High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

Recovery of T cell subsets after autologous bone marrow transplantation is mainly due to proliferation of mature T cells in the graft

In 22 patients with malignancies, treated with high-dose chemoradiotherapy and autologous bone marrow transplantation (BMT), peripheral blood T cell subsets and functions were studied. In ten cytomegalovirus (CMV)-negative patients, CD4+ and CD8+ T cells (representing T cells of the helper/inducer phenotype and T cells of the suppressor/cytotoxic phenotype, respectively), recovered slowly and simultaneously. In 12 CMV-positive patients, however, CD8+ T cells recovered more rapidly than CD4+ T cells and rose to increased counts. No T cells with an immature phenotype (CD1+, OKT6+) were observed. Lymphocyte stimulation by herpes simplex virus infected fibroblasts (and by CMV-infected fibroblasts in CMV-positive patients) in contrast remained high and even increased after BMT in both groups. These data indicate that T cell recovery after autologous BMT is mainly due to proliferation of mature T cells present in the BM graft and not to generation of new T cells from T cell precursors.     

Clinical Significance of the Epidermal Growth Factor Receptor and HER2 Receptor in Resectable Gastric Cancer

Background: Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance.Methods: This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay.Results: There was a wide variability of EGFR (1–1,239 fmol/mg of protein) and HER2 (7–20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P = .03 and P = .02, respectively).Conclusions: There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.     

Rapid progression of midventricular obstruction in adults with double-chambered right ventricle

OBJECTIVE: The purpose of this study was to determine the rate of progression of midventricular obstruction in adolescents and adults with double-chambered right ventricle. METHODS: Clinical and echocardiographic findings in 45 patients (mean age 26 +/- 6 years, range 15-44) diagnosed with double-chambered right ventricle were retrospectively analyzed. Twenty patients underwent surgical repair before the age of 15 years. The relationship between Doppler midventricular pressure gradient and patient age was analyzed in 25 patients without previous repair. Sequential change in midventricular obstruction was determined for patients with 2 or more Doppler echocardiographic examinations performed within at least a 2-year interval. RESULTS: Right midventricular pressure gradient in nonrepaired patients was 70 +/- 38 mm Hg (range 25-150). A significant relationship between midventricular obstruction and patient age (r = 0.64, P <.001) was found. Midventricular pressure gradient at initial evaluation was 32 +/- 27 mm Hg in 16 patients < 25 years and 73 +/- 45 mm Hg in 9 patients >/= 25 years (P <.03). After the initial study, 5 patients underwent surgical repair and 13 patients without repair were followed up for a period of 6.1 +/- 2.7 years (range 2-9), in which midventricular pressure gradient increased from 32 +/- 26 mm Hg to 67 +/- 35 mm Hg (P <.001). The slope of the change in midventricular pressure gradient was 6.2 +/- 3 mm Hg per year of follow-up. Seven more patients underwent surgical repair during follow-up due to progression of the obstruction. There was no mortality nor residual midventricular obstruction in surgically repaired patients. CONCLUSIONS: Mild right midventricular obstruction shows a fast rate of progression in adolescents and young adults. Thus, close clinical and echocardiographic follow-up is advised, and surgical repair should be considered if significant progression of obstruction is detected.     

MR pharmacokinetic modeling of the patellar cartilage differentiates normal from pathological conditions

PURPOSE: To study the pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) of the patellar cartilage under normal and pathological conditions. MATERIALS AND METHODS: DCE-MRI was obtained in 22 cases. There were 17 patients with degenerative patellar conditions (eight with chondromalacia and nine with osteoarthritis) and five normal subjects. The cartilage pharmacokinetic parameters of K(trans) (vascular permeability), k(ep) (extraction ratio), upsilon(e) (extravascular extracellular space [EES] volume fraction), and upsilon(p) (intravascular space volume fraction) were extracted. RESULTS: Statistically significant differences were observed between the different groups (normal cartilage, chondromalacia and osteoarthritis) for K(trans) and upsilon(e). K(trans) values were (mean +/- SD) 1.06 +/- 0.62, 11.97 +/- 8.91, and 21.21 +/- 16.03 mL x minute(-1) x 100 mL(-1) (P < 0.02), respectively; and upsilon(e) values were 0.71 +/- 0.69, 3.59 +/- 2.21, and 10.51 +/- 8.20% (P < 0.002). Reproducibility of the pharmacokinetic calculations was assessed with a second set of analyses of 10 random cases one week after the first analysis, showing a test-retest root mean square (RMS) coefficient of variation of 9.78% for K(trans) and 14.72% for upsilon(e). CONCLUSION: The vascular permeability and EES fraction of cartilage increases with the severity of the degeneration. Pharmacokinetic models allow to study the vascular properties of the cartilage and may have applications as a surrogate index in longitudinal studies to quantify the evolution of drug trials.     

