Cyclosporine as prophylaxis for graft-versus-host disease: a randomized study in patients undergoing marrow transplantation for acute nonlymphoblastic leukemia

Seventy-five patients, 13 to 49 years of age, with acute nonlymphoblastic leukemia in first remission were treated with cyclophosphamide, fractionated total body irradiation, and marrow transplantation from an HLA-identical sibling and randomized to receive either cyclosporine (CSP) (n = 36) or methotrexate (MTX) (n = 39) as prophylaxis for graft-v-host disease (GVHD). All patients engrafted, and 22 who were given CSP and 21 who were given MTX, are alive at 20 to 47 (median, 35) months (P = .5). Engraftment as assessed by granulocyte recovery (P less than .0005) and platelet transfusion requirement (P = .01) was faster in patients on CSP. Twelve patients (33%) on CSP and 22 (56%) on MTX developed acute GVHD of grades II through IV (P = .07) and 15 of 30 on CSP and 14 of 32 on MTX that were at risk developed chronic GVHD. The most frequent causes of death were interstitial pneumonitis and marrow relapse of leukemia, which occurred with similar frequency in both groups. Beneficial effects observed in patients on CSP included less severe mucositis and shorter duration of hospitalization; adverse effects included renal function impairment and hypertension. These data confirm that CSP is a useful immunosuppressant in patients undergoing marrow transplantation but fail to show a significant improvement in survival as compared with the standard regimen of MTX.     

High Fluctuation Between Anticoagulants,Frequent Off-Label Dosing,and No Difference Concerning Outcomes: Results of a Real-Life Cohort Study

BackgroundRecently published studies indicated a high proportion of patients taking direct oral anticoagulants (DOACs) are off-label under- or overdosed. The present study aimed at investigating whether off-label dosages are corrected over time and whether off-label doses are associated with differences in bleeding rates, ischemic stroke, or venous thromboembolism.MethodsIn this retrospective cohort study, patients presenting to our emergency department between January 1 and December 31, 2018, with therapeutic oral anticoagulation were included (ie, vitamin-K antagonists [VKAs], rivaroxaban, apixaban, edoxaban, and dabigatran) and follow-up for a maximum of 2 years until December 31, 2019, was made. Detailed chart reviews were performed for each case concerning characteristics, indication, bleeding complications, or changes in the used substance or dosage.ResultsWe reviewed 2588 consultations of 1228 patients receiving therapeutic oral anticoagulation. During the maximum follow-up period of 2 years vitamin K antagonists and rivaroxaban lost the largest proportions in favor of apixaban. The overall distribution of dosage correctness remained almost unimproved (correct dosing in 62.5%, underdosing in 23.6%, coverdosing in 13.9%).The corresponding outcomes did not differ with respect to bleeding events, ischemic stroke, or venous thromboembolism among various anticoagulants as well as between correct and off-label doses.ConclusionsA rising proportion of existing oral anticoagulation regimes was changed to apixaban, while the proportion of off-label dosages of all oral anticoagulants remained stable. No difference in bleeding rates, de novo strokes, or thromboembolisms was found between anticoagulants as well as between correct and off-label doses.     

Monocytoid B-cell lymphoma: its evolution and relationship to other low- grade B-cell neoplasms

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.     

Marrow transplantation with or without donor buffy coat cells for 65 transfused aplastic anemia patients

Sixty-five multiply transfused patients with severe aplastic anemia were given cyclophosphamide followed by grafts anemia were given cyclophosphamide followed by grafts from HLA-identical siblings. The effect of the administration of viable donor buffy coat cells following the marrow inoculum was evaluated with regard to graft rejection and survival. Results in 43 patients so treated are presented along with those in 22 concurrent patients given marrow alone. Most patients given buffy coat had positive in vitro tests of sensitization indicating a high risk for graft rejection, while all but one of the patients given marrow alone had negative tests. Thirty of the 43 (70%) patients given marrow and buffy coat are alive between 10 and 61 mo (median 36) after grafting; 4 died after graft rejection and 6 with acute or chronic graft-versus-host disease (GVHD). Eleven of the 22 (50%) patients given marrow alone are alive between 29 and 65 mo (median 52); 7 died after graft rejection and 3 with GVHD. The addition of buffy coat cell infusions to the marrow inoculum reduced the risk of rejection and increased survival in the currently reported transfused patients when compared to patients grafted before 1976. However, there was an increased risk of chronic GVHD. Recipients of marrow from female donors survived slightly better (73%) than recipients of male marrow (58%).     

X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X- linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease.     

