Background Deficient levels of 25-hydroxyvitamin D [25(OH)D] have been associated with increased fracture risk. Racial differences in fracture risk may be related to differences in bioavailable vitamin D due to single nucleotide polymorphism (SNP) variations in the Vitamin D Binding Protein (DBP). Methods We measured 25(OH)D levels in 12,781 middle-aged white and black participants [mean age 57 years (SD 5.7), 25% black] in the ARIC Study who attended the second examination from 1990–1992. Participants were genotyped for two DBP SNPs (rs4588 and rs7041). Incident hospitalized fractures were measured by abstracting hospital records for ICD-9 codes. We used Cox proportional hazards models to evaluate the association between 25(OH)D levels and risk of fracture with adjustment for possible confounders. Interactions were tested by race and DBP genotype. Results There were 1,122 incident fracture-related hospitalizations including 267 hip fractures over a median of 19.6 years of follow-up. Participants with deficient 25(OH)D (<20 ng/ml) had a higher risk of any fracture hospitalization [HR=1.21 (95% CI 1.05–1.39)] and hospitalization for hip fracture [HR=1.35 (1.02–1.79)]. No significant racial interaction was noted (p-interaction=0.20 for any fracture; 0.74 for hip fracture). There was no independent association of rs4588 and rs7041 with fracture. However, there was a marginal interaction for 25(OH)D deficiency with rs7041 among whites (p-interaction=0.065). Whites with both 25(OH)D deficiency and the GG genotype [i.e. with predicted higher levels of DBP and lower bioavailable vitamin D] were at the greatest risk for any fracture [HR=1.48 (1.10–2.00)] compared to whites with the TT genotype and replete 25(OH)D (reference group). Conclusions Deficient 25(OH)D levels are associated with higher incidence of hospitalized fractures. Marginal effects were seen in whites for the DBP genotype associated with lower bioavailable vitamin D, but results inconclusive. Further investigation is needed to more directly evaluate the association between bioavailable vitamin D and fracture risk.

Clinicians must evaluate patient and pathologic criteria and engage in informed discussions with patients when determining which adjuvant radiation techniques are appropriate. Future strategies being explored include using tumor genetics to identify low-risk patients and switching from paradigms that omit radiotherapy to those that omit endocrine therapy.

Radiation therapy represents a vital component in the multidisciplinary management of soft tissue sarcomas. Combined with limb-preserving surgery, radiation therapy represents a standard of care treatment option for patients with high-grade sarcomas. Radiation therapy for soft tissue sarcoma continues to evolve with changes in timing, techniques, and targets. Over the past 2 decades, increasing data have supported the role of preoperative radiotherapy with the potential for lower total doses of radiation and improved long-term function coming at the cost of increased wound complications for certain locations. Retroperitoneal sarcomas represent a location where preoperative treatment is becoming the standard of care based on anatomic constraints and challenges with delivering postoperative radiotherapy. Multiple radiation therapy techniques exist to deliver treatment; currently both 3-dimensional conformal radiotherapy and intensity-modulated radiation therapy (IMRT) are appropriate options, although increasing data support the role of IMRT in reducing dose to critical structures (bone, bowel, kidneys, vessels) while maintaining target coverage. Traditional target volumes have included larger fields; however, recent prospective data have demonstrated that image guidance in conjunction with smaller treatment volumes may reduce toxicity while not increasing marginal failures, although follow-up is short. Because of the toxicity associated with treatment, novel radiotherapy strategies are being used such as stereotactic radiotherapy as well as the use of tumor genetics to identify patients most likely to benefit most from radiotherapy.

Myelodysplastic syndromes (MDS) are a heterogeneous category of myeloid neoplasms that represent the most common class of acquired bone marrow failure syndromes in adults. MDS is typically associated with a hypoproliferative macrocytic anemia, but atypical findings on initial diagnostic evaluations can raise concern for a distinct pathophysiological process and lead to the investigation of alternative etiologies. Here, we report a case of MDS with a concomitant hypoproliferative microcytic and hypochromic anemia that led to the identification of acquired hemoglobin H due to a novel somatic ATRX mutation.

e19041 Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease that is the result of macrophage hyperactivation, leading to disordered cellular phagocytosis that is highly fatal if left untreated. The precise precipitating factor that leads to HLH is presently unknown. Secondary HLH is more common in adults and has numerous causes, including several autoimmune diseases, rheumatological disorders, cancers, and infections. These predisposing conditions are similar in that they are characterized by increased rates of cellular replication and often accompanied by significant oxidative stress. Lipoprotein changes in HLH have not been previously described. Methods: Between August 2018 and June 2020, three cases of secondary HLH were discovered to have profound hypolipoproteinemia with severely reduced total cholesterol, undetectable LDL-C, and extremely depressed HDL-C levels. As a result, a retrospective review of the University of Michigan HLH registry was performed, identifying cases of HLH where full lipid panels were performed as part of their diagnosis and/or treatment between 2012 and 2020. 18 total patients were identified with a confirmed diagnosis of HLH and who had a full lipid panel performed as a part of their diagnostic evaluation. Results: 100% of patients were found to have HDL-C less than 30 mg/dL, consistent with severe HDL-C deficiency, and 84% had HDL-C less than 20 mg/dL. Similarly, 74% of patients were found to have LDL-C < 100 mg/dL, 47% with LDL-C < 50 mg/dL, and 33% had undetectable LDL-C levels. Median total cholesterol was 124 mg/dL, median LDL-C was 35 mg/dL, and median HDL-C was 7 mg/dL. Notably, these reductions were not explained by the observed variability in hypertriglyceridemia, and marked hypertriglyceridemia > 500 mg/dL was not seen in 88% of patients, with a median triglyceride value of 279. Interestingly, one patient displayed an opposite phenotype with extreme hyperlipidemia, with total cholesterol of 727 mg/dL and LDL-C of 658 md/dL. Conclusions: Severe derangements in circulating lipoproteins appear to be a common finding within sHLH.These findings have not been previously described within the context of the disease. Herein, we provide a framework for hypothesizing why HLH may potentially occur in the setting of hypolipidemia. Furthermore, we provide an additional hypothesis that serves to justify why these changes may occur in an evolutionary context.

Diffuse large B-cell lymphoma and follicular lymphoma are the most commonly encountered non-Hodgkin lymphomas in clinical practice. Both are biologically heterogeneous, with management strategies that are becoming increasingly complex. Diffuse large B-cell lymphoma typically exhibits aggressive behavior but can be cured in the majority of cases with immunochemotherapy. While R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard of care for decades, the recent combination of polatuzumab-vedotin-R-CHP (rituximab plus cyclophosphamide, doxorubicin, and prednisone) has demonstrated improved progression-free survival for patients with intermediate- and intermediate-high–risk disease. Numerous novel therapies, including targeted agents and immunotherapy-based approaches, have recently been approved for relapsed/refractory disease and have led to improved outcomes. Follicular lymphoma is an indolent lymphoma that remains incurable with standard approaches. Overall survival in most patients is excellent, although a proportion of patients will have early relapsing disease and poorer outcomes. The availability of novel agents in the relapsed/refractory setting has shifted the treatment algorithm, which requires thoughtful consideration of sequencing. This article will review recent developments in the treatment of diffuse large B-cell lymphoma and relapsed/refractory follicular lymphoma.

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