Erectile dysfunction

In Spain, based on the IIEF, 19% of males between 25 and 70 years old present some degree of erectile dysfunction (ED). Therefore, around 2,000,000 Spanish men present this condition and could require medical attention for it. Here, we present an up-date of the most important aspects of erectile dysfunction (pathophysiology, diagnosis and treatment). We review, in detail, the oral treatments and future drugs that are presently in the premarketing experimental phase. Diagnostic and therapeutic management of the patient with erectile dysfunction should be individualized, taking into account the goals of each patient. It is highly recommendable to carry out a basic assessment (comprehensive clinical history, physical examination, recommended lab testing). If previously undiagnosed diseases are discovered (diabetes, arteriosclerosis, etc.) these should be treated and modifiable risk factors should be corrected. There are numerous therapeutic options for the treatment of erectile dysfunction. Replacement therapy with testosterone should only be used in males with ED and low levels of this hormone, under medical supervision. At present, first line treatment consists of the administration of oral drugs (sildenafil, apomorphine). There are two new PDE 5 inhibitors (tadalafil and vardenafil) that will be released on the market 2003, which will provide better selectivity. Moreover, several drugs for oral administration are in the initial phases of research that will facilitate erection via a direct penile action. When oral drugs are contraindicated, are not effective or when they are unpopular with the patient, the second line of treatment is intracavernous injection. Prostaglandin E1 is the initial drug of choice in patients using intracavernous autoinjection for the first time and has a high efficacy. Implantation of a penis prosthesis and penile revascularisation are appropriate for highly selected patients. Psychotherapy can be an option for men with ED of psychogenic origin, either as a monotherapy or combined with sildenafil or apomorphine.     

Active surveillance is superior to radical nephrectomy and equivalent to partial nephrectomy for preserving renal function in patients with small renal masses: Results from the DISSRM registry

Purpose

We compared renal function outcomes among patients in the surveillance and intervention arms of the DISSRM registry.

Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus

Posttransplantation diabetes mellitus (PTDM) is a common complication of kidney transplantation, associated with poorer graft and patient outcomes. Tacrolimus is a strong immunosuppressive drug associated with low acute rejection rates, but a higher risk for PTDM. High trough levels of tacrolimus during the first month after transplantation have been found to be a significant risk factor for the development of PTDM. The aim of this single-center study was to identify the risk factors for the development of PTDM among kidney transplant recipients under tacrolimus therapy. We examined 73 cadaveric kidney transplant recipients receiving tacrolimus between 1994 and 2003. Age, donor and recipient gender, dialysis method, body mass index (BMI), first year weight gain, mismatches, incidence of acute rejection and delayed graft function, hepatitis C serology, first year cumulative steroid dose, first tacrolimus blood level, first tacrolimus blood level <15 ng/mL, and corresponding tacrolimus daily doses and concentration/dose ratios (CDR) were also collected. PTDM was defined as at least 2 fasting blood glucose values > or =126 mg/dL, according to the World Health Organization criteria. Incidence of first year PTDM was 27.4%. Patients with PTDM showed significantly higher age, BMI, first tacrolimus blood level, first tacrolimus CDR, and CDR with tacrolimus blood level <15 ng/mL as well as less 1-year weight gain. After logistic regression, age (relative risk [RR] 1.060, confidence interval [CI] 95%, 1.001-1.122; P = .043) and first tacrolimus blood level (RR 1.154; CI 95%, 1.038-1.283; P = .008) remain significant risk factors for developing PTDM. Older age and initial tacrolimus blood levels were the main risk factors for PTDM among our group of patients. Kidney transplant recipients who develop PTDM maintain a high CDR of tacrolimus.     

Down-modulation of neutrophil production by erythropoietin in human hematopoietic clones

In clonogenic assays of hematopoietic progenitors, high concentrations (4 U/mL) of erythropoietin (epo) reduced the formation of granulocyte- macrophage (GM) colonies and diminished the number of granulocytes formed per culture plate. Fetal progenitors were more sensitive to these effects of epo than were progenitors from adults, displaying these reductions at greater than or equal to 1 U epo/mL. The mechanism was investigated by growing fetal progenitors stimulated by recombinant GM-CSF, in the absence of epo, and when eight-cell clones first appeared, mapping their location, then adding epo, and assessing its effect on the subsequent differentiation of the clones. In the absence of epo, the clones developed exclusively into GM colonies. However, if developing clones were presented with epo, 85% matured into GM colonies, but 15% became multilineage or normoblast colonies. In addition, developing clones that were presented with epo produced colonies that contained fewer neutrophils. These effects of epo on neutrophil generation were observed with each of three varieties of recombinant epo, and also with purified human epo, but were not observed using epo that had been neutralized with rabbit anti-epo antiserum.