, 5 of whom subsequently experienced adverse events requiring discontinuation of the biologic. Many patients were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialed on tofacitinib. Conclusions The diverse presentation of IBD and IBD-mimics necessitates periodic consideration of the differential diagnosis, and reassessment of treatment in presumed IBD patients without appropriate clinical response. The substantial differences and often conflicting treatment approaches to IBD versus IBD-mimics directly impact the quality and cost of patient care.

Abstract Background We compared long-term mortality and readmission rates after COVID-19 hospitalization based on rural-urban status and assessed the impact of COVID-19 vaccination introduction on clinical outcomes by rurality. Methods The study comprised adults hospitalized for COVID-19 at 17 hospitals in 4 US states between March 2020 and July 2022, followed until May 2023. The main analysis included all patients, whereas a sensitivity analysis focused on residents from 4 states containing 17 hospitals. Additional analyses compared the pre- and postvaccination periods. Results The main analysis involved 9325 COVID-19 hospitalized patients: 31% were from 187 rural counties in 31 states; 69% from 234 urban counties in 44 states; the mean age was 65 years (rural, 66 years; urban, 64 years); 3894 women (rural, 41%; urban, 42%); 8007 Whites (rural, 87%; urban, 83%); 1738 deaths (rural, 21%; urban, 17%); and 2729 readmissions (rural, 30%; urban, 29%). During a median follow-up of 602 days, rural residence was associated with a 22% higher all-cause mortality (log-rank, P < .001; hazard ratio, 1.22; 95% confidence interval, 1.10-1.34, P < .001), and a trend toward a higher readmission rate (log-rank, P = .038; hazard ratio, 1.06; 95% confidence interval, .98-1.15; P = .130). The results remained consistent in the sensitivity analysis and in both pre- and postvaccination time periods. Conclusions and Relevance Patients from rural counties experienced higher mortality and tended to be readmitted more frequently following COVID-19 hospitalization over the long term compared with those from urban counties, a difference that remained even after the introduction of COVID-19 vaccines.

Cardiogenic shock continues to carry a high mortality rate despite contemporary care, with no breakthrough therapies shown to improve survival over the past few decades. It is a time‐sensitive condition that commonly results in cardiovascular complications and multisystem organ failure, necessitating multidisciplinary expertise. Managing patients with cardiogenic shock remains challenging even in well‐resourced settings, and an important subgroup of patients may require cardiac replacement therapy. As a result, the idea of leveraging the collective cognitive and procedural proficiencies of multiple providers in a collaborative, team‐based approach to care (the “shock team”) has been advocated by professional societies and implemented at select high‐volume clinical centers. A slowly maturing evidence base has suggested that cardiogenic shock teams may improve patient outcomes. Although several registries exist that are beginning to inform care, particularly around therapeutic strategies of pharmacologic and mechanical circulatory support, none of these are currently focused on the shock team approach, multispecialty partnership, education, or process improvement. We propose the creation of a Cardiogenic Shock Team Collaborative—akin to the successful Pulmonary Embolism Response Team Consortium—with a goal to promote sharing of care protocols, education of stakeholders, and discovery of how process and performance may influence patient outcomes, quality, resource consumption, and costs of care.

ImportanceStroke is a leading cause of death and disability in the US. Accurate and updated measures of stroke burden are needed to guide public health policies.ObjectiveTo present burden estimates of ischemic and hemorrhagic stroke in the US in 2019 and describe trends from 1990 to 2019 by age, sex, and geographic location.Design, Setting, and ParticipantsAn in-depth cross-sectional analysis of the 2019 Global Burden of Disease study was conducted. The setting included the time period of 1990 to 2019 in the US. The study encompassed estimates for various types of strokes, including all strokes, ischemic strokes, intracerebral hemorrhages (ICHs), and subarachnoid hemorrhages (SAHs). The 2019 Global Burden of Disease results were released on October 20, 2020.ExposuresIn this study, no particular exposure was specifically targeted.Main Outcomes and MeasuresThe primary focus of this analysis centered on both overall and age-standardized estimates, stroke incidence, prevalence, mortality, and DALYs per 100 000 individuals.ResultsIn 2019, the US recorded 7.09 million prevalent strokes (4.07 million women [57.4%]; 3.02 million men [42.6%]), with 5.87 million being ischemic strokes (82.7%). Prevalence also included 0.66 million ICHs and 0.85 million SAHs. Although the absolute numbers of stroke cases, mortality, and DALYs surged from 1990 to 2019, the age-standardized rates either declined or remained steady. Notably, hemorrhagic strokes manifested a substantial increase, especially in mortality, compared with ischemic strokes (incidence of ischemic stroke increased by 13% [95% uncertainty interval (UI), 14.2%-11.9%]; incidence of ICH increased by 39.8% [95% UI, 38.9%-39.7%]; incidence of SAH increased by 50.9% [95% UI, 49.2%-52.6%]). The downturn in stroke mortality plateaued in the recent decade. There was a discernible heterogeneity in stroke burden trends, with older adults (50-74 years) experiencing a decrease in incidence in coastal areas (decreases up to 3.9% in Vermont), in contrast to an uptick observed in younger demographics (15-49 years) in the South and Midwest US (with increases up to 8.4% in Minnesota).Conclusions and RelevanceIn this cross-sectional study, the declining age-standardized stroke rates over the past 3 decades suggest progress in managing stroke-related outcomes. However, the increasing absolute burden of stroke, coupled with a notable rise in hemorrhagic stroke, suggests an evolving and substantial public health challenge in the US. Moreover, the significant disparities in stroke burden trends across different age groups and geographic locations underscore the necessity for region- and demography-specific interventions and policies to effectively mitigate the multifaceted and escalating burden of stroke in the country.

