Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone) for Waldenstrom macroglobulinemia: preliminary report

Fourteen consecutively referred, symptomatic patients with Waldenstrom's macroglobulinemia (ages 52-87 yr) have been treated with the 5-drug M-2 protocol (BCNU, cyclophosphamide, vincristine, melphalan, and prednisone). Three patients were previously treated and 11 patients were untreated. The majority of patients were symptomatic from hyperviscosity. All patients have responded to therapy. Two patients have achieved complete remissions and 12 patients partial remissions to date. None of the patients with symptomatic hyperviscosity has required plasmapheresis since therapy with the M-2 has been initiated. Lymphadenopathy, hepatosplenomegaly, and anemia have also responded to treatment. Follow-up data are limited, with survival from initiation of therapy with the M-2 ranging from 2+ to 35% mo (median 17+ mo) 2+-40+ mo from time of diagnosis). Combination chemotherapy for Waldenstrom's macroglobulinemia with the M-2 protocol appears to increase the response rate in patients with symptomatic disease. Further survival analysis will be carried out.     

Influence of Cytokines on the Growth Kinetics and Immunophenotype of Daughter Cells Resulting From the First Division of Single CD34+Thy-1+lin- Cells

There is a need to determine whether culture conditions may existfor ex vivo expansion of hematopoeitic stem cells (HSC), which favorsolely proliferative self-renewal of HSC as opposed to proliferationwith differentiation. Using single cells, we studied the effects ofindividual and combinations of cytokines in serum-free medium on thekinetics of the first cell doubling and the resulting phenotype of eachof individual daughter cell. CD34⁺Thy-1⁺lincells were plated 1 cell per well in Terasaki plates inserum-free medium containing cytokines. Each well containing a singlecell was monitored daily over 7 days for maintenance, division, or death. When division occurred in an individual well, the phenotype ofthe daughter cells was determined by staining with anti-CD34 fluorescein isothiocyanate (FITC)- and phycoerythrin (PE)-conjugated lineage specific antibodies. The cumulative percent of wells with anundivided single cell, wells in which the cell had divided, and wellsin which the cell had died were scored. The number of doublets withconserved phenotype (CD34⁺lin) wascompared to those wells with one or more differentiated daughter cells(CD34⁺lin⁺). Over 7 days, cells cultured insingle factors showed that between 13% (interleukin-6 [IL-6]) and29% (thrombopoietin [TPO]) of the cells were undivided, between 13%(IL-1) and 35% (TPO) of the cells doubled, and between 35% (TPO) andgreater than 60% (IL-11, IL-1, or hepatocyte growth factor[HGF]) died. When combinations of cytokines were usedover 7 days, between 5% (FLT-3 ligand [FLT-3L], stemcell factor [SCF], IL-3, IL-6, granulocytecolony-stimulating factor [G-CSF],  nerve growth factor[NGF]) and 22% (FLT-3L + HGF) of the cellsremained undivided, between 15% (HGF, IL-1, IL-11, G-CSF) and 68%(SCF + TPO) of the cells had doubled and between 27% (FLT-3L + TPO) and 70% (HGF, IL-1, IL-11, G-CSF) died. The combination of FLT-3L + TPO induced the highest total percent (64.6%) of cells withconserved phenotype (percent conserved doublets + percent with 1 cellconserved), followed by SCF + TPO, (50%) and the combination ofFLT-3L, SCF, IL-3, IL-6, G-CSF, NGF (53%). These combinations alsoproduced the highest yield of cells with conserved phenotype after onedivision (FLT-3L + TPO  81 cells/100 initial cells, SCF + TPO  68 cells/100 initial cells) (P = .01). Observation of thetime of the initial cell division and phenotype of the daughter cellsallowed us to identify candidate combinations of cytokines that promotemaintenance of lin cells (TPO), or recruit the primitivecells to divide and undergo phenotypic self-renewal (FLT-3L + TPO,SCF + TPO).     

Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research

Resistant hypertension is a common clinical problem faced by both primary care clinicians and specialists. While the exact prevalence of resistant hypertension is unknown, clinical trials suggest that it is not rare, involving perhaps 20% to 30% of study participants. As older age and obesity are 2 of the strongest risk factors for uncontrolled hypertension, the incidence of resistant hypertension will likely increase as the population becomes more elderly and heavier. The prognosis of resistant hypertension is unknown, but cardiovascular risk is undoubtedly increased as patients often have a history of long-standing, severe hypertension complicated by multiple other cardiovascular risk factors such as obesity, sleep apnea, diabetes, and chronic kidney disease. The diagnosis of resistant hypertension requires use of good blood pressure technique to confirm persistently elevated blood pressure levels. Pseudoresistance, including lack of blood pressure control secondary to poor medication adherence or white coat hypertension, must be excluded. Resistant hypertension is almost always multifactorial in etiology. Successful treatment requires identification and reversal of lifestyle factors contributing to treatment resistance; diagnosis and appropriate treatment of secondary causes of hypertension; and use of effective multidrug regimens. As a subgroup, patients with resistant hypertension have not been widely studied. Observational assessments have allowed for identification of demographic and lifestyle characteristics associated with resistant hypertension, and the role of secondary causes of hypertension in promoting treatment resistance is well documented; however, identification of broader mechanisms of treatment resistance is lacking. In particular, attempts to elucidate potential genetic causes of resistant hypertension have been limited. Recommendations for the pharmacological treatment of resistant hypertension remain largely empiric due to the lack of systematic assessments of 3 or 4 drug combinations. Studies of resistant hypertension are limited by the high cardiovascular risk of patients within this subgroup, which generally precludes safe withdrawal of medications; the presence of multiple disease processes (eg, sleep apnea, diabetes, chronic kidney disease, atherosclerotic disease) and their associated medical therapies, which confound interpretation of study results; and the difficulty in enrolling large numbers of study participants. Expanding our understanding of the causes of resistant hypertension and thereby potentially allowing for more effective prevention and/or treatment will be essential to improve the long-term clinical management of this disorder.     

Acute enteritis associated with Coxsackievirus A19 in a kidney transplant patient

Diarrhea is a frequent complication after kidney transplantation, with an incidence rate between 22% and 51%. In many cases, the cause remains unknown. We describe here the first case, to our knowledge, of persistent diarrhea associated with Coxsackievirus A19 (CVA19) in a kidney transplant recipient. The patient was a 46‐year‐old man who received a deceased‐donor kidney. He experienced delayed graft function because of donor kidney donation after circulatory determination of death. Maintenance immunosuppression consisted of low‐dose cyclosporine, high‐dose mycophenolate mofetil (MMF) (3 g/day), and prednisone (10 mg/day). He had severe diarrhea for 2 weeks associated with acute renal failure. No pathogens were found in the stool cultures. Enterovirus detection was positive by real‐time polymerase chain reaction, and sequence analysis found CVA19 (from Enterovirus C group). Area under the curve of MMF was 48 mg.h/L. Because of the persistence of diarrhea, MMF was stopped and replaced by azathioprine. The diarrhea disappeared, but serum creatinine did not return to baseline. CVA19 rarely causes gastroenteritis. This case illustrates that MMF is not always the direct cause of diarrhea, and that new clinical infectious diseases will be detected with the expansion of molecular‐based DNA diagnostics.