Accurate 3D reconstruction of complex blood vessel geometries from intravascular ultrasound images: in vitro study

We present a technique that accurately reconstructs complex three dimensional blood vessel geometry from 2D intravascular ultrasound (IVUS) images. Biplane x-ray fluoroscopy is used to imagethe ultrasound catheter tip at a few key points along its path as the catheter is pulled through the blood vessel. An interpolating spline describes the continuous catheterpath. The IVUS images are located orthogonal to the path, resulting in a non-uniform structured scalar volume of echo densities. Isocontour surfaces are used to view the vessel geometry, while transparency and clipping enable interactive exploration of interior structures. The two geometries studied are a bovine artery vascular graft having U-shapeand a constriction, and a canine carotid artery having multiple branches and a constriction. Accuracy of the reconstructions is established by comparing the reconstructions to (1) silicone moulds of the vessel interior, (2) biplane x-ray images, and (3) the original echo images. Excellent shape and geometry correspondence was observed in both geometries. Quantitative measurements made at key locations of the 3D reconstructions also were in good agreement with those made in silicone moulds. The proposed technique is easily adoptable in clinical practice, since it uses x-rays with minimal exposure and existing IVUS technology.     

Diuretic-induced hyponatremia and osteoporotic fractures in patients admitted to the emergency department

Objective

Hyponatremia is a complication of diuretic treatment and has been recently identified as a novel factor associated with osteoporosis and fractures. The impact of diuretic-associated electrolyte disorders on osteoporotic fractures (OF) has rarely been studied systematically.

Design and setting

We conducted a study in patients presenting to the emergency department at the University Hospital Bern. In this retrospective case series analysis of prospectively gathered data, over a 2-year period we identified 10,823 adult (≥50 years) outpatients with a measured baseline serum sodium, at admission to the hospital. OF patients were compared to a control group without fractures using standard statistical methods.

Results

Four hundred and eighty (5%) patients had 547 OF. The OF group had a higher mean age (73 vs. 68 years, p < 0.0001), smaller proportion of men (37% vs. 58%, p < 0.0001), higher hospitalisation rate (83% vs. 62%, p < 0.0001) and longer hospital stay (8 vs. 6 days, p < 0.0001). Any diuretic agent (p < 0.0001), loop diurietics (p = 0.02), spironolactone (p = 0.02) and amiloride (p < 0.01) were used significantly more in OF patients, but not thiazides (p = 0.68). The prevalence of hyponatremia increased significantly (p < 0.0001) with the number of diuretics taken. Advanced age (odds ratio [OR] 1.04, p < 0.0001), hyponatremia (OR 1.46, p = 0.011) higher serum creatinine (OR 1.53, p = 0.0001), furosemide use alone (OR 1.40, p = 0.01) and co-treatment with amiloride (OR 2.22, p = 0.02) were associated with a higher risk for OF.

Conclusions

This study highlights the clinical association of hyponatremia during the use of certain diuretics (i.e. furosemide or in combination, i.e. amiloride) with an increased risk of osteoporosis associated fractures. Although evidence-based data is currently lacking a pragmatic approach concerning hyponatremia monitoring and correction appears reasonable in selected groups of patients.     

Can Achilles and patellar tendon structures predict musculoskeletal injuries in combat soldiers?

Aiming to investigate whether Achilles tendon (AT) structure and patellar tendon (PT) structure are risk factors for musculoskeletal injuries in combat soldiers, 168 participants were recruited from an infantry commander's course. The AT and PT were examined pre‐course using UTC to capture the structure of four echo‐type fibers (I–IV). All injuries were assessed by military physicians pre‐course and throughout the 14‐week course. Soldiers who were injured during the course had a significantly higher pre‐course prevalence of AT and PT echo‐type III and echo‐type IV compared to soldiers that were not injured during the course. Variables that were found to be associated with injured/non‐injured participants were echo‐type III + IV of the PT (OR = 1.44, 95% CI = 1.24‐1.68) and echo‐type III of the AT (OR = 1.69, 95% CI = 1.35‐2.12). ROC analyses showed that the best model, exhibiting both high sensitivity and low specificity, was that participants with PT echo‐type III + IV > 10% or AT echo‐type III >8.5% had the highest risk of being injured during the course. In conclusions, the tendon structure at the beginning of high‐intensity activity or physical training program might be a risk factor for subsequent injury during the course. Soldiers and high‐level athletes should be aware of the cutoff points for fiber types in tendon structure that might put them at high risk for future injury. At‐risk soldiers/athletes should be provided with an intervention program before they start their training program, with the aim of improving the tendon structure and preventing subsequent injury.