Background: Cutaneous malignant mixed tumor (MMT) is a rare sweat gland–derived tumor characterized by admixed malignant epithelial cells and chondromyxoid stroma. Approximately 50 cases have been described in the literature. Metastasis, which may occur in more than one-third of cases, is most common in the lung. Methods: We summarized the clinicopathologic features of a patient with cutaneous MMT metastatic to the lungs. A literature review of similar cases was completed using Web of Science, Scopus, and PubMed databases. Results: A woman in her 70s presented with an enlarging mass on her left eyebrow; histopathologic examination showed large islands of atypical cells with increased mitotic activity, admixed with necrosis on a background of fibrotic and chondromyxoid stroma. Multiple lung nodules were identified during follow-up. Examination of a pulmonary core needle biopsy specimen was consistent with metastatic cutaneous MMT. Literature review identified 10 cases published between 1980 and 2017. Most primary tumors were large (≥4 cm). Local recurrence was uncommon, and the lung was the only metastatic site in 5 cases. Histopathologically, metastatic tumors were described as more cellular, with diminished stromal tissue compared with the primary lesion. Conclusion: This is 1 of the 11 reports of cutaneous MMT with metastasis to the lungs found in the English-language literature published after 1980. Of note, most reports were published before 1990, making this case study one of the few contemporary descriptions of cutaneous MMT with pulmonary metastases. We think that the present case report will increase the awareness of this rare tumor.

376 Background: Germline genetic testing (GGT) is becoming increasingly important in the management of genitourinary (GU) malignancies as novel targeted drug therapies emerge. Selection for genetic studies and testing has historically been highly selective and based on pathologic characteristics, family history, and age of diagnosis. The aim of our study was to investigate the prevalence of pathogenic variants (PGVs) in inherited cancer susceptibility genes utilizing a universal testing approach and to characterize the rate of PGVs that would have been missed based on current NCCN guidelines. Methods: A multisite single-institutional prospective study (INTERCEPT) offered GGT to all patients with new or active diagnoses of GU malignancies (bladder, prostate, and renal cancers) from April 1, 2018 to March 31, 2020 at Mayo Clinic Arizona, Mayo Clinic Florida and Mayo Clinic Rochester. Participants were offered GGT with a panel of >80 genes through Invitae Corp. Demographic, tumor characteristics and genetic results were evaluated. PGVs were classified as high-, intermediate-, or low- penetrance variants based on published literature. Respective NCCN GU GGT guidelines were used to determine if the PGVs discovered using our universal testing approach would have been missed with guideline-directed GGT. Results: A total of 3095 pan-cancer patients were enrolled in the study; 601 of which had a GU malignancy including: prostate cancer (358 patients), renal cancer (137), and bladder cancer (106). The mean age of enrollment was 66.8 years (SD 9.1), 89% were male, and 85.9% of patients were Non-Hispanic white. PGVs were identified in 82 of all GU patients (13.6%) and variants of undetermined significance (VUS) in 289 (48.1%) patients. PGV prevalence breakdown by cancer type was: 13.7% of prostate, 13.1% renal, and 14.2% bladder cancer patients. The proportion of high penetrance PGVs varied by malignancy type. Of all patients, 326 (54.2%) had advanced (stage III/IV) disease and 377 (64.4%) of these were metastatic upon initial evaluation. The majority of all PGVs identified were incremental, defined as PGVs that would not have been identified based on guideline-concordant GGT: 100% (15/15 patients) with bladder, 77.8% (14/18) with renal, and 57.1% (28/49) with prostate cancer. Conclusions: Universal GGT for prostate, renal and bladder cancer revealed that over 1 in 10 patients harbored potentially actionable PGVs, most of which would not have been identified with guidelines-based GGT. Utilization of GGT can impact our understanding of GU cancer pathogenesis, aid in familial cascade testing, and influence treatment decisions.