RESUMO
INTRODUCTION: International guidelines support the use of low molecular weight heparins for the treatment of thromboembolism and thromboprophylaxis during pregnancy. However, evidence of the benefit and harm associated with specific low molecular weight heparins such as enoxaparin is dated. No current systematic review and meta-analysis describing the safety and efficacy of enoxaparin for thromboembolism and thromboprophylaxis during pregnancy exists. METHODS: PubMed, Embase, and Cochrane databases were searched on August 17, 2018 for clinical trials or observational studies in pregnant women receiving enoxaparin; patients with a prosthetic heart valve were excluded. Risk ratios (RR) with 95% confidence intervals (CI) were calculated using a random effects model, and heterogeneity was measured using the I2 statistic. RESULTS: Of the 485 records identified in the search, 24 studies published clinical trials, and observational studies were found dating back to 2000. Only one observational cohort and one randomized control trial focused on the use of enoxaparin for thromboprophylaxis and therefore efficacy was not assessed; the other studies included women with recurrent pregnancy loss (15 studies), history of placental vascular complications (five studies), and recurrent in vitro fertilization failure (two studies) and were therefore analyzed in terms of safety only. Bleeding events were non-significantly more often reported for enoxaparin compared to untreated controls (RR 1.35 [0.88-2.07]) but less often reported for enoxaparin versus aspirin (RR 0.93 [0.62-1.39]); thromboembolic events, thrombocytopenia, and teratogenicity were rarely reported events; in patients with a history of recurrent pregnancy loss, encouragingly the rates of pregnancy loss were significantly lower for enoxaparin compared to untreated controls (RR 0.58 [0.34-0.96]) and enoxaparin + aspirin versus aspirin alone (RR 0.42 [0.32-0.56]) as well as observably lower for enoxaparin versus aspirin alone (RR 0.39 [0.15-1.01]), though significant heterogeneity was observed (I2 > 60). CONCLUSION: Literature on the efficacy and safety of enoxaparin for thromboembolism and thromboprophylaxis remains scanty, and therefore efficacy was not assessed; in terms of safety, when including other indications for enoxaparin in pregnancy, we found that enoxaparin was associated with significantly lower complications than aspirin. Given differences in study design and study heterogeneity, pregnancy loss results should be interpreted with caution. Moreover, reports of thromboembolic events, thrombocytopenia, and congenital malformations were rare. FUNDING: Sanofi.
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Anticoagulantes/uso terapêutico , Enoxaparina/uso terapêutico , Complicações na Gravidez/epidemiologia , Tromboembolia Venosa/prevenção & controle , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Aspirina/uso terapêutico , Enoxaparina/administração & dosagem , Enoxaparina/efeitos adversos , Feminino , Hemorragia/induzido quimicamente , Humanos , Gravidez , Resultado da Gravidez/epidemiologiaRESUMO
This study applied multi-faceted Rasch measurement to examine rater bias in the assessment of essays written by college students learning English as a foreign language. Four raters who had received different academic training from four distinctive disciplines applied a six-category rating scale to analytically rate essays on an argumentative topic and on a descriptive topic. FACETS, a Rasch computer program, was utilized to pinpoint bias patterns by analyzing the rater-topic, rater-category, and topic-category interactions. Results showed: argumentative essays were rated more severely than were descriptive essays; the linguistics-major rater was the most lenient rater, while the literature-major rater was the severest one; and the category of language use received the severest ratings, whereas content was given the most lenient ratings. The severity hierarchies for raters, essay topics, and rating categories suggested that raters' academic training and their perceptions of the importance of categories were associated with their bias patterns. Implications for rater training are discussed.
