Three-step high-dose sequential chemotherapy in patients with newly diagnosed multiple myeloma

BACKGROUND AND OBJECTIVES: High-dose chemotherapy (HDT) with autologous peripheral blood progenitor cell (PBPC) transplant has been increasingly used for newly diagnosed multiple myeloma (MM) in recent years. Presently available results suggest an improvement in the complete remission rate and survival as compared to conventional chemotherapy. However, there is no plateau in the survival curves, and experiments with new treatment schedules and conditioning regimens are warranted. DESIGN AND METHODS: In a non-randomised controlled trial, 20 patients underwent three-step HDT following conventional vincristine/doxorubicin/dexamethasone (VAD)-based induction. In the intensification phase patients received high-dose cyclophosphamide (HD-CY), high-dose etoposide (HD-VP), and mitoxantrone (NOV) plus melphalan (L-PAM) with haemopoietic rescue. Maintenance treatment with interferon was given until relapse. Actuarial overall survival (OS) and event-free survival (EFS) curves were plotted according to the method of Kaplan and Meier. In five of the eight patients achieving complete remission (CR), the molecular disease was monitored by polymerase chain reaction technique (PCR). RESULTS: Overall 18/20 (90%) patients responded, with a CR rate of 40%. After an average follow-up of 40 months, median EFS and OS are 25.5 and 44.6 months, respectively. Monoclonal cells were detectable in the post-treatment bone marrow and in the aphereses of the five CR patients monitored by PCR. CONCLUSION: The present three-step HDT regimen, including conditioning with mitoxantrone and melphalan, proved to be feasible and safe. Our results are in agreement with the hypothesis that HDT results in an increased remission rate and in prolonged survival in newly diagnosed MM, but a cure is unlikely.     

Determinants of end-systolic pressure-volume relations during acute regional ischemia in situ

The influence of extent and location of regional ischemia, baseline left ventricular systolic function, and autonomic reflexes on in situ left ventricular end-systolic pressure-volume relations (ESPVRs) during coronary occlusion were studied in 13 open-chest dogs. Circumflex or left anterior descending arteries were randomly occluded (at proximal or distal sites) for 3 minutes in reflex-blocked (n = 6, hexamethonium/vagotomy) and unblocked (n = 7) animals. Pressure-volume data were obtained by the conductance-catheter technique, with ESPVRs determined by transient inferior vena caval occlusion. Ischemic zone size was estimated for each occlusion by radiolabeled microspheres. The relative influence of each variable on ESPVR change with ischemia was determined by multiple regression analysis. As in previous studies, regional ischemia displaced ESPVRs to the right by an amount that varied directly with ischemic bed size (y = +0.48x, r = 0.76, p less than 0.001). However, in contrast to previous data, coronary occlusion also reduced the ESPVR slope (end-systolic elastance, Ees) in the majority of cases. The extent of slope change was primarily dependent on the baseline elastance (Eesbase), such that the higher the initial elastance, the larger its subsequent reduction for any amount of ischemia (delta Ees = -0.78Eesbase, r = 0.94, p less than 0.001). Active reflexes added an offset constant to this relation (+3.15 mm Hg/ml, p less than 0.001). In addition, Ees fell slightly more with larger ischemic regions. Thus, although previous studies have reported primarily rightward parallel shifts in ESPVR with regional ischemia, the present data also demonstrate that the slope of the relation is often reduced. Greater baseline elastances typical of in situ, as opposed to isolated, ventricles probably explain the differences in apparent responses.     

Balloon occlusion of the carotid artery for the angiographic visualization of Blalock-Taussig shunts and pulmonary arteries

We describe the use of a balloon catheter to occlude the right or left carotid artery as a way of directing contrast material to the pulmonary arteries. This procedure was carried out in the postoperative study of 14 children who had undergone a Blalock-Taussig shunt. The method was reliable, and the angiograms provided excellent visualization of the pulmonary arteries using only small volumes of contrast material.     

