Capture-based targeted sequencing using a T-cell control in myeloid malignancies and idiopathic cytopenias.

We report on a study of next-generation sequencing in 257 patients undergoing investigations for cytopenias. We sequenced bone marrow aspirates using a target enrichment panel comprising 82 genes and used T cells from paired blood as a control. One hundred and sixty patients had idiopathic cytopenias, 81 had myeloid malignancies and 16 had lymphoid malignancies or other diagnoses. Forty-seven of the 160 patients with idiopathic cytopenias had evidence of somatic pathogenic variants consistent with clonal cytopenias. Only 39 genes of the 82 tested were mutated in the 241 patients with either idiopathic cytopenias or myeloid neoplasms. We confirm that T cells can be used as a control to distinguish between germline and somatic variants. The use of paired analysis with a T-cell control significantly reduced the time molecular scientists spent reporting compared to unpaired analysis. We identified somatic variants of uncertain significance (VUS) in a higher proportion (24%) of patients with myeloid malignancies or clonal cytopenias compared to less than 2% of patients with non-clonal cytopenias. This suggests that somatic VUS are indicators of a clonal process. Lastly, we show that blood depleted of lymphocytes can be used in place of bone marrow as a source of material for sequencing.

Changes in Functional Outcomes After an Inpatient Rehabilitation Program for Solid-Organ Transplant Recipients.

Introduction: Outpatient exercise training has been shown to be beneficial for solid organ transplant recipients. Little is known about the effects of inpatient rehabilitation programs for recipients with a more complicated postoperative course. Research Question: This study was designed to (1) describe the changes in functional outcomes after an inpatient rehabilitation program, and (2) determine whether the changes in lower body strength and quadriceps strength are associated with changes in functional exercise capacity. Design: This was a single-arm prospective longitudinal study. The recipients participated in an inpatient rehabilitation program twice a day, 7 days a week for 3 to 4 weeks. Outcome Measures Included: 2-Minute Walking Test, Timed Up and Go, Berg Balance Scale, 30-Second Sit to Stand, biceps and quadriceps strength, Functional Independence Measure, SF-36, and Canadian Occupational Performance Measure. Results: Twenty-eight patients (54% female, mean age = 55 [11]) completed the study. Participants were mostly liver (42%) and lung recipients (35%). There were statistically significant improvements in all outcomes after the intervention. There was no relationship between changes in functional exercise capacity and quadriceps strength or lower body strength. Conclusion: An inpatient rehabilitation program may improve several functional outcomes and health-related quality of life in transplant recipients with a complicated postoperative course.

Prospective Evaluation of Whole-Body MRI versus FDG PET/CT for Lesion Detection in Participants with Myeloma.

Purpose To compare disease detection of myeloma using contemporary whole-body (WB) MRI and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT protocols and to correlate imaging with laboratory estimates of disease burden, including molecular characteristics. Materials and Methods In this observational, prospective study, participants were recruited from November 2015 to March 2018 who had a diagnosis of myeloma, who were planned to undergo chemotherapy and autologous stem cell transplantation, and who underwent baseline WB-MRI and FDG PET/CT (ClinicalTrials.gov identifier NCT02403102). Baseline clinical data, including genetics, were collected. Paired methods were used to compare burden and patterns of disease. Results Sixty participants (mean age, 60 years ± 9 [standard deviation]; 35 men) underwent baseline WB-MRI and FDG PET/CT. WB-MRI showed significantly higher detection for focal lesions at all anatomic sites (except ribs, scapulae, and clavicles) and for diffuse disease at all sites. Two participants presented with two or more focal lesions smaller than 5 mm only at WB-MRI but not FDG PET/CT. Participants with diffuse disease at MRI had higher plasma cell infiltration (percentage of nucleated cells: median, 60% [interquartile range {IQR}, 50%-61%] vs 15% [IQR, 4%-50%]; P = .03) and paraprotein levels (median, 32.0 g/L [IQR, 24.0-48.0 g/L] vs 20.0 g/L [IQR, 12.0-22.6 g/L]; P = .02) compared with those without diffuse disease. All genetically high-risk tumors showed diffuse infiltration at WB-MRI. Conclusion WB-MRI helped detect a higher number of myeloma lesions than FDG PET/CT, and diffuse disease detected at WB-MRI correlated with laboratory measures of disease burden and molecular markers of risk. Keywords: MR-Imaging, Skeletal-Appendicular, Skeletal-Axial, Bone Marrow, Hematologic Diseases, Oncology Clinical trial registration no. NCT02403102. Supplemental material is available for this article. © RSNA, 2021.

Mutation of JAK2 in the myeloproliferative disorders: timing, clonality studies, cytogenetic associations, and role in leukemic transformation.

The identification of an acquired mutation of JAK2 in patients with myeloproliferative disorders has raised questions about the relationship between mutation-positive and mutation-negative subtypes, timing of the JAK2 mutation, and molecular mechanisms of disease progression. Here we demonstrate that patients with V617F(-) essential thrombocythemia do not commonly progress to become V617F(+). Consistent with the concept of distinct pathogenetic mechanisms, we show that patients with and without the JAK2 mutation have different patterns of cytogenetic abnormality, with virtually all patients carrying the 20q deletion or trisomy 9 being V617F(+). We also investigated the existence of a "pre-JAK2" phase by comparing the proportion of clonally derived granulocytes, estimated from X-chromosome inactivation patterns (XCIPs), with the proportion of V617F(+) granulocytes. Our results demonstrate that inherent XCIP variability between granulocytes and T cells produces a systematically biased pattern of results that may be misinterpreted as evidence for an excess of clonally derived granulocytes, an observation that limits the utility of XCIP analysis in this context. Lastly, we studied 4 patients with V617F(+) myeloproliferative disorders who subsequently developed acute myeloid leukemia. In 3 patients the leukemic cells were V617F(-), suggesting that in these patients the leukemia arose in a V617F(-) cell.

Etilefrine for the prevention of priapism in adult sickle cell disease.

Priapism is a common complication of sickle cell disease (SCD) that could lead to erectile dysfunction and psychosocial problems. Treatment of established fulminant priapism is usually not satisfactory. It is therefore important to prevent this complication of SCD. The alpha-adrenergic agonist etilefrine (50-100 mg/d) produced a good clinical response in 13 of 18 (72%) adults who have recurrent priapism; 17 had SCD and one sickle cell trait. After a follow-up of 1-48 months, none of the 18 people on etilefrine developed hypertension or sexual dysfunction. Similar efficacy and safety profiles of the drug have been reported previously.