Treatment of chronic myeloid leukemia in 2007

The treatment of chronic myeloid leukemia (CML) has considerably evolved since imatinib mesylate has been introduced as a new therapeutic weapon for this disease. The 5-year updated results of the IRIS study confirmed that imatinib mesylate is the best first line therapy for chronic phase CML with an overall survival of 90%. Responses improve with time and complete cytogenetic and major molecular levels reach 87 and 70% respectively at 5 years. However, despite these remarkable improvements, new problems arise as sub-optimal responses, imatinib-resistances with recently identified BCR-ABL protein point mutations, responsible for a variety of therapeutic consequences : imatinib dose increase, alternative treatments with second generation tyrosine kinase inhibitors (TKIs : dastinib, nilotinib) or allogeneic stem cell transplantation. The treatment of accelerated and blastic phases relies on imatinib +/- conventional chemotherapy, ideally followed by allogeneic stem cell transplantation, as newly developed TKIs are currently evaluated within this frame. Finally, BCR-ABL(T315I) mutations remain a new therapeutic critical challenge as none of the three TKIs (imatinib, nilotinib, dasatinib) can efficiently control such diseases.     

Validation of the Portuguese version of Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in Brazilian cancer patients

Goals of work  

The purpose of this study was to validate the Portuguese version of the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) in order to establish its assessment properties, including validity and reliability in a sample of Brazilian cancer patients.     

Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.     

Cryopreservation with hydroxyethylstarch (HES) + dimethylsulfoxide (DMSO) gives better results than DMSO alone

This study compares the cryopreservation of PBSC by means of HES 3% + DMSO 5% ina mechanical freezer with the cryopreservation of PBSC by means of DMSO 10% in an automated rate controlled freezer. The cells harvested from the same patient were divided in two equal parts and frozen according to both methods. Cryopreservation with HES +DMSO is better than DMSO alone in terms of viability (p<0.001) and Granulocyte Macrophage Colony Forming Unit (GM-CFU) activity (p<0.05). The freezing curves differ essentially in the slope down after the surfusion peak. However, surfusion peaks are similar in both conditions. The relevance of mechanical freezing is the saving of time and the safety of such a procedure.     

Human papillomavirus detection by hybrid capture II and residual or recurrent high-grade squamous cervical intraepithelial neoplasia after large loop excision of the transformation zone (LLETZ)

AIMS AND BACKGROUND: The purpose of this study was to assess the association between highly-oncogenic types HPV DNA detection by Hybrid Capture II (HCII) and residual or recurrent high-grade cervical intraepithelial neoplasia (CIN 2 or 3) during the follow-up of women submitted to large loop excision of the transformation zone (LLETZ). STUDY DESIGN: In this cohort study, 94 women submitted to LLETZ because of CIN 2 or 3 between March 2001 and September 2002 were followed up twice yearly until September 2003. Follow-up visits consisted of an interview regarding clinical, social and demographic characteristics complemented with gynecological examination with specimen collection for Pap test and HCII and colposcopy. Eighty-one patients attended the first visit (mean 4.8 months, range 3-6) and 75 the second visit (mean 10.9 months, range 7-17 months). McNemar's test to assess the variation of HPV DNA detection following LLETZ, odds ratios (OR) to evaluate the correlation between HPV DNA positivity and residual/recurrent CIN during follow-up, and logistic regression to assess the risk of residual/recurrent CIN were used. RESULTS: There was a strong and significant reduction in HPV detection after LLETZ (P < 0.001). HPV DNA detection was correlated with residual/recurrent CIN at the first (OR = 103.4; 95% CI 5.5 to 1961.2) and second (OR = 12.7; 95% CI 1.1 to 345.5) follow-up visits. Multivariate analysis showed HPV persistence as a stand-alone risk factor for residual/recurrent CIN (OR = 50.3; 95% CI 3.8 to 663.1). CONCLUSIONS: High risk HPV DNA detection decreased substantially after CIN treatment with LLETZ, but HPV persistence was strongly correlated with residual/recurrent CIN.     