Epidemiology and Effects of Bacterial Infections in Patients With Cirrhosis Worldwide

1. Download high-res image (290KB)
2. Download full-size image

     

Haemodynamic changes during modified ultrafiltration immediately following the first stage of the Norwood reconstruction

BACKGROUND: Modified ultrafiltration has been shown to reverse haemodilution and improve ventricular function following cardiopulmonary bypass. There has been concern, however, about the safety and efficacy of modified ultrafiltration after the first stage of Norwood reconstruction for palliation of neonates with hypoplasia of the left heart and its variants. METHODS: We reviewed the intraoperative course of all patients undergoing the first stage of Norwood reconstruction between September 1, 2000, and August 31, 2002. RESULTS: The first stage of reconstruction was performed in 99 neonates, 78 with classical hypoplasia of the left heart, and 21 with variants. Mean weight at surgery was 3.1 plus or minus 0.7 kilograms. Genetic syndromes, weight less than or equal to 2.5 kilograms, and/or major additional cardiac or non-cardiac anomalies, were present in 44 patients. We deemed these patients to constitute the group at high risk. A modified Blalock-Taussig shunt was utilized in 95 patients, and a conduit from the right ventricle to the pulmonary arteries in 4. Deep hypothermic circulatory arrest was used in all patients for a mean period of 45 minutes, plus or minus 15 minutes. Total support time on cardiopulmonary bypass plus deep hypothermic circulatory arrest was 100 minutes plus or minus 26 minutes. Modified ultrafiltration was performed in all patients. The mean duration of modified ultrafiltration was 10 plus or minus 2 minutes, and the total volume of filtrate removed was 104 plus or minus 29 millilitres per kilogram. There were no complications from modified ultrafiltration, and no patient required discontinuation of modified ultrafiltration for haemodynamic instability. During modified ultrafiltration, the haematocrit increased from 31 percent plus or minus 4 to 46 percent plus or minus 6. Heart rate decreased from 170 plus or minus 17 beats per minute to 158 plus or minus 16 beats per minute. Systolic blood pressure increased from 57 plus or minus 12 to 63 plus or minus 13 millimetres of mercury, and diastolic blood pressure from 30 plus or minus 8 to 35 plus or minus 7 millimetres of mercury. All these values are significant at a p value of less than 0.0001. Hospital morality in the patients at low risk was 3 of 55 (5.5 percent), but was 12 of 44 (27.3 percent) in the patients deemed to be at high-risk. CONCLUSIONS: Modified ultrafiltration is safe procedure following the first stage of Norwood reconstruction, with improvement in all haemodynamic parameters measured. Modified ultrafiltration is an additional incremental strategy, which may contribute to the overall improvement in outcome following surgical palliation of patients with hypoplasia of the left heart or its variants.     

Resistance to CD95-mediated apoptosis of CD40-activated chronic lymphocytic leukemia B cells is not related to lack of DISC molecules expression

In B-cell chronic lymphocytic leukemia (CLL), accumulation of neoplastic B cells may be the result of dysregulated apoptosis. One of the major molecules triggering apoptosis, CD95 (FAS), is not expressed on CLL B cells at resting conditions. However, CD40 triggering of CLL B cells upregulates receptors belonging to the tumor necrosis factor (TNF) superfamily, like CD95. In the present study, we analyzed in B cells from 20 CLL patients the effect of CD40/CD40L interaction on: (i) CD95 modulation; (ii) CD95-mediated apoptosis and (iii) mRNA and protein expression of the death-inducing signaling complex (DISC) molecules.CD40 activation of CLL B cells was carried out by coculture with CD40L-transfected cells and cytofluorimetric analyses were performed to study CD95 modulation and apoptosis induction by an anti-CD95 moAb. Despite strong CD95 upregulation on the membrane of all the cases studied, only a minority of cases analyzed (3/20) proved weakly responsive to CD95-mediated apoptosis. Multiplex RT-PCR was used to analyze FLICE, FAS, FADD and TRADD mRNAs before and after CD40 triggering. In agreement with the cytofluorimetric data, FAS mRNA appeared significantly increased after CD40 triggering; the other molecules involved in DISC formation and in CD95-mediated apoptosis were also expressed without relevant differences between resting and activated conditions. Western blot analyses further confirmed FLICE and FADD protein expression by resting and activated CLL cells. Our findings demonstrate that, following CD40 triggering, CLL B cells are resistant to CD95-mediated apoptosis despite a strong CD95 upregulation on the membrane and a normal mRNA or protein expression of the DISC components.     

