Acquired aplastic anemia (AA) is a life-threatening bone marrow aplasia caused by the autoimmune destruction of hematopoietic stem and progenitor cells. There are no existing diagnostic tests that definitively establish AA, and diagnosis is currently made via systematic exclusion of various alternative etiologies, including inherited bone marrow failure syndromes (IBMFSs). The exclusion of IBMFSs, which requires syndrome-specific functional and genetic testing, can substantially delay treatment. AA and IBMFSs can have mimicking clinical presentations, and their distinction has significant implications for treatment and family planning, making accurate and prompt diagnosis imperative to optimal patient outcomes. We hypothesized that AA could be distinguished from IBMFSs using 3 laboratory findings specific to the autoimmune pathogenesis of AA: paroxysmal nocturnal hemoglobinuria (PNH) clones, copy-number–neutral loss of heterozygosity in chromosome arm 6p (6p CN-LOH), and clonal T-cell receptor (TCR) γ gene (TRG) rearrangement. To test our hypothesis, we determined the prevalence of PNH, acquired 6p CN-LOH, and clonal TRG rearrangement in 454 consecutive pediatric and adult patients diagnosed with AA, IBMFSs, and other hematologic diseases. Our results indicated that PNH and acquired 6p CN-LOH clones encompassing HLA genes have ∽100% positive predictive value for AA, and they can facilitate diagnosis in approximately one-half of AA patients. In contrast, clonal TRG rearrangement is not specific for AA. Our analysis demonstrates that PNH and 6p CN-LOH clones effectively distinguish AA from IBMFSs, and both measures should be incorporated early in the diagnostic evaluation of suspected AA using the included Bayesian nomogram to inform clinical application.
Background The COVID‐19 pandemic has disrupted medical care, increased isolation, and exacerbated anxiety in breast cancer patients. Since March 2020, Breastcancer.org experienced a sustained surge in requested pandemic‐related information and support. To characterize the pandemic‐related experiences of breast cancer patients, we surveyed the Breastcancer.org Community early in the COVID‐19 era. Methods Breastcancer.org Community members were invited to complete an online questionnaire regarding their experience during the pandemic. Self‐reported data on demographics, comorbidities, care disruptions, anxiety, coping ability, telemedicine use, and satisfaction with care were collected. Results were analyzed using Stata 16.0 (Stata Corp., Inc). Results Included were 568 current and previous breast cancer patients, primarily with U.S. residence. Overall, 43.8% reported at least one comorbidity associated with severe COVID‐19 illness and 61.9% experienced care delays. Moderate to extreme anxiety about contracting COVID‐19 was reported by 36.5%, increasing with number of comorbidities (33.0% vs. 55.4%, p = 0.021), current breast cancer diagnosis (30.4% vs. 42.5%, p = 0.011), and poorer coping ability (15.5% vs. 53.9%, p < 0.0001). Moderate to extreme anxiety about cancer care disruptions was reported by 29.1%, increasing with current breast cancer diagnosis (19.1% vs. 38.9%, p < 0.0001), actual delayed care (18.9% vs. 35.3%, p < 0.0001), and poorer coping ability (13.1% vs. 57.7%, p < 0.0001). Most utilized telehealth and found it helpful, but also expressed increased anxiety and subjectively expressed that these were less preferable. Conclusion Early in the COVID‐19 pandemic, anxiety was reported by a large proportion of breast cancer patients, with increased prevalence in those with risk factors. Attention to mental health is critical, as emotional distress not only harms quality of life but may also compromise outcomes.
Bone marrow (BM) niche-derived signals are critical for facilitating engraftment after hematopoietic stem cell (HSC) transplantation (HSCT). HSCT is required for restoration of hematopoiesis in patients with inherited bone marrow failure syndromes (iBMFS). Shwachman-Diamond syndrome (SDS) is a rare iBMFS associated with mutations in SBDS. Previous studies have demonstrated that SBDS deficiency in osteolineage niche cells causes bone marrow dysfunction that promotes leukemia development. However, it is unknown whether BM niche defects caused by SBDS deficiency also impair efficient engraftment of healthy donor HSC following HSCT, a hypothesis that could explain morbidity seen after clinical HSCT for patients with SDS. Here, we report a mouse model with inducible Sbds deletion in hematopoietic and osteolineage cells. Primary and secondary BM transplantation (BMT) studies demonstrated that SBDS deficiency within BM niches caused poor donor hematopoietic recovery and specifically poor HSC engraftment after myeloablative BMT. We have additionally identified multiple molecular and cellular defects within niche populations that are driven by SBDS deficiency and that are accentuated or develop specifically following myeloablative conditioning. These abnormalities include altered frequencies of multiple niche cell subsets including mesenchymal lineage cells, macrophages and endothelial cells; disruption of growth factor signaling, chemokine pathway activation, and adhesion molecule expression; and p53 pathway activation, and signals involved in cell cycle arrest. Taken together, this study demonstrates that SBDS deficiency profoundly impacts recipient hematopoietic niche function in the setting of HSCT, suggesting that novel therapeutic strategies targeting host niches could improve clinical HSCT outcomes for patients with SDS.
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