Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Padrões de Referência , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
RATIONALE: Crystalline light chain inclusion-associated kidney disease affects mainly tubular epithelial cells and is often clinically manifested as Fanconi syndrome. However, only very few case reports about the crystalline deposits within the podocytes are available, and the nature of the pathogenic monoclonal light chain implicated in these cases is still unknown. We report a case of crystalline inclusion-associated kidney disease manifested as crystalline podocytopathy in which we identified the complete structure of the pathogenic monoclonal light chain as belonging to the germ-line gene of Vκ1-39. PATIENT CONCERNS: We describe a 65-year-old woman with crystalline light chain inclusion-associated kidney disease showing mild proteinuria and renal insufficiency with monoclonal gammopathy of undetermined significance without Fanconi syndrome. She had crystalline inclusions mainly within podocytes, tubular epithelial cells and histiocytes in the kidney. Light microscopy showed vacuolation of podocytes and tubular epithelial cells, while eosin negative pale needle-like crystals were present within these cells. Electron microscopy showed accumulation of club-like crystals with high electron density in podocytes, proximal tubular epithelial cells and interstitial histiocytes. Clonal analysis revealed that a pathogenic monoclonal light chain was derived from germline gene, Vκ1-39. DIAGNOSES: The diagnosis of crystalline light chain inclusion-associated kidney disease was made. INTERVENTIONS AND OUTCOMES: Bortezomib and dexamethasone were started and her renal function improved to eGFR 36âmL/min/1.73âm after 9 courses of therapy. LESSONS: Patients with light chain crystalline podocytopathy may have a similar pathogenic monoclonal light chain derived from the same germline gene, Vκ1-39, to that of patients with light chain proximal tubulopathy.
Assuntos
Cadeias Leves de Imunoglobulina/efeitos adversos , Nefropatias/etiologia , Nefropatias/fisiopatologia , Podócitos/patologia , Idoso , Feminino , Humanos , Cadeias Leves de Imunoglobulina/genéticaRESUMO
BACKGROUND: Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan. METHODS: An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period. RESULTS: Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was -33.61 mg h/dL, and the 95 % confidence interval was -70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups. CONCLUSION: Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy. TRIAL REGISTRY: http://www.clinicaltrials.jp ; Identifier: JapicCTI-132398.
Assuntos
Febuxostat/uso terapêutico , Supressores da Gota/uso terapêutico , Síndrome de Lise Tumoral/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Alopurinol/uso terapêutico , Febuxostat/efeitos adversos , Feminino , Gota , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/prevenção & controle , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Tiazóis/uso terapêutico , Síndrome de Lise Tumoral/sangue , Ácido Úrico/sangue , Xantina Oxidase , Adulto JovemRESUMO
Lenvatinib significantly prolonged progression-free survival (PFS) versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) in the phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. This subanalysis evaluated the efficacy and safety of lenvatinib in Japanese patients who participated in SELECT. Outcomes for Japanese patients (lenvatinib, n = 30; placebo, n = 10) were assessed in relationship to the SELECT population (lenvatinib, n = 261; placebo, n = 131). The primary endpoint was PFS; secondary endpoints included overall survival, overall response rate, and safety. Lenvatinib PFS benefit was shown in Japanese patients (median PFS: lenvatinib, 16.5 months; placebo, 3.7 months), although significance was not reached, presumably due to sample size (hazard ratio, 0.39; 95% confidence interval, 0.10-1.57; P = 0.067). Overall response rates were 63.3% and 0% for lenvatinib and placebo, respectively. No significant difference was found in overall survival. The lenvatinib safety profile was similar between the Japanese and overall SELECT population, except for higher incidences of hypertension (any grade: Japanese, 87%; overall, 68%; grade ≥3: Japanese, 80%; overall, 42%), palmar-plantar erythrodysesthesia syndrome (any grade: Japanese, 70%; overall, 32%; grade ≥3: Japanese, 3%; overall, 3%), and proteinuria (any grade: Japanese, 63%; overall, 31%; grade ≥3: Japanese, 20%; overall, 10%). Japanese patients had more dose reductions (Japanese, 90%; overall, 67.8%), but fewer discontinuations due to adverse events (Japanese, 3.3%; overall, 14.2%). There was no difference in lenvatinib exposure between the Japanese and overall SELECT populations after adjusting for body weight. In Japanese patients with radioiodine-refractory differentiated thyroid cancer, lenvatinib showed similar clinical outcomes to the overall SELECT population. Some differences in adverse event frequencies and dose modifications were observed. Clinical trial registration no.: NCT01321554.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacocinética , Povo Asiático , Carcinoma/mortalidade , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Radioisótopos do Iodo , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/farmacocinética , Quinolinas/farmacocinética , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
The clinical path for the treatment of acute myeloid leukemia (AML) patients has been in practice in our hospital since 2003. In the clinical path, laboratory technologists take on the role of explaining the microscopic findings in bone marrow and peripheral blood samples to patients (with or without their families) using the view-sharing microscope in our laboratory. From July 2003 to October 2014, 56 patients were enrolled in the AML clinical path and given an explanation of their bone marrow and peripheral blood samples. The patients' median age was 62, and the median time spent for explanation was 40 minutes. We conducted a questionnaire feedback survey involving those who enrolled, and the results showed significant improvement in the recognition of the disease pathophysiology, treatment efficacy, and the importance of precautions against infectious diseases. Based on the feedback, we have made marked efforts to provide patients with an improved environment during the explanatory session. This includes installing a special display for the patients, drawing a schematic illustration that shows how the blood cells differentiate, and putting them into operation in a hematology ward to promote patient privacy and precautions against infectious diseases. Hematological laboratory technologists have played an important role in patient care in our hospital. To perform their role as effectively as possible, hematological laboratory technologists participate in the conferences of the Department of Hematology and Oncology regularly, in which medical staff members can discuss the conditions and clinical courses of patients. We aim to contribute to patient satisfaction by sophisticating specialized knowledge as hematological laboratory technologists and cooperate with other medical staff members.
Assuntos
Sangue , Medula Óssea , Procedimentos Clínicos , Neoplasias Hematológicas/diagnóstico , Hematologia/organização & administração , Pessoal de Laboratório Médico , Ciência de Laboratório Médico/organização & administração , Equipe de Assistência ao Paciente , Educação de Pacientes como Assunto/métodos , Papel Profissional , Sociedades Médicas/organização & administração , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/patologia , Humanos , Japão , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Manejo de Espécimes , Inquéritos e Questionários , Adulto JovemAssuntos
Aneurisma Infectado/etiologia , Aspergilose/microbiologia , Aspergillus/isolamento & purificação , Hospedeiro Imunocomprometido , Aneurisma Intracraniano/etiologia , Sinusite Esfenoidal/microbiologia , Adulto , Aneurisma Infectado/tratamento farmacológico , Aneurisma Infectado/microbiologia , Aneurisma Infectado/fisiopatologia , Antifúngicos/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Aspergilose/fisiopatologia , Aspergilose/cirurgia , Aspergillus/imunologia , Evolução Fatal , Feminino , Humanos , Aneurisma Intracraniano/tratamento farmacológico , Aneurisma Intracraniano/microbiologia , Aneurisma Intracraniano/fisiopatologia , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/imunologia , Recidiva , Sinusite Esfenoidal/imunologia , Sinusite Esfenoidal/fisiopatologia , Sinusite Esfenoidal/cirurgia , Adulto JovemRESUMO
Overcoming drug resistance remains a major obstacle to curing relapsed or refractory lymphoma and obtaining a beneficial long-term prognosis for patients, despite the introduction of several salvage regimens to date. Our ultimate purpose is to establish a standard second-line salvage chemotherapy regimen for curing relapsed/refractory lymphoma. In this basic pre-clinical study, we evaluated a combination regimen consisting of 9-ß-D: -arabinofuranosyl-2-fluoroadenine (F-araA) and carboplatin that targeted nucleotide excision repair (NER) of DNA in five representative leukemia lineages in vitro. Isobologram analysis demonstrated that simultaneous exposure to these two drugs produced synergistic interactions in U937 and K562 cells, in which lines showed enhanced NER activity by the measurement of UV or drug-induced DNA strand break (comet assay), or quantitation of ERCC1 mRNA (RT-PCR), a key enzyme for NER. Histone γH2AX formation was synergistically induced, but no such formation was observed after exposure to either agent alone in K562 cells. In summary, we synergistically inhibited the NER activity of leukemia cells by treating them with a combination of F-araA and carboplatin, suggesting that this combinatory regimen could be used as a novel salvage therapy for refractory or drug-resistant lymphoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/farmacologia , Reparo do DNA/efeitos dos fármacos , Leucemia/tratamento farmacológico , Vidarabina/análogos & derivados , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Células K562 , Linfoma/tratamento farmacológico , Terapia de Salvação , Vidarabina/farmacologiaRESUMO
This study was designed to determine the optimal high dose for cytosine arabinoside (ara-C) in combination with fludarabine, granulocyte colony-stimulating factor, and mitoxantrone (FLAGM) in adult patients with relapsed or refractory acute myeloid leukemia. Nine patients were enrolled at increasing dosage levels of ara-C (8, 12, and 16 g/m2 per dose level). Ara-C and fludarabine were administered once a day at level 1, once or twice a day at level 2, and twice a day at level 3. All patients had grade 4 hematologic toxicity. The most common adverse events were of grade 2 or less, with nausea and vomiting being the most common (6 events), followed by diarrhea (5 events), and rash (5 events). Of the 13 grade 3 nonhematologic toxicities reported, the 2 most common were febrile neutropenia (6 events) and disseminated intravascular coagulation (3 events). No early deaths were observed. FLAGM with high-dose ara-C was considered safe for patients, and the recommended dosage of ara-C in this study was 2 g/m2 every 12 hours for a total dose of 16 g/m2.
Assuntos
Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/uso terapêutico , Vidarabina/análogos & derivados , Adulto , Citarabina/efeitos adversos , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Japão , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Mitoxantrona/efeitos adversos , Recidiva , Vidarabina/efeitos adversos , Vidarabina/uso terapêuticoRESUMO
To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARalpha at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARalpha fusion transcript after 3 courses of intensive consolidation therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Proteínas de Fusão Oncogênica/análise , Adolescente , Adulto , Idoso , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , RNA Neoplásico/análise , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Tretinoína/uso terapêuticoRESUMO
The combination of cytarabine (ara-C) with fludarabine is a common approach to treating resistant acute myeloid leukemia. Success depends on a fludarabine triphosphate (F-ara-ATP)-mediated increase in the active intracellular metabolite of ara-C, ara-C 5'-triphosphate (ara-CTP). Therapy-resistant leukemia may exhibit ara-C resistance, the mechanisms of which might induce cross-resistance to fludarabine with reduced F-ara-ATP formation. The present study evaluated the effect of combining ara-C and fludarabine on ara-C-resistant leukemic cells in vitro. Two variant cell lines (R1 and R2) were 8-fold and 10-fold more ara-C resistant, respectively, than the parental HL-60 cells. Reduced deoxycytidine kinase activity was demonstrated in R1 and R2 cells, and R2 cells also showed an increase in cytosolic 5'-nucleotidase II activity. Compared with HL-60 cells, R1 and R2 cells produced smaller amounts of ara-CTP. Both variants accumulated less F-ara-ATP than HL-60 cells and showed cross-resistance to fludarabine nucleoside (F-ara-A). R2 cells, however, accumulated much smaller amounts of F-ara-ATP and were more F-ara-A resistant than R1 cells. In HL-60 and R1 cells, F-ara-A pretreatment followed by ara-C incubation produced F-ara-ATP concentrations sufficient for augmenting ara-CTP production, thereby enhancing ara-C cytotoxicity. No potentiation was observed in R2 cells. Nucleotidase might preferentially degrade F-ara-A monophosphate over ara-C monophosphate, leading to reduced F-ara-ATP production and thereby compromising the F-ara-A-mediated potentiation of ara-C cytotoxicity in R2 cells. Thus, F-ara-A-mediated enhancement of ara-C cytotoxicity depended on F-ara-ATP accumulation in ara-C-resistant leukemic cells but ultimately was associated with the mechanism of ara-C resistance.
Assuntos
Arabinofuranosilcitosina Trifosfato/farmacologia , Citarabina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Arabinofuranosilcitosina Trifosfato/agonistas , Arabinofuranosilcitosina Trifosfato/metabolismo , Sinergismo Farmacológico , Células HL-60 , Humanos , Leucemia Mieloide Aguda/metabolismo , Vidarabina/agonistas , Vidarabina/farmacologiaRESUMO
The cytotoxic action of the deoxyadenosine analogue 9-beta-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) depends on the incorporation into DNA after being phosphorylated to F-ara-A triphosphate (F-ara-ATP) by deoxycytidine kinase (dCK). The mechanisms of resistance to F-ara-A were investigated in a newly established variant of L1210 mouse leukemia cells (L1210/F). L1210/F was more than 41-fold more resistant to F-ara-A than the parental cell line and had a 55% lower dCK activity. Interestingly, L1210/F showed a modest level of cross-resistance to deoxycytidine analogues phosphorylated by dCK, for instance, 1-beta-D-arabinofuranosylcytosine (ara-C). The comparative study of F-ara-A and ara-C demonstrated that the difference in the accumulation of their respective triphosphates was minor. In contrast, the incorporation of F-ara-A into DNA was strikingly suppressed compared with that of ara-C. In general, the high natural triphosphate levels interfere with corresponding analogue incorporation into DNA. The deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate pool sizes in L1210/F cells were increased by 4.9-fold and 1.9-fold, respectively, compared with the parental cells. Treatment with hydroxyurea increased the ratio of F-ara-ATP to dATP 2.1-fold and enhanced the action of F-ara-A in L1210/F. This is the first cell line to show that the profoundly defective incorporation of F-ara-A into DNA during competition with excess dATP confers a high degree of resistance to F-ara-A.
Assuntos
DNA/metabolismo , Nucleotídeos de Desoxiadenina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Vidarabina/análogos & derivados , Animais , Ligação Competitiva , Biotransformação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citarabina/farmacocinética , Nucleotídeos de Desoxiadenina/análise , Nucleotídeos de Desoxicitosina/análise , Interações Medicamentosas , Hidroxiureia/farmacologia , Camundongos , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Vidarabina/farmacocinéticaRESUMO
Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.
Assuntos
Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Japão , Leucemia Mieloide de Fase Crônica/complicações , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Piperazinas/toxicidade , Pirimidinas/toxicidade , Indução de Remissão , Fatores de Tempo , Resultado do TratamentoRESUMO
Previous studies including ours have demonstrated that DNA repair is one of the important targets of fludarabine. The aim of this study is to clarify a mechanistic interaction of carboplatin and F-ara-A, from the perspective of F-ara-A-mediated inhibition of DNA repair initiated by carboplatin. Using human quiescent lymphocytes, we focused on DNA repair, since these cells provide a model of dormant cells. To evaluate the carboplatin-induced DNA incision and its repair, we used the alkaline comet assay. When lymphocytes were incubated with carboplatin, a dose-dependent increase in the tail-moment was observed. Then, tail-moment decreased in proportion to the incubation period in fresh media and recovered to the control level at 4 h. DNA rejoining was completely inhibited by F-ara-A at 10 microM through 0 to 6 h after washing out of these drugs and this F-ara-A-induced inhibition was concentration-dependent. Cellular damage after drug exposure was evaluated with the induction of apoptosis as well as cytotoxic effect. Exposure to carboplatin alone did not induce any apparent cellular damage in quiescent lymphocytes. In contrast, a more than additive induction of apoptosis as well as an enhancement of cytotoxic action was observed in cells treated with a combination of carboplatin and F-ara-A. In the CEM cell line, there was no enhancement of the cytotoxic action of these drugs, despite the clear demonstration of an inhibitory effect on DNA repair. These results indicate that chemotherapy with carboplatin opened a new target for F-ara-A by initiating DNA repair in quiescent cells.
Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Vidarabina/análogos & derivados , Vidarabina/farmacologia , Apoptose , Arabinonucleotídeos/farmacologia , Proliferação de Células/efeitos dos fármacos , Interações Medicamentosas , Humanos , Linfócitos/patologia , Células Tumorais CultivadasRESUMO
The outcome for adult patients with BCR-ABL-positive acute lymphoblastic leukemia (ALL) remains dismal and long-term survival can hardly be achieved except by allogeneic hematopoietic stem cell transplantation (HSCT). The Japan Adult Leukemia Study Group (JALSG) has recently started a phase 2 trial with intensive chemotherapy and imatinib for newly diagnosed BCR-AB-positive ALL patients, and we present here the interim results for the first 24 patients. All patients except one case of early death (96%) attained complete remission (CR) after a single course of remission induction therapy. Polymerase chain reaction (PCR) negativity was achieved in 28% of the patients on day 28, in 50% on day 63, and in up to 78% during the follow-up period. The toxicity profile was almost similar to that with chemotherapy alone. As a result, 15 patients (63%) could receive an allogeneic HSC transplant during their first CR. Although the number of patients is small and the observation period is too short, the combination therapy is very promising and produces high-quality CR for most newly diagnosed patients with BCR-ABL-positive ALL. This is especially useful because it provides the patients with a better chance to receive an allogeneic HSC transplant.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/administração & dosagem , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Benzamidas , Feminino , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/diagnóstico , Piperazinas/toxicidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Pirimidinas/toxicidade , Indução de Remissão/métodos , Análise de Sobrevida , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
Imatinib mesylate (imatinib), a selective inhibitor of BCR-ABL tyrosine kinase, has shown excellent efficacy in patients with chronic myelogenous leukemia (CML) in the chronic phase, however, it does not in those in the accelerated phase or blastic crisis. In patients with CML who have undergone allogeneic stem cell transplantation, imatinib has the capability to induce hematological and even molecular response, and provides a prolonged survival among those in the chronic and accelerated phases. It has been demonstrated that major cytogenic response is a surrogate marker for survival in cases receiving imatinib. It has also been demonstrated that a genome-wide cDNA microarray enables the prediction of sensitivity to imatinib. The acquired resistance in patients who failed to respond to imatinib seemed to be induced by several point mutations in the BCR-ABL gene, which were likely to affect the binding of imatinib with BCR-ABL. Polyclonal cells which harbor distinct mutations in a single patient seemed to be selected in vivo under the selective pressure of imatinib, indicating the rationale of combined treatment with other types of agents. Recently, SPIRIT (STI571 Prospective International Randomized Trials) have been conducted, in which the efficacy of imatinib monotherapy, and imatinib combined with interferon or cytarabine were compared. New agents which inhibit the signaling pathway related to BCR-ABL, such as adaphostin (NSC680410), farnesyltransferase inhibitor SCH66336, MAP kinase inhibitor PD184352, PD98059, U0126, and antibiotic geldanamycin, have shown excellent activity combined with imatinib in vitro.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Humanos , Mesilato de Imatinib , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagemRESUMO
Complete elimination of the plasma cell dyscrasia is a rational therapeutic goal, as intercepting supply of precursor protein is a necessary condition for a major regression of amyloid deposits. High-dose melphalan with autologous stem cell transplantation has shown the ability to induce complete hematological response (HR) along with recovery of organ dysfunction. However, the rate of HR with this treatment rarely exceeds 40%. We describe here the first known case of successful reduced intensity allogeneic stem cell transplantation (RIST) for a patient with primary amyloidosis complicated with nephrotic syndrome but without cardiac disease, who had obtained only partial HR by high-dose melphalan with autologous stem cell transplantation. RIST may be feasible and be capable of achieving complete HR along with recovery from nephrotic syndrome with acceptable toxicity.
Assuntos
Amiloidose/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Melfalan/uso terapêutico , Paraproteinemias/terapia , Amiloidose/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/terapia , Paraproteinemias/complicações , Proteinúria/etiologia , Proteinúria/terapia , Indução de Remissão/métodos , Terapia de Salvação/métodos , Transplante Homólogo , Falha de TratamentoRESUMO
Enhanced DNA repair activity is important for the development of cellular resistance to alkylating agents. Here, we quantitated the kinetics of DNA excision repairs initiated by 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in human leukemia CCRF-CEM cells. CEM cells that had been established resistant to BCNU (CEM-R) were evaluated in comparison with parental CEM cells (CEM-S). The excision repair kinetics were quantitated as the amount of DNA single strand breaks, which were generated from the incision/excision of the damaged DNA and were diminished by the rejoining of renewed DNA, using the single cell gel electrophoresis (Comet) assay. CEM-R cells were 10-fold more resistant to BCNU than CEM-S cells, and also showed cross-resistance to melphalan and cisplatin. In response to the treatment with BCNU, both CEM-S and CEM-R cells initiated an incision/excision reaction at the end of the incubation period, and completed the rejoining process within 4 hr. While CEM-S cells could not repair the damage induced by the high concentration of BCNU, CEM-R cells completed the repair process regardless of BCNU concentrations, suggesting enhanced excision repairs in CEM-R cells. The excision repair activity of CEM-R cells was increased with regard to the incision reaction and to the rate of the repair. Similar results were obtained using ultraviolet C, suggesting enhanced nucleotide excision repair in CEM-R cells. Thus, the enhanced DNA excision repairs were successfully quantitated in the resistant leukemic cell line using the Comet assay. The evaluation of the repair activity may predict the sensitivity of cancer cells to chemotherapy and provide a clue to overcome the resistance.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Carmustina/farmacologia , Reparo do DNA/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , Raios Ultravioleta , Ensaio Cometa/métodos , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Humanos , Células Tumorais CultivadasRESUMO
We describe the successful treatment of pyoderma gangrenosum (PG) that developed in a patient with myelodysplastic syndrome (MDS). A 63-year-old Japanese man with MDS was admitted to our hospital because of a large skin ulcer on his neck in November 2001. The initial diagnosis was infectious dermatitis, and antimicrobial therapy was performed, using imipenem/cilastatin, isepamicin, and amphotericin B. However, this therapy was not effective, and the lesion worsened. Cultures of blood, throat swab, and ulcer pus yielded no microorganisms. A biopsy of the skin lesion revealed a severe infiltration of neutrophils in the dermis, without any evidence of infection. The lesion was finally diagnosed as PG, and systemic administration of corticosteroid hormone was started in December 2001. The patient was initially pulsed with 1 g methylprednisolone daily for 3 days. The dose was immediately reduced, and the treatment was maintained with 30 mg prednisolone daily. The skin lesion responded markedly to the therapy, and C-reactive protein became negative. The patient was discharged in February 2002 because the lesion was almost cured. Prednisolone administration was tapered after 6-month maintenance therapy. No recurrence of PG was seen, although his MDS transformed into leukemia in April 2003. Only 31 cases of MDS developing PG have been reported in the past 20 years in Japan. This report describes one such rare patient who was successfully treated with the use of high-dose pulse methylprednisolone and long-term maintenance therapy.
Assuntos
Síndromes Mielodisplásicas , Pioderma Gangrenoso/diagnóstico , Diagnóstico Diferencial , Humanos , Masculino , Metilprednisolona/administração & dosagem , Pessoa de Meia-Idade , Pescoço , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/patologia , Úlcera Cutânea/diagnóstico , Úlcera Cutânea/tratamento farmacológico , Úlcera Cutânea/patologiaRESUMO
Survivin, a unique member of the inhibitor of the apoptosis protein (IAPs) family, is over-expressed in many cancers but not in normal differentiated adult tissues. Using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we investigated patterns of survivin gene expression in a group of 12 patients with chronic myeloid leukemia (CML) representing both chronic and blastic phases of the disease. All 6 patients in chronic phase CML were uniformly negative for the survivin transcript, in contrast to 4 Philadelphia chromosome-positive (Ph+) CML patients in blastic crisis, all of whom (100%) were positive for survivin with tangible levels of expression. However, survivin expression was markedly down-regulated in 2 atypical CML patients with Philadelphia chromosome-negative (Ph-) blastic crisis. Our data indicates that up-regulation of survivin expression may be involved in typical CML evolution from the chronic into the blastic phase of the disease.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Proteínas Associadas aos Microtúbulos/biossíntese , Apoptose/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Células HL-60 , Humanos , Proteínas Inibidoras de Apoptose , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias , Cromossomo Filadélfia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , SurvivinaRESUMO
We have sought to clarify the potential activity of the S-phase-specific antileukemic agent 1-beta-D-arabinofuranosylcytosine (ara-C), an inhibitor of DNA synthesis, in quiescent cells that are substantially non-sensitive to nucleoside analogues. It was hypothesized that the combination of ara-C with DNA damaging agents that initiate DNA repair will expand ara-C cytotoxicity to non-cycling cells. The repair kinetics, which included incision of damaged DNA, gap-filling by DNA synthesis and rejoining by ligation, were evaluated using the single cell gel electrophoresis (Comet) assay and the thymidine incorporation assay. When normal lymphocytes were treated with ultraviolet C or with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), the processes of DNA excision repair were promptly initiated and rapidly completed. When the cells were incubated with ara-C prior to irradiation or BCNU treatment, the steps of DNA synthesis and rejoining in the repair processes were both inhibited. The ara-C-mediated inhibition of the repair processes was concentration-dependent, with the effect peaking at 10 microM. The combination of ara-C with these DNA repair initiators exerted subsequent cytotoxicity, which was proportional to the extent of the repair inhibition in the presence of ara-C. In conclusion, ara-C was cytotoxic in quiescent cells undergoing DNA repair. This might be attributed to unrepaired DNA damage that remained in the cells, thereby inducing lethal cytotoxicity. Alternatively, ara-C might exert its own cytotoxicity by inhibiting DNA synthesis in the repair processes. Such a strategy may be effective against a dormant subpopulation in acute leukemia that survives chemotherapy.