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INTRODUCTION: Bone involvement in Multiple Myeloma results from increased osteoclast formation and activity that occurs in proximity to myeloma cells. The role of Alkaline Phosphatse (ALP) in this process and the diagnostic significance of plasma levels in patients with MM are unclear. AIM: To compare plasma ALP levels in patients with MM and solid cancers and metastatic lesions to the bone. RESULTS: In this observational retrospective study we enrolled 901 patients were enrolled: 440 patients (49%) with Multiple Myeloma, 461 (51%) with solid cancers. All 901 patients had bone lesions. Among patients with Multiple Myeloma, ALP values were mainly in the range of normality than those observed in patients with solid cancers and bone lesions. This difference is independent of stage, number and type of bone lesions. CONCLUSION: This study suggests that plasma ALP has a different clinical significance in MM than in other neoplasms and could be used as a discriminating marker in presence of bone lesions. In particular, lower or normal values, should suggest further investigations such as urinary and serum electrophoresis, associated with bone marrow aspirate in case of the presence of a monoclonal component, in order to confirm or exclude a MM diagnosis.
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Programmed cell death protein 1 (PD-1), is a cell surface receptor with an important role in down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. PD-1/PDL1 axis represents a checkpoint to control immune responses and it is often used as a mechanism of immune escaping by cancers and infectious diseases. Many data demonstrate its important role in solid tumors and report emerging evidences in lymphoproliferative disorders. In this review, we summarized the available data on the role of PD-1/PD-L1 checkpoint in lymphoproliferative diseases and the therapeutics use of monoclonal blocking antibodies.
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Antígeno B7-H1/fisiologia , Neoplasias Hematológicas/imunologia , Receptor de Morte Celular Programada 1/fisiologia , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/imunologia , Neoplasias Hematológicas/terapia , Doença de Hodgkin/imunologia , Doença de Hodgkin/terapia , Humanos , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/terapia , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/terapia , Receptor de Morte Celular Programada 1/imunologia , Evasão TumoralRESUMO
The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.
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Arsenicais/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Proteínas de Fusão Oncogênica/sangue , Óxidos/administração & dosagem , Tretinoína/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Trióxido de Arsênio , Arsenicais/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução/métodos , Itália , Cinética , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Óxidos/uso terapêutico , Prognóstico , Tretinoína/uso terapêutico , Adulto JovemRESUMO
The incidence of cytomegalovirus (CMV) reactivations in patients with multiple myeloma (MM) receiving autologous stem cell transplantation (ASCT) is relatively low. However, the recent increased use of novel agents, such as bortezomib and/or immunomodulators, before transplant, has led to an increasing incidence of Herpesviridae family virus infections. The aim of the study was to establish the incidence of post-engraftment symptomatic CMV reactivations in MM patients receiving ASCT, and to compare this incidence with that of patients treated with novel agents or with conventional chemotherapy before transplant. The study was a survey of 80 consecutive patients who underwent ASCT after treatment with novel agents (Group A). These patients were compared with a cohort of 89 patients treated with VAD regimen (vincristine, doxorubicin, and dexamethasone) before ASCT (Group B). Overall, 7 patients (4.1%) received an antiviral treatment for a symptomatic CMV reactivation and 1 died. The incidence of CMV reactivations was significantly higher in Group A than in Group B (7.5% vs. 1.1%; P = 0.048). When compared with Group B, the CMV reactivations observed in Group A were significantly more frequent in patients who received bortezomib, whether or not associated with immunomodulators (9.4% vs. 1.1%; P = 0.019), but not in those treated with immunomodulators only (3.7% vs. 1.1%; P = 0.396). These results suggest that MM patients treated with bortezomib-based regimens are at higher risk of developing a symptomatic CMV reactivation after ASCT.
