Tandem high-dose chemotherapy and autologous stem cell transplantation in refractory/relapsed Hodgkin's lymphoma: a monocenter prospective study

We designed a prospective study to evaluate the feasibility and efficacy of tandem high-dose chemotherapy (HDCT) in the treatment of refractory or relapsed Hodgkin's lymphoma (HL). Thirty-two patients were treated with salvage chemotherapy (IGEV, ifosfamide, gemcitabine, and vinorelbine) and chemo-sensitive patients received a first HDCT course with melphalan 200 mg/m(2) (MEL200) and a second BEAM course. The median time interval between the two HDCT courses was 66 days. The median number of reinfused CD34(+) cells was 4.7 x 10(6)/kg after MEL200 and 5.8 x 10(6)/kg after BEAM. The hematological reconstitution after both HDCT courses did not differ. No grade III or IV renal, hepatic, lung, cardiac, and neurological toxicity was observed. Severe (grade III and IV) oral mucositis was the most prominent complication affecting 60 and 50% of patients after MEL200 and BEAM, respectively. Fever of unknown origin occurred in 65 and 70% of patients after MEL200 and BEAM, respectively. One patient died from septic shock during the aplasia period following BEAM. In an intention-to-treat analysis, the overall response rate increased after each stage of protocol, ranging from 47% to 65% and 75% after IGEV, MEL200, and BEAM, respectively. Tandem HDCT is feasible and effective in patients with relapsed or refractory HL.     

Pneumonia severity index class v patients with community-acquired pneumonia: characteristics, outcomes, and value of severity scores

BACKGROUND: Community-acquired pneumonia (CAP) with a pneumonia severity index (PSI) score in risk class V (PSI-V) is a potentially life-threatening condition, yet the majority of patients are not admitted to the ICU. The aim of this study was to characterize CAP patients in PSI-V to determine the risk factors for ICU admission and mortality, and to assess the performance of CAP severity scores in this population. METHODS: Prospective observational study including hospitalized adults with CAP in PSI-V from 1996 to 2003. Clinical and laboratory data, microbiological findings, and outcomes were recorded. The PSI score; modified American Thoracic Society (ATS) score; the confusion, urea, respiratory rate, low BP (CURB) score, and CURB plus age of >/= 65 years score were calculated. A reduced score based on the acute illness variables contained in the PSI was also obtained. RESULTS: A total of 457 patients were included in the study (mean [+/- SD] age, 79 +/- 11 years), of whom 92 (20%) were admitted to the ICU. Patients in the ward were older (mean age, 82 +/- 10 vs 70 +/- 10 years, respectively) and had more comorbidities. ICU patients experienced significantly more acute organ failures. The mortality rate was higher in ICU patients, but also was high for non-ICU patients (37% vs 20%, respectively; p = 0,003). A low level of consciousness (odds ratio [OR], 3.95; 95% confidence interval [CI], 2 to 5) and shock (OR, 24.7; 95% CI, 14 to 44) were associated with a higher risk of death. The modified ATS severity rule had the best accuracy in predicting ICU admission and mortality. CONCLUSIONS: Most CAP patients PSI-V were treated on a hospital ward. Those admitted to the ICU were younger and had findings of more acute illness. The PSI performed well as a mortality prediction tool but was less appropriate for guiding site-of-care decisions.     

Skinfold thickness and blood pressure across C-344T polymorphism of CYP11B2 gene

OBJECTIVE: To ascertain whether body adiposity is associated with the C-344T polymorphism of the CYP11B2 gene codifying for aldosterone synthase. DESIGN: A cross-sectional epidemiological evaluation of a highly homogeneous unselected general population of Caucasians. METHODS: Lifestyle, medical history, anthropometrics, subscapular, triceps and suprailiac skinfold thickness, lying blood pressure and biochemical measures were recorded in a population-based study among 1386 unselected subjects (56.5% women) living in a secluded valley. All were genotyped for C-344T allele status. Continuous variables were compared across genotypes with analysis of covariance and correlations evaluated using the Pearson method. Odds ratios (OR) were calculated for the TT and CT genotype versus the CC homozygotes and compared with the T-carriers with a logistic model. RESULTS: The C-344T genotypic frequency did not deviate from Hardy-Weinberg equilibrium. In women, higher values of triceps and subscapular skinfold thickness were found in the CC homozygotes than in the T-carriers. In this sex, skinfold thickness also directly correlated with both systolic and diastolic blood pressure in the T-carriers only. The logistic regression for the dependent variable arterial hypertension showed an influence of triceps [OR 1.07, 95% confidence interval (CI) 1.02-1.12, P=0.006], subscapular (OR 1.13, 95% CI 1.06-1.20, P<0.0001) and suprailiac (OR 1.08, 95% CI 1.01-1.15, P=0.03) skinfold in T-carrier women only. These relationships were not detectable in men. The aldosterone-to-renin ratios were comparable across genotypes and sexes. CONCLUSION: The C-344T polymorphism of the CYP11B2 gene seems to exert a sex-specific influence on body adiposity, independent of adrenal aldosterone.     

