Citations

Abstract Identifying individuals at risk for short-term fracture is essential to offer prompt beneficial treatment, especially since many fractures occur in those without osteoporosis by DXA-aBMD. We evaluated whether deficits in bone microarchitecture and density predict short-term fracture risk independent of the clinical predictors, DXA-BMD and FRAX. We combined data from eight cohorts to conduct a prospective study of bone microarchitecture at the distal radius and tibia (by HR-pQCT) and 2-year incidence of fracture (non-traumatic and traumatic) in 7327 individuals (4824 women, 2503 men, mean 69 ± 9 years). We estimated sex-specific hazard ratios (HR) for associations between bone measures and 2-year fracture incidence, adjusted for age, cohort, height, and weight, and then additionally adjusted for FN aBMD or FRAX for major osteoporotic fracture. Only 7% of study participants had FN T-score ≤ −2.5, whereas 53% had T-scores between −1.0 and −2.5 and 37% had T-scores ≥−1.0. Two-year cumulative fracture incidence was 4% (296/7327). Each SD decrease in radius cortical bone measures increased fracture risk by 38%-76% for women and men. After additional adjustment for FN-aBMD, risks remained increased by 28%-61%. Radius trabecular measures were also associated with 2-year fracture risk independently of FN-aBMD in women (HRs range: 1.21 per SD for trabecular separation to 1.55 for total vBMD). Decreased failure load (FL) was associated with increased fracture risk in both women and men (FN-aBMD ranges of adjusted HR = 1.47-2.42). Tibia measurement results were similar to radius results. Findings were also similar when models were adjusted for FRAX. In older adults, FL and HR-pQCT measures of cortical and trabecular bone microarchitecture and density with strong associations to short-term fractures improved fracture prediction beyond aBMD and FRAX. Thus, HR-pQCT may be a useful adjunct to traditional assessment of short-term fracture risk in older adults, including those with T-scores above the osteoporosis range.

AbstractThe challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients.

Microvascular remodeling and capillary repopulation can occur after autologous hematopoietic stem cell transplant (HSCT) in patients with systemic sclerosis and systemic lupus erythematosus (SLE). We aim to report evidence for microvascular remodeling after autologous HSCT as observed by nailfold videocapillaroscopy (NVC). We describe a rare occurrence of features consistent with systemic sclerosis and SLE in a 33-year-old female with a complex clinical course refractory to conventional treatments, ultimately requiring autologous HSCT. We performed NVC before and after HSCT using optical video and light microscopy. At the microvascular level, morphologic changes in the capillary vascular bed were observed after HSCT. Pretransplant damage in capillary structure was noted as evidenced on NVC with architectural loss, ramifications, capillary drop, and decreased density. Posttransplant NVC revealed an increase in capillary density with evidence of microvascular remodeling. Further studies on the clinical use and impact of microvascular remodeling on disease progression are needed and looking into the application of NVC scoring to assess clinical response would be meaningful.

Introduction: Vertebral compression fractures (VCFs) pose a considerable healthcare burden and are linked to elevated morbidity and mortality. Despite available anti-osteoporotic treatments (AOTs), guideline adherence is lacking. This study aims to evaluate subsequent hip fracture incidence after index VCF and to elucidate AOT prescribing patterns in VCF patients, further assessing the impact of surgical interventions on these patterns. Materials and Methods: Patients with index VCFs between 2010 and 2021 were identified using the PearlDiver database. Diagnostic and procedural data were recorded using International Classification of Diseases (ICD-9, ICD-10) and Current Procedural Terminology (CPT) codes. Patients under age 50 and follow-up <one year following index VCF were excluded. Patients were categorized based on whether they received AOT within one year, preceding and after index VCF, and were subsequently propensity-matched 1:3 based on age, sex, and Elixhauser Comorbidity Index (ECI) score to compare hip fracture incidence following index VCF. Sub-analysis was performed for operatively managed VCFs (kyphoplasty/vertebroplasty). Statistical tests included Chi-squared for categorical outcomes, and Kruskal–Wallis for continuous measures. Results: Of 637,701 patients, 72.6% were female. The overall subsequent hip fracture incidence was 2.6% at one year and 12.9% for all-time follow-up. Propensity-matched analysis indicated higher subsequent hip fracture rates in patients initiated on AOT post-index VCF (one year: 3.8% vs. 3.5%, p = 0.0013; all-time: 14.3% vs. 13.0%, p < 0.0001). Conclusions: The study reveals an unexpected increase in subsequent hip fractures among patients initiated on AOT post-index VCF, likely due to selection bias. These findings highlight the need for refined osteoporosis-management strategies to improve guideline adherence, thereby mitigating patient morbidity and mortality.

ObjectiveAvacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long‐term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide.MethodsWe performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow‐up.ResultsFifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6–37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52–72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration.ConclusionWe describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow‐up, and adverse events, including infection, were observed.

Takayasu arteritis is a chronic inflammatory vasculitis with granulomatous panarteritis particularly impacting large vessels including the aorta and its branches, especially the subclavian arteries, with clinical manifestation dependent on the involved artery. Sequelae of the active disease vary, including stenosis, occlusions, or aneurysmal dilatations of the large vessels. The prevalence of Takayasu arteritis is higher in the Asian population and in Japan, but quite low in the United States, varying from 0.9–8.4 per million people. Ocular manifestations are rare and lead to a delay in diagnosis and appropriate treatment. Ocular manifestations include Takayasu retinopathy, anterior ischemic optic neuropathy (AION), retinal artery occlusion (RAO) and retinal vein occlusion (RVO). We present two cases in which central retinal artery occlusion (CRAO) was associated with Takayasu arteritis. CRAO is an ophthalmic emergency with an incidence of 1.9 per 100,000 person years in the United States; only 5% of cases are arteritic, which can be observed with inflammatory vasculitides secondary to the formation of immune deposits.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Abstract Background: Residual disease after neoadjuvant chemotherapy (NAC) in breast cancer (BC) confers poor outcomes. Trastuzumab emtansine (T-DM1) is approved for HER2+ patients with residual disease after NAC. However, many patients still develop recurrence. H2NVAC is a multi-epitope CD4 helper T cell activating vaccine that includes a pool of 4 degenerate HER2-derived HLA-DR epitopes admixed with GM-CSF. Our previous phase I trial showed that this vaccine was safe and generated robust, long-lasting T and B cell immune responses. Method: We conducted a safety run-in phase of H2NVAC in combination with T-DM1 in stage II-III HER2+ BC with residual disease after NAC. Patients were treated with H2NVAC and T-DM1 for 6 cycles, followed by 2 boosters at 3 and 12 months. Dose-limiting toxicity (DLT) was defined as any grade (G) ≥ 3 toxicity occurring within 21 days after the first vaccination. Results: 20 patients were enrolled (median age 51; 27-69 years), including 80% White and 15% Black. 90% had hormone receptor-positive disease. There was no DLT observed in the safety run-in cohort. All adverse events (AEs) during the DLT period were grades 1 and 2, with fatigue being the most common (60% G1, 5% G2), followed by peripheral sensory neuropathy (55% G1, 5% G2), and injection site reaction (50% G1). Across all treatment cycles, the 10 most common AEs that were at least possibly related to treatment in all cycles are summarized in the table below. The injection site reaction was the most common AE, with 85% G1 and 15% G2. Conclusion: H2NVAC, in combination with T-DM1, was safe, with a favorable side effect profile. There was no DLT observed. The most common AE was injection site reaction, with the majority being G1. A multicenter, randomized, placebo-controlled, phase II trial of H2NVAC vs. placebo in combination with trastuzumab emtansine is currently ongoing through the ACCRU consortium (NCT04197687). Adverse Events Grades 1 2 N % N % Injection site reaction 17 85.0 3 15.0 Aspartate aminotransferase increase 13 65.0 Alanine aminotransferase increase 9 45.0 Fatigue 7 35.0 2 10.0 Peripheral sensory neuropathy 7 35.0 2 10.0 Alkaline phosphatase increase 8 40.0 Nausea 7 35.0 1 5.0 Arthralgia 7 35.0 Myalgia 5 25.0 1 5.0 Platelet count decrease 6 30.0 Citation Format: Saranya Chumsri, Sharmila Giri, Andy J. Ness, David W. Hillman, Nadine Norton, Davitte Cogen, Brian M. Necela, Aziza Nassar, Donald W. Northfelt, Pooja Advani, Rohit Rao, Kostandinos Sideras, Alvaro Moreno-Aspitia, Brenda J. Ernst, Kathryn J. Ruddy, Matthew P. Goetz, Keith L. Knutson. Safety and tolerability of multi-epitope HER2 peptide vaccines in combination with trastuzumab emtansine in HER2-positive breast cancer patients with residual disease after neoadjuvant chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5005.