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Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácidos Borônicos/uso terapêutico , Infecções por Citomegalovirus/epidemiologia , Hospedeiro Imunocomprometido , Mieloma Múltiplo/terapia , Pirazinas/uso terapêutico , Transplante de Células-Tronco , Adulto , Idoso , Bortezomib , Estudos de Casos e Controles , Estudos de Coortes , Infecções por Citomegalovirus/imunologia , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Incidência , Quimioterapia de Indução , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Transplante Autólogo , Vincristina/uso terapêuticoRESUMO
Bisphosphonates (BPs) are used intravenously to treat cancer-related conditions for the prevention of pathological fractures. Osteonecrosis of the jaw (BRONJ) is a rare complication reported in 4-15% of patients. We studied, retrospectively, 55 patients with multiple myeloma or Waldenstrom's macroglobulinemia followed up from different haematological departments who developed BRONJ. All patients were treated with BPs for bone lesions and/or fractures. The most common trigger for BRONJ was dental alveolar surgery. After a median observation of 26 months, no death caused by BRONJ complication was reported. In all, 51 patients were treated with antibiotic therapy, and in 6 patients, this was performed in association with surgical debridement of necrotic bone, in 16 with hyperbaric O(2) therapy/ozonotherapy and curettage and in 12 with sequestrectomy and O(2)/hyperbaric therapy. Complete response was observed in 20 cases, partial response in 21, unchanged in 9 and worsening in 3. The association of surgical treatment with antibiotic therapy seems to be more effective in eradicating the necrotic bone than antibiotic treatment alone. O(2) hyperbaric/ozonotherapy is a very effective treatment. The cumulative dosage of BPs is important for the evolution of BRONJ. Because the most common trigger for BRONJ was dental extractions, all patients, before BP treatment, must achieve an optimal periodontal health.
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High HbF levels and F cells are correlated with reduced morbidity and mortality in sickle cell disease (SCD). This paper was designed to determine the HbF and F cells levels in Congolese sickle cell anemia (SCA) patients in order to determine their impact on the expression of SCD. Population and Method. HbF levels were measured in 89 SCA patients (mean age 11.4 yrs) using a standard HPLC method. F cell quantitation was done in a second group of SCA patients (n = 42, mean age 8.9 yrs) and compared with a control group (n = 47, mean age 5 yrs). F cells were quantified by a cytofluorometric system (MoAb-HbF-FITC; cut off at 0.5%). Results. The mean value of HbF was 7.2% ± 5.0 with heterogeneous distribution, most patients (76%) having HbF < 8%. Mean values of F-cells in SCA patients and control group were 5.4% ± 7.6 (median: 2.19%; range 0,0-30,3%) and 0.5% ± 1.6 (median 0.0, range 0-5.18), respectively. SCA patients with F cells >4.5% developed less painful crisis and had higher percentage of reticulocytes. Conclusion. Congolese SCA patients displayed low levels of HbF and F-cells that contribute to the severity of SCD.
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Tuberculous meningoencephalitis is a rare disease associated with high morbidity and mortality. We report a patient with hairy cell leukemia in complete remission who, after a single cycle of chemotherapy with cladribine, presented fever and neurological deficits. Laboratory diagnosis of tuberculous meningoencephalitis was made by polymerase chain reaction testing for Mycobacterium tuberculosis in cerebrospinal fluid. Despite the prompt institution of antitubercular-therapy, patient's general condition did not improve and he died. Mycobacterial infection should be considered in patients with intra-cranial lesions, affected by hematological malignancies and persistent immunosuppression.
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Antineoplásicos/efeitos adversos , Cladribina/efeitos adversos , Terapia de Imunossupressão/efeitos adversos , Leucemia de Células Pilosas/tratamento farmacológico , Meningoencefalite/induzido quimicamente , Tuberculose Meníngea/induzido quimicamente , Antineoplásicos/administração & dosagem , Cladribina/administração & dosagem , Evolução Fatal , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Meníngea/tratamento farmacológicoRESUMO
Translocation t(4;11)(q21;q23) leading to formation of MLL-AF4 fusion gene is found in about 10% of newly diagnosed B-cell acute lymphoblastic leukemia (ALL) in adult patients. Patients expressing this chromosomal aberration present typical biological, immunophenotypic, and clinical features. This form of leukemia is universally recognized as high-risk leukemia and treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) could be a valid option to improve prognosis, but data obtained from the literature are controversial. In this review, we briefly describe pathogenetic, clinical, and prognostic characteristics of adult t(4;11)(q21;q23)/MLL-AF4 positive ALL and provide a review of the clinical outcome reported by the most important cooperative groups worldwide.
