Antonella Santucci

Ambulatory blood pressure. An independent predictor of prognosis in essential hypertension.

To determine the prognostic significance of ambulatory blood pressure, we prospectively followed for up to 7.5 years (mean, 3.2) 1187 subjects with essential hypertension and 205 healthy normotensive control subjects who had baseline off-therapy 24-hour noninvasive ambulatory blood pressure monitoring. Prevalence of white coat hypertension, defined by an average daytime ambulatory blood pressure lower than 131/86 mm Hg in women and 136/87 mm Hg in men in clinically hypertensive subjects, was 19.2%. Cardiovascular morbidity, expressed as the number of combined fatal and nonfatal cardiovascular events per 100 patient-years, was 0.47 in the normotensive group, 0.49 in the white coat hypertension group, 1.79 in dippers with ambulatory hypertension, and 4.99 in nondippers with ambulatory hypertension. After adjustment for traditional risk markers for cardiovascular disease, morbidity did not differ between the normotensive and white coat hypertension groups (P = .83). Compared with the white coat hypertension group, cardiovascular morbidity increased in ambulatory hypertension in dippers (relative risk, 3.70; 95% confidence interval, 1.13 to 12.5), with a further increase of morbidity in nondippers (relative risk, 6.26; 95% confidence interval, 1.92 to 20.32). After adjustment for age, sex, diabetes, and echocardiographic left ventricular hypertrophy (relative risk versus subjects with normal left ventricular mass, 1.82; 95% confidence interval, 1.02 to 3.22), cardiovascular morbidity in ambulatory hypertension was higher (P = .0002) in nondippers than in dippers in women (relative risk, 6.79; 95% confidence interval, 2.45 to 18.82) but not in men (P = .91). Our findings suggest that ambulatory blood pressures stratifies cardiovascular risk in essential hypertension independent of clinic blood pressure and other traditional risk markers including echocardiographic left ventricular hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

Full Haplotype-Mismatched Hematopoietic Stem-Cell Transplantation: A Phase II Study in Patients With Acute Leukemia at High Risk of Relapse

PURPOSE Establishment of hematopoietic stem-cell (HSC) transplantation from mismatched relatives is feasible for patients with acute leukemia. As our original method of graft processing was unsuitable for large-scale clinical studies, we use automated devices for CD34+ cell purification. PATIENTS AND METHODS Sixty-seven patients with acute myeloid leukemia (AML; 19 complete remission [CR] 1, 14 CR 2, nine CR > 2, 25 in relapse) and 37 with acute lymphoid leukemia (ALL; 14 CR 1, eight CR 2, two CR > 2, 13 in relapse) were conditioned with total-body irradiation, thiotepa, fludarabine, and antithymocyte globulin. Peripheral-blood progenitor cells were mobilized with recombinant human granulocyte colony-stimulating factor and depleted of T-cells using CD34+ cell immunoselection. No post-transplantation graft-versus-host disease (GvHD) prophylaxis was administered. RESULTS Primary engraftment was achieved in 94 of 101 assessable patients. Six of the seven patients who rejected the primary graft, engrafted after a second transplantation. Overall, 100 of 101 patients engrafted. Acute GvHD developed in eight of 100 patients, and chronic GvHD, in five of 70 assessable patients. Thirty-eight patients died of nonleukemic causes. Relapse occurred in nine of 66 patients receiving transplantation in remission and in 17 of 38 receiving transplantation in relapse. Median follow-up of the 40 patients who survived event-free was 22 months (range, 1 to 65 months). Event-free survival (+/- standard deviation) rate was 48% +/- 8% and 46% +/- 10%, respectively, for the 42 AML and 24 ALL patients receiving transplantation in remission. CONCLUSION Our transplantation procedure provides reliable, reproducible CD34+ cell purification, high engraftment rates, and prevention of GvHD. The mismatched-related transplant emerges as a viable, alternative source of stem cells for acute leukemia patients without matched donors and/or those who urgently need transplantation.

Adverse prognostic significance of concentric remodeling of the left ventricle in hypertensive patients with normal left ventricular mass.

