Influence of passive leg elevation on the right ventricular function in anaesthetized coronary patients

INTRODUCTION: The aim of the present study was to evaluate the haemodynamic effects of passive leg elevation on the right ventricular function in two groups of patients, one with a normal right ventricular ejection fraction (RVEF) and one with a reduced RVEF. METHODS: Twenty coronary patients undergoing elective coronary artery bypass grafting surgery were studied by a RVEF pulmonary artery catheter. The haemodynamic data reported were collected before the induction of anaesthesia (time point 1), just before (time point 2) and 1 min (time point 3) after the legs were simultaneously raised at 60°, and 1 min after the legs were lowered (time point 4). The patients were divided into two groups: group A, with preinduction RVEF > 45%; and group B, with preinduction RVEF < 40%. RESULTS: In group A (n = 10), at time point 3 compared with time point 2, the heart rate significantly decreased (from 75 ± 10 to 66 ± 7 beats/min). The right ventricular end diastolic volume index (from 105 ± 17 to 133 ± 29 ml/m(2)), the right ventricular end systolic volume index (from 61 ± 13 to 77 ± 24 ml/m(2)), the systolic systemic arterial/right ventricular pressure gradient (from 93 ± 24 to 113 ± 22 mmHg) and the diastolic systemic arterial/right ventricular pressure gradient (from 58 ± 11 to 66 ± 12 mmHg) significantly increased. Also in group A, the cardiac index did not significantly increase (from 3.28 ± 0.6 to 3.62 ± 0.6 l/min/m(2)), the RVEF was unchanged, and the right ventricular end diastolic volume/pressure ratio (RVED V/P) did not significantly decrease (from 48 ± 26 to 37 ± 13 ml/mmHg). In group B (n = 6) at the same time, the heart rate (from 72 ± 15 to 66 ± 12 beats/min), the right ventricular end diastolic volume index (from 171 ± 50 to 142 ± 32 ml/m(2)) and the RVED V/P (from 71 ± 24 to 39 ± 7 ml/mmHg) significantly decreased. The cardiac index and the diastolic systemic arterial/right ventricular pressure gradient were unchanged in group B, while the RVEF and the systolic systemic arterial/right ventricular pressure gradient did not significantly increase, and the right ventricular end-systolic volume index did not significantly decrease. All results are expressed as mean ± standard deviation. CONCLUSIONS: We conclude that passive leg elevation caused a worse condition in the right ventricle of group B because, with stable values of cardiac index, of systolic systemic arterial/right ventricular pressure gradient and of diastolic systemic arterial/right ventricular pressure gradient (which supply oxygen), the RVED V/P (to which oxygen consumption is inversely related) markedly decreased. This is as opposed to group A, where the cardiac index, the systolic systemic arterial/right ventricular pressure gradient and the diastolic systemic arterial/right ventricular pressure gradient increased, and the RVED V/P slightly decreased. Passive leg elevation must therefore be performed cautiously in coronary patients with a reduced RVEF

Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura

Rituximab 375 mg/m2weekly for four weeks has significant activity in patients with immune thrombocytopenia. We evaluated the activity of lower dose rituximab (100 mg iv weekly for 4 weeks) in 28 adults with idiopathic thrombocytopenic purpura. Overall (platelet count &gt; 50×109/L) and complete responses (platelet count &gt; 100×109/L) were achieved in 21/28 (75%) and 12/28 (43%) patients respectively. The median time to response and time to complete response were 31 and 44 days respectively. After a median follow-up of 11 months (range 3-18), 7/21 (33%) patients relapsed and 3 needed further treatments. In patients with idiopathic thrombocytopenic purpura, lower dose rituximab seems to show similar activity to standard dose. ©2008 Ferrata Storti Foundation

Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO)\u201d

Background Allogeneic stem cell transplantation is a potentially curative treatment for myelofibrosis, although its use is limited by a high rate of transplant-related mortality. In this study, we evaluated the outcome of patients with myelofibrosis who underwent allogeneic stem cell transplantation, and the impact of prognostic factors. Design and Methods One hundred patients were transplanted in 26 Italian centers between 1986 and 2006. We analyzed the influence of the patients\u2019 characteristics and the clnical features of their disease before stem cell transplantation and of transplant procedures on transplant-related mortality, overall survival, and relapse-free survival by means of univariate and multivariate analyses. Results The median age of the patients at the time of stem cell transplantation was 49 years (range, 21-68) and 90% of them had an intermediate or high Dupriez score. Forty-eight percent received a myeloablative conditioning regimen and 78% received stem cells from matched sibling donors. The cumulative incidence of engraftment at day 90 after transplant was 87% (95% CI, 0.87-0.97). The cumulative 1-year and 3-year incidences of transplant-related mortality were 35% and 43%, respectively. The estimated 3-year overall and relapse-free survival rates after stem cell transplantation were 42% and 35%, respectively. In multivariate analysis, negative predictors of transplant-related mortality were year of stem cell transplantation before 1995, unrelated donor, and a long interval between diagnosis and transplantation. There was a trend towards longer overall and relapse-free survival in patients receiving peripheral blood stem cells rather than bone marrow as the source of their graft (p=0.070 and p=0.077, respectively). The intensity of the conditioning regimen (myeloablative versus reduced intensity regimens) did not significantly influence the outcome. Conclusions We conclude that the outcome of myelofibrosis patients who underwent allogeneic stem cell transplantation significantly improved after 1996 due to the reduction in transplant-related mortality.We observed that a reduction in transplant-related mortality was associated with the choice of a matched sibling donor, whereas longer overall survival was associated with the use of peripheral blood as the source of stem cells