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Aspergilose/etiologia , Trato Gastrointestinal/microbiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/complicações , Estrongiloidíase/etiologia , Idoso , Aspergillus/isolamento & purificação , Feminino , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/microbiologia , PrognósticoRESUMO
INTRODUCTION: Sickle cell disease is associated with a wide range of clinical and laboratory findings depending on genetic modulators and environmental factors. The most severe forms of sickle cell disease occur in patients with the Bantu haplotype. The purpose of this study was to determine the hematological profile of Congolese patients with homozygous sickle cell disease during periods of remission. PATIENTS AND METHODS: Hemograms were performed in two series of patients with sickle cell disease in remission, i.e., one including 89 patients with a mean age of 8.7 years and the other including 42 patients with a mean age of 8.9 years. Hemograms were performed using an automated counter and reticulocytes were counted manually on peripheral blood smears. Fetal hemoglobin level (HbF) was measured by chromatography (HPLC). The mean values obtained were compared with those obtained in a sickle-cell-disease-free control group. Some parameters were also compared with those obtained in a group of patients exhibiting complications of sickle cell disease. RESULTS: Hemograms in the first series of patients demonstrated the following values: Hb: 7.2 g/dl; Hct 23.1%, red cells: 2.47 tera/L, leukocytes: 14.9 giga/L; VGM: 95.3 fL; CCMH:30.3% L and platelets:345,3 giga/L. Blood count showed 30.4% of polynuclear neutrophils, 33% de lymphocytes, 0.8% of polynuclear basophiles, 14% of monocytes, 7.8% of polynuclear eosinophils and 14% of erythroblasts. Mean HbF level was 7.2% and reticulocytes were at 88%. In the sickle cell disease-free group, the leukocyte rate was almost three fold higher than in the patient group exhibiting sickle cell disease in remission even though rates were higher than during complications. CONCLUSION: Hemogram profiles in Congolese patients with sickle cell disease are similar to those reported in the literature for subjects exhibiting the Bantou haplotype. Leukocytosis was associated with esinophilia and monocytosis suggested a topical state and chronic inflammation.
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Anemia Falciforme/sangue , Contagem de Células Sanguíneas , Estudos de Casos e Controles , Criança , República Democrática do Congo , Hemoglobina Fetal/análise , Humanos , Leucocitose/sangueAssuntos
Endoscopia Gastrointestinal/métodos , Adesivo Tecidual de Fibrina/uso terapêutico , Hemorragia Gastrointestinal/terapia , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Feminino , Adesivo Tecidual de Fibrina/administração & dosagem , Hemorragia Gastrointestinal/induzido quimicamente , Hemostasia/efeitos dos fármacos , Humanos , MasculinoRESUMO
The systemic inflammation associated to the simultaneous activation of blood coagulation and the alterated blood fibrinolysis, leads to microvascular endothelial injury, acute organ dysfunction and possibly death. Activated Protein C, a natural, multifunctional protein, has demonstrated antithrombotic, anti-inflammatory, and profibrinolitic properties and may be an important modulator of the vicious cycle whereby inflammation initiates coagulation and coagulation amplifies inflammation. Protein C couples with its receptor, EPCR (endothelial-cell protein-C receptor), and the ligand-receptor complex then interact with thrombin-thrombomodulin on endothelial surface to produce activated protein C (APC). Once activated, protein C then interact with its cofactor, protein S, to catalyze the inactivation of factors Va and VIIILa, two important accelerators of the clotting cascade, reducing thrombin generation and microvascular thrombosis. In addiction to its anticoagulant activity APC promotes profibrinolytic activity through the inhibition of plasminogen activator inhibitor-1, which is upregulated during inflammation. Inhibition of thrombin generation by APC decreases inflammation by inhibiting platelet activation, neutrophil recruitment, and mast-cell degranulation. APC also shows direct antiinflammatory properties, including blocking of cytokines production by monocytes and blocking cell adhesion. Moreover, APC has antiapoptotic properties that may contribute to its efficacy. In conclusion, APC, besides its physiologic role in the coagulation cascade, plays a key role in the pathophysiology of systemic inflammation justifying its potential therapeutic role in sepsis and systemic inflammatory responses.