Alloreactive donor lymphocytes (DLI) after allogeneic hematopoietic stem cell transplantation (HSCT): study of toxicity and efficacy

Adoptive immunotherapy represents a new therapeutic tool able to eradicate or to improve the course of various hematological malignancies and solid tumors. Alloreactive lymphocytes present within the hematopoietic transplant have been shown to be responsible for the occurrence of acute and chronic graft-versus-host-disease (GVHD). Retrospective analysis of survival curves after allogeneic bone marrow transplantation performed for leukemia have shown that GVHD was accompanied with lower relapse rates suggesting graft-versus leukemia (GVL) affect. T cell-depletion demonstrated the inverse balance existing between GVHD/GVL and relapse. Allogeneic bulk lymphocyte infusions were further used for successful treatment of relapse after transplantation in CML patients. However they were responsible for some cases of lethal acute GVHD and myelosuppressions in some patients. The concept of allogeneic transplantations after reduced intensity conditioning regimen (RICT) has recently emerged as a new strategy to treat cancer. This strategy exploited the immunological properties of the graft followed or not by donor lymphocyte infusions (DLI) while reducing the toxicity of the preparative regimen. Different means to perform RICT have been described, however the systematic use of DLI (bulk or escalating doses) after these transplantations remains controversial. Hereby, we report a summary of historical data that lead to the concept of adoptive immunotherapy and its applications.     

Monosomy 11q: Report of two familial cases and review of the literature

We present four children from two families with the typical 11q- phenotype resulting from an unbalanced segregation of a parental translocation. In the first family, the father had a 46,XY,t(5;11)(q24;q23.3) constitution. The father of the three other children had a 46,XY,t(11;17)(q23;p13) translocation. Despite associated partial deletion, three of the children has a typical 11q-phenotype. The fourth one, whose pregnancy was terminated in the second trimester, had a hypoplastic left heart but no other considered gross anomalies. A review of 36 previous cases, including 5 due to translocation (4 familial rearrangements, and 1 of unknown origin) is given with emphasis on the relationships between breakpoints and phenotype. Undescribed manifestations in our patients include agenesis of corpus callosum adactyly and malrotation of the gut. © 1993 Wiley-Liss, Inc.     

Inolimomab in steroid-refractory acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: retrospective analysis and comparison with other interleukin-2 receptor antibodies

BACKGROUND: The use of monoclonal antibodies against interleukin-2 receptor (IL-2R)-alpha chains could be an effective treatment of acute graft-versus-host disease (GvHD). Experimental model and clinical studies have reported various results. METHODS: Inolimomab is a murine anti-IL-2R. Eighty-five patients were evaluated retrospectively for the safety and efficacy of inolimomab given for the treatment of steroid-resistant acute GvHD (aGvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Diseases were immune deficiency, hematological malignancies, or solid tumors. Seventy-six percent of the patients received a myeloablative regimen. The source of HSCT was bone marrow for 45 patients, peripheral blood for 36 patients, and cord blood for 4 patients. Donors were 49 siblings and 36 unrelated. Acute GvHD was diagnosed within a median of 28 days after transplantation (grade II, 26 patients; grade III, 26 patients; grade IV, 33 patients). Inolimomab was administered in the event of steroid-resistant aGvHD with a median dose of 0.468 mg per kg (median period of treatment: 18 days). RESULTS: Twenty-five complete responses and 29 partial responses (total response rate: 63%) were observed with no side effects. There was no correlation between aGvHD grading and quality of response. Better responses were observed in cutaneous aGvHD. The overall survival probability was 26% (median follow-up: 20 months). Fifty-seven percent of patients died of toxicity related mortality, mostly aGvHD. Response to inolimomab seemed sustained (11% relapse in responders). CONCLUSION: Inolimomab is well-tolerated and effective for severe steroid-resistant aGvHD. The optimum regimen remains to be defined.