Prevalence and clinical features of selective immunoglobulin A deficiency in coeliac disease: an Italian multicentre study

Background—Selective immunoglobulin A (IgA)deficiency (SIgAD) is associated with coeliac disease (CD).
Aim—To make a retrospective study of theassociation of SIgAD with CD in Italy.
Methods—Hospital medical records of 2098 patientsconsecutively diagnosed as having CD were reviewed.
Results—Of 2098 patients with CD, 54 (2.6%) hadSIgAD, representing a 10-16-fold increase over that in the populationin general. This increase was not influenced by age or geographicalfactors. Patients with SIgAD had a higher incidence of silent forms(7/54, 13%), recurrent infections (16/54, 29.6%), and atopic diseases (7/54, 13%) than those without. The association with autoimmune andmalignant diseases and the outcome after eating a gluten free diet weresimilar in patients with or without SIgAD. In all patients with SIgAD,antibodies for IgA gliadin and endomysium were absent, but serum levelsof IgG anti-gliadin antibodies were high in almost all of them (51/54).
Conclusions—Serum IgA should be measured in orderto be able to interpret negative results for IgA anti-gliadinantibodies and anti-endomysial antibodies in patients being screenedfor CD. Since some patients with CD and SIgAD may be negative for IgGanti-gliadin antibodies, an intestinal biopsy should be performed inall suspected cases.

Keywords:coeliac disease; IgA deficiency

     

Determinants of platelet activation in human essential hypertension

Experimental data suggest that oxidative stress might be enhanced in hypertension and contribute to platelet activation. We hypothesized that both oxidative stress and platelet activation could be related to the clinical characteristics of hypertensive patients. The urinary excretion of 11-dehydrothromboxane (TX) B2, reflecting in vivo platelet activation, was measured in 75 patients with mild to severe essential hypertension and 75 pair-matched, healthy controls. The urinary excretion of 8-iso-prostaglandin (PG) F2alpha was determined as an index of in vivo lipid peroxidation. Urinary 11-dehydro-TXB2 was significantly higher in essential hypertensives compared with controls. Although no statistically significant difference in urinary 8-iso-PGF2alpha was observed between patients and controls, plasma vitamin C was lower and plasma homocysteine higher in hypertensive patients than in controls. Both urinary 11-dehydro-TXB2 and 8-iso-PGF2alpha were higher in patients with advanced hypertensive retinopathy compared with patients without retinopathy. Multivariate linear regression analysis identified urinary 8-iso-PGF2alpha, plasma fibrinogen, homocysteine, and vitamin E as the only variables independently correlated with urinary 11-dehydro-TXB2. Logistic regression analysis showed that high urinary 8-iso-PGF2alpha, plasma fibrinogen, and homocysteine, as well as low plasma vitamin E, advanced retinopathy, elevated diastolic blood pressure, and the absence of antihypertensive treatment, were predictors of high urinary 11-dehydro-TXB2. We demonstrated increased oxidative stress and persistent platelet activation in essential hypertensives with advanced vascular lesions. These findings might help identify hypertensive patients who are at increased risk of cardiovascular events and who might benefit from long-term antiplatelet therapy.