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Proteína C/fisiologia , Coagulação Sanguínea/fisiologia , Humanos , Inflamação/imunologia , Proteína C/uso terapêutico , Deficiência de Proteína C/congênito , Deficiência de Proteína C/fisiopatologiaRESUMO
Although the occurrence of thrombosis in acute promyelocytic leukemia (APL) has been reported during retinoic acid treatment, no studies carried out in large clinical cohorts have specifically addressed this issue. We analyzed 124 APL patients treated with the all-trans retinoic acid and idarubicin protocol and compared clinico-biologic characteristics of 11 patients who developed thrombosis with those of 113 patients who had no thrombosis. In seven patients, the events were recorded during induction, whereas in four patients deep vein thrombosis occurred in the post-induction phase. Comparison of clinico-biological characteristics of patients with and without thrombosis revealed in the former group higher median white blood cell (WBC) count (17 x 10(9)/l, range 1.2-56, P=0.002), prevalence of the bcr3 transcript type (72 vs 48%, P=0.01), of FLT3-ITD (64 vs 28%, P=0.02), CD2 (P=0.0001) and CD15 (P=0.01) expression. No correlation was found with sex, age, French-American-British subtype, all-trans-retinoic acid syndrome or with thrombophilic state that was investigated in 5/11 patients. Our findings suggest that, in APL patients consistent biologic features of leukemia cells may predict increased risk of developing thrombosis.
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Antineoplásicos/efeitos adversos , Leucemia Promielocítica Aguda/tratamento farmacológico , Trombose/induzido quimicamente , Tretinoína/efeitos adversos , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagem , Antígenos CD2 , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/imunologia , Contagem de Leucócitos , Antígenos CD15 , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Fatores de Risco , Sequências de Repetição em Tandem/genética , Trombose/genética , Trombose/imunologia , Tretinoína/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea/métodos , Leucemia Promielocítica Aguda/terapia , Adolescente , Adulto , Amsacrina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carmustina/administração & dosagem , Criança , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Terapia de Salvação/métodos , Transplante AutólogoRESUMO
PURPOSE: To provide specialists and general practitioners with a review of the more recent data about anthracycline-induced cardiotoxicity and diagnostic methods utilized to reveal it. DESIGN: Reviewers identified studies concerning anthracycline cardiotoxicity, with special emphasis to those dealing with its pathogenesis and tools utilized for diagnosing it, by searching MEDLINE and reviewing references for retrieved articles. RESULTS: Three different clinical patterns of cardiotoxicity were described: acute, chronic and late. Highly sensitive tests are necessary for evaluating, during the time, the cardiotoxic effects associated with anthracycline-based therapy and to predict the development of cardiac dysfunction. For this reason, endomyocardic biopsy and radionuclide-based angiocardiography are considered the "gold standard". However, the bidimensional echocardiography is the most commonly performed because of its high specificity and sensitivity combined with low costs. CONCLUSIONS: The peer review of the most recent scientific literature clearly demonstrate that cardiotoxicity is an important complication of anthracycline-based therapy and that the cumulative dose greater than 550 mg/m2 is the main independent risk factor. For the evaluation of anthracycline-related cardiotoxicity, bidimensional echocardiography remains still the easier and faster method.
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Antibióticos Antineoplásicos/efeitos adversos , Cardiopatias/induzido quimicamente , Antibióticos Antineoplásicos/química , Ecocardiografia , Cardiopatias/classificação , Cardiopatias/diagnóstico por imagem , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Cintilografia , Fatores de RiscoRESUMO
In all, 134 elderly patients (median age 66 years, range 60-75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idarubicina/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Idarubicina/efeitos adversos , Leucemia Promielocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Resultado do Tratamento , Tretinoína/efeitos adversosRESUMO
Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.