OBJECTIVES We examined the prognostic significance of concentric remodeling of the left ventricle in patients with essential hypertension and normal left ventricular mass on echocardiography. BACKGROUND An echocardiographic pattern of concentric remodeling of the left ventricle has been associated with clinical features of increased cardiovascular risk, but the independent prognostic value of this finding in hypertensive patients with normal left ventricular mass has not been established. METHODS Six hundred ninety-four patients with essential hypertension and normal left ventricular mass (< 125 g/m2) on echocardiography were prospectively followed up for < or = 7.7 years (mean 2.71). Baseline echocardiography and 24-h noninvasive ambulatory blood pressure monitoring were performed in all patients at the time of initial diagnostic evaluation. Concentric remodeling was defined by the thickness of the septum or posterior wall divided by the left ventricular radius at end-diastole > or = 0.45. RESULTS Prevalence of concentric remodeling was 39.2%. During follow-up there were 29 cardiovascular morbid events. Cardiovascular morbidity, expressed as the combined number of fatal and nonfatal events per 100 patient-years, was 1.53 in the overall study group, 1.12 in the subgroup with normal left ventricular geometry and 2.39 in that with concentric remodeling. After assessment of the independent association with several covariates (age, gender, diabetes, left ventricular mass index, mean clinic blood pressure and mean 24-h ambulatory blood pressure) in Cox proportional hazard models, the risk of cardiovascular morbid events was higher in the group with concentric remodeling than in that with normal geometry (relative risk 2.56, 95% confidence interval 1.20 to 5.45, p < 0.01). CONCLUSIONS Concentric remodeling of the left ventricle, defined by the thickness of the septum or posterior wall divided by the left ventricular radius at end-diastole > or = 0.45, is an important and independent predictor of increased cardiovascular risk in hypertensive patients with normal left ventricular mass on echocardiography.

Competing risk analysis using R: an easy guide for clinicians

In the last decade with widespread use of quantitative analyses in medical research, close co-operation between statisticians and physicians has become essential from the experimental design through all phases of complex statistical analysis. On the other hand, easy-to-use statistical packages allow clinicians to perform basic statistical analyses themselves. Since the software they most commonly use does not perform in depth competing risk analysis, we recommend an add-on package for the R statistical software. We provide all the instructions for downloading it from internet and illustrate how to use it for analysis of a sample dataset of patients who underwent haematopoietic stem cell transplantation for acute leukaemia.

Prognostic value of left ventricular mass and geometry in systemic hypertension with left ventricular hypertrophy

To determine the independent prognostic significance of left ventricular (LV) mass and geometry (concentric vs eccentric pattern) in hypertensive subjects with LV hypertrophy at echocardiography, 274 subjects were followed for up to 8.7 years (mean 3.2). All patients had systemic hypertension and LV mass > or = 125 g/body surface area (BSA) and underwent ambulatory blood pressure (BP) monitoring and echocardiography before treatment. Eccentric and concentric hypertrophy were defined by the ratio between LV posterior wall thickness and LV radius at telediastole <0.45 and > or = 0.45, respectively. Age, sex ratio, body mass index, office BP and serum glucose, cholesterol, and triglycerides did not differ between the groups with eccentric (n=145) and concentric (n=129) hypertrophy. Average 24-hour daytime, and nighttime systolic ambulatory BPs were higher in concentric than in eccentric hypertrophy (all p <0.01). LV mass was slightly greater in concentric than in eccentric hypertrophy (157 vs 149 g/BSA, p <0.05). Endocardial and midwall shortening fraction were lower in concentric than in eccentric hypertrophy (96.5% vs 106.0% of predicted and 71.4% vs 89.7% of predicted, respectively; both p <0.01). The rate of major cardiovascular morbid events was 2.20 and 3.34 per 100 patient-years in eccentric and concentric hypertrophy, respectively (log rank test, p=NS). Age >60 and LV mass above median (145 g/BSA) were significant adverse prognostic predictors, while LV geometry (eccentric vs concentric hypertrophy) and ambulatory BP were not. The event rates per 100 patient-years were 1.38 and 3.98, respectively, in the patients with LV mass below and above median (age-adjusted relative risk 2.70; 95% confidence interval [CI] 1.03 to 6.63; p=0.015). In hypertensive subjects with established LV hypertrophy, LV mass, but not its geometric pattern, provides important prognostic information independent of conventional risk markers including office and ambulatory BP.