Pyruvate kinase deficiency: the genotype-phenotype association

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of glycolysis causing chronic non-spherocytic haemolytic anaemia. The disease is transmitted as an autosomal recessive trait, clinical symptoms usually occurring in compound heterozygotes for two mutant alleles and in homozygotes. The severity of haemolysis is highly variable, ranging from very mild or fully compensated forms to life-threatening neonatal anaemia necessitating exchange transfusions. Erythrocyte PK is synthesised under the control of the PK-LR gene located on chromosome 1. One hundred eighty different mutations in PK-LR gene, mostly missense, have been so far reported associated to PK deficiency. First attempts to delineate the genotype-phenotype association were mainly based on the analysis of the enzyme's three-dimensional structure and the observation of the few homozygous patients. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined. However, the clinical manifestations of red cell enzyme defects are not merely dependent on the molecular properties of the mutant protein but rather reflect the complex interactions of additional factors, including genetic background, concomitant functional polymorphisms of other enzymes, posttranslational or epigenetic modifications, ineffective erythropoiesis and differences in splenic function.     

Peginterferon alfa-2b and weight-based or flat-dose ribavirin in chronic hepatitis C patients: a randomized trial

This prospective, multicenter, community-based and academic-based, open-label, investigator-initiated, U.S. study evaluated efficacy and safety of pegylated interferon (PEG-IFN) alfa-2b plus a flat or weight-based dose of ribavirin (RBV) in adults with chronic hepatitis C. Patients (n = 5027) were randomly assigned to receive PEG-IFN alfa-2b 1.5 microg/kg/week plus flat-dose (800 mg/day) or weight-based (800-1400 mg/day) RBV for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (genotype 2/3 patients). Primary end point was sustained virologic response (undetectable [<125 IU/mL] serum hepatitis C virus RNA at 24-week follow-up). Sustained virologic response, but not end-of-treatment, rates were significantly higher with weight-based than with flat-dose RBV (44.2% versus 40.5%; P = 0.008). Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P = 0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P = 0.056). In genotype 2/3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration. Besides greater hemoglobin reductions with weight-based RBV, safety profiles were similar across RBV dosing groups, including the 1400-mg/day group. CONCLUSION: PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups. RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated.     

Neutron scattering reveals extremely slow cell water in a Dead Sea organism

Intracellular water dynamics in Haloarcula marismortui, an extremely halophilic organism originally isolated from the Dead Sea, was studied by neutron scattering. The water in centrifuged cell pellets was examined by means of two spectrometers, IN6 and IN16, sensitive to motions with time scales of 10 ps and 1 ns, respectively. From IN6 data, a translational diffusion constant of 1.3 x 10(-5) cm(2) s(-1) was determined at 285 K. This value is close to that found previously for other cells and close to that for bulk water, as well as that of the water in the 3.5 M NaCl solution bathing the cells. A very slow water component was discovered from the IN16 data. At 285 K the water-protons of this component displays a residence time of 411 ps (compared with a few ps in bulk water). At 300 K, the residence time dropped to 243 ps and was associated with a translational diffusion of 9.3 x 10(-8) cm(2) s(-1), or 250 times lower than that of bulk water. This slow water accounts for approximately 76% of cell water in H. marismortui. No such water was found in Escherichia coli measured on BSS, a neutron spectrometer with properties similar to those of IN16. It is hypothesized that the slow mobility of a large part of H. marismortui cell water indicates a specific water structure responsible for the large amounts of K(+) bound within these extremophile cells.