Low dose rituximab in adult patients with idiopathic thrombocytopenic purpura

Rituximab 375 mg/sqm weekly for 4 weeks has significant activity in patients with idiopathic thrombocytopenic purpura (ITP). In this setting, different biological and clinical evidence suggests the possible use of lower doses of Rituximab. Twenty-eight adult patients, median age 43 years (range 16–71 years), with previously treated, active and symptomatic ITP were treated prospectively with Rituximab at the fixed dose of 100 mg iv weekly for 4 weeks. Exclusion criteria were positive HIV, HBsAg and pregnancy test, any B-cell lymphoprolipherative disease or other malignancies. Response assessment was evaluated considering the rate of overall and complete responses (OR = platelet count ≥ 50 x 109/L; CR= platelet count ≥ 100 x 109/L and discontinuation of steroid therapy, if present), the time to response (TTR; time necessary to reach a platelet count ≥ 50 x 109/L), the time to complete response (TCR; time necessary to reach a platelet count ≥ 100 x 109/L) and the duration of response. B-cell count and pharmacokinetics (PK) were monitored and related with clinical outcome. Stepwise logistic regression was used to assess whether response was associated with age, gender, diagnosis-Rituximab interval and basal CD20+ve lymphocytes. Results were considered statistical significant when P ≤ 0.05. All patients completed the therapeutic program receiving the four infusions of Rituximab as scheduled, none experiencing short term toxicity. All patients achieved B-cell depletion. OR and CR were achieved in 21/28 (75%) and 12/28 (43%) patients, respectively. CR rate was associated with younger age (OR=0.92 CI95%[0.85;0.99]). The median TTR and TCR were 31 and 44 days, significantly longer then those observed with standard dose in patients with similar characteristics (Haematologica 2003;88:538). After a median follow-up of 11 months (range 3–18), 7/21 (33%) patients relapsed, and 3 needed further treatments. PK data showed a concentration time-course profile of Rituximab that was super-imposable, once corrected for the difference in the dose, to that observed previously in patients treated with standard dose, diseases with a median value of 4.1 micrograms/milliliter (range 0–11.9), 12 weeks after the start of treatment. In patients with ITP, low dose Rituximab led to short and mid-term response rates similar to standard dose but with slower timing of response. 2007, The American Society of Hematolog

CSPG4-Specific CAR.CIK Lymphocytes as a Novel Therapy for the Treatment of Multiple Soft-Tissue Sarcoma Histotypes

Purpose: No effective therapy is available for unresectable soft-tissue sarcomas (STS). This unmet clinical need prompted us to test whether chondroitin sulfate proteoglycan 4 (CSPG4)-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CAR.CIK) are effective in eliminating tumor cells derived from multiple STS histotypes in vitro and in immunodeficient mice.Experimental Design: The experimental platform included patient-derived CAR.CIK and cell lines established from multiple STS histotypes. CAR.CIK were transduced with a retroviral vector encoding second-generation CSPG4-specific CAR (CSPG4-CAR) with 4-1BB costimulation. The functional activity of CSPG4-CAR.CIK was explored in vitro, in two- and three-dimensional STS cultures, and in three in vivo STS xenograft models.Results: CSPG4-CAR.CIK were efficiently generated from patients with STS. CSPG4 was highly expressed in multiple STS histotypes by in silico analysis and on all 16 STS cell lines tested by flow cytometry. CSPG4-CAR.CIK displayed superior in vitro cytolytic activity against multiple STS histotypes as compared with paired unmodified control CIK. CSPG4-CAR.CIK also showed strong antitumor activity against STS spheroids; this effect was associated with tumor recruitment, infiltration, and matrix penetration. CSPG4-CAR.CIK significantly delayed or reversed tumor growth in vivo in three STS xenograft models (leiomyosarcoma, undifferentiated pleomorphic sarcoma, and fibrosarcoma). Tumor growth inhibition persisted for up to 2 weeks following the last administration of CSPG4-CAR.CIK.Conclusions: This study has shown that CSPG4-CAR.CIK effectively targets multiple STS histotypes in vitro and in immunodeficient mice. These results provide a strong rationale to translate the novel strategy we have developed into a clinical setting