Regression modeling of competing risk using R: an in depth guide for clinicians

We describe how to conduct a regression analysis for competing risks data. The use of an add-on package for the R statistical software is described, which allows for the estimation of the semiparametric proportional hazards model for the subdistribution of a competing risk analysis as proposed by Fine and Gray. J Am Stat Assoc 1999; 94: 496–509.

Acute Antihyperglycemic Mechanisms of Metformin in NIDDM: Evidence for Suppression of Lipid Oxidation and Hepatic Glucose Production

To establish the antihyperglycemic mechanisms of metformin in non-insulin-dependent diabetes mellitus (NIDDM) independently of the long-term, aspecific effects of removal of glucotoxicity, 21 NIDDM subjects (14 obese, 7 nonobese) were studied on two separate occasions, with an isoglycemic (plasma glucose ∼9 mM) hyperinsulinemic (two-step insulin infusion, 2 h each, at the rate of 4 and 40 mU · m−2 · min−1) clamp combined with [3−3H]glucose infusion and indirect calorimetry, after administration of either metformin (500 mg per os, at –5 and –1 h before the clamp) or placebo. Compared with placebo, hepatic glucose production (HGP) decreased ∼30% more after metformin (from 469 ± 50 to 330 ± 54 μmol/min), but glucose uptake did not increase. Metformin suppressed free fatty acids (FFAs) by ∼17% (from 0.42 ± 0.04 to 0.35 ± 0.04 mM) and lipid oxidation by ∼25% (from 4.5 ± 0.4 to 3.4 ± 0.4 μmol · kg−1 · min−1) and increased glucose oxidation by ∼ 16% (from 16.2 ± 1.4 to 19.3 ± 1.3 μmol.kg−1 · min−1) compared with placebo (P < 0.05), but did not affect nonoxidative glucose metabolism, protein oxidation, or total energy expenditure. Suppression of FFA and lipid oxidation after metformin correlated with suppression of HGP (r = 0.70 and r = 0.51, P < 0.001). The effects of metformin in obese and nonobese subjects were no different. We conclude that the specific, antihyperglycemic effects of metformin in the clinical condition of hyperglycemia in NIDDM are primarily due to suppression of HGP, not stimulation of glucose uptake, and are mediated, at least in part, by suppression of FFA and lipid oxidation.

AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features

Acute myeloid leukemia (AML) with mutated NPM1 usually carries normal karyotype (NK), but it may harbor chromosomal aberrations whose significance remains unclear. We addressed this question in 631 AML patients with mutated/cytoplasmic NPM1. An abnormal karyotype (AK) was present in 93 of 631 cases (14.7%), the most frequent abnormalities being +8, +4, -Y, del(9q), +21. Chromosome aberrations in NPM1-mutated AML were similar to, but occurred less frequently than additional chromosome changes found in other AML with recurrent cytogenetic abnormalities according to WHO classification. Four of the 31 NPM1-mutated AML patients karyotyped at different time points had NK at diagnosis but AK at relapse: del(9q) (n = 2), t(2;11) (n = 1), inv(12) (n = 1). NPM1-mutated AML with NK or AK showed overlapping morphologic, immunophenotypic (CD34 negativity), and gene expression profile (down-regulation of CD34 and up-regulation of HOX genes). No difference in survival was observed among NPM1-mutated AML patients independently of whether they carried a NK or an AK, the NPM1-mutated/FLT3-ITD negative cases showing the better prognosis. Findings in our patients point to chromosomal aberrations as secondary events, reinforce the concept that NPM1 mutation is a founder genetic lesion, and indicate that NPM1-mutated AML should be clinically handled as one entity, irrespective of the karyotype.

Improved Outcome With T-Cell–Depleted Bone Marrow Transplantation for Acute Leukemia

PURPOSE To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation. PATIENTS AND METHODS Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis. RESULTS Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status. CONCLUSION Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.

Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas.

Cytoplasmic mutated nucleophosmin (NPM) defines the molecular status of a significant fraction of myeloid sarcomas