Assuntos
Multilinguismo , Variações Dependentes do Observador , Psicometria/estatística & dados numéricos , Estudantes/psicologia , Redação , Comparação Transcultural , Docentes , Humanos , Literatura , TaiwanRESUMO
A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Adulto JovemRESUMO
We analyzed the association between achievement of early complete cytogenetic response (CCyR) and event-free survival (EFS) and overall survival (OS) in patients with newly diagnosed chronic myeloid leukemia in chronic phase treated with imatinib 400 mg (n = 73), or imatinib 800 mg daily (n = 208), or second- generation tyrosine kinase inhibitors (n = 154). The overall CCyR rates were 87%, 91%, and 96%, respectively (P = .06); and major molecular response (MMR) rates were 77%, 87%, and 89%, respectively (P = .05). Their 3-year EFS rates were 85%, 92%, and 97% (P = .01), and OS rates were 93%, 97%, and 100% (P = .18), respectively. By landmark analysis, patients with 3-, 6-, and 12-month CCyR had significantly better outcome: 3-year EFS rates of 98%, 97%, and 98% and OS rates of 99%, 99%, and 99%, respectively, compared with 83%, 72%, and 67% and 95%, 90%, and 94%, in patients who did not achieve a CCyR. Among patients achieving CCyR at 12 months, the depth of molecular response was not associated with differences in OS or EFS. In conclusion, second tyrosine kinase inhibitors induced higher rates of CCyR and MMR than imatinib. The achievement of early CCyR remains a major determinant of chronic myeloid leukemia outcome regardless of whether MMR is achieved or not.
Assuntos
Leucemia Mieloide de Fase Crônica/diagnóstico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Análise Citogenética , Humanos , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: Many patients with chronic myeloid leukemia who have failed initial therapy with a tyrosine kinase inhibitor achieve a cytogenetic response that is not complete (ie, partial or minor). This study analyzes the clinical benefit of such responses and identifies value in achieving such responses. Patients with less than complete cytogenetic response to second -line therapy or beyond should be considered to have benefit from therapy and the value of this considered in the context of which alternative options are available. BACKGROUND: Complete cytogenetic response (CCyR) is the gold standard for response to therapy for patients with chronic myeloid leukemia (CML) because it is associated with a survival benefit. However, patients who have failed initial therapy with a tyrosine kinase inhibitor (TKI) frequently achieve only partial or minor cytogenetic responses. The clinical benefit of such responses is unclear. PATIENTS AND METHODS: We analyzed the records of all 165 consecutive patients treated in clinical trials with TKI as second-line therapy or beyond after failure to prior imatinib therapy. RESULTS: A CCyR was achieved with second-line TKI therapy or beyond in 52% of patients, whereas 7% achieved a partial cytogenetic response (PCyR), 14% a minor cytogenetic response (mCyR), 14% complete hematologic response (CHR) only, and 17% no response. The 3-year survival probability was 98% for those with CCyR, compared to 83% with PCyR, 83% for mCyR, 76% for CHR, and 71% for no response. Survival free from transformation rates at 3 years were 93%, 73%, 84%, 88%, and 0%, respectively. CONCLUSIONS: CCyR is associated with the greatest survival benefit among patients treated with second-line therapy or beyond and remains the optimal cytogenetic goal of therapy. However, patients with partial and minor cytogenetic response derive a benefit compared to patients who have no response. This benefit should be recognized and evaluated against any alternative option available to a given patient before a change in therapy is recommended.
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Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Aberrações Cromossômicas/efeitos dos fármacos , Bandeamento Cromossômico , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Different definitions of progression-free survival (PFS) and event-free survival (EFS) may result in perceived differences in outcomes with tyrosine kinase inhibitor (TKI) therapies in chronic myelogenous leukemia (CML). PATIENTS AND METHODS: We analyzed the outcome of 435 patients with early chronic-phase, Philadelphia chromosome-positive CML treated with imatinib (n = 281), nilotinib (n = 78), and dasatinib (n = 76) using definitions of PFS and EFS used in the International Randomized Study of Interferon Versus STI571 (IRIS), Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENEST-nd), Dasatinib Versus Imatinib Study in Treatment-Naïve CML Patients (DASISION), and MD Anderson Cancer Center (MDACC) trials. Definitions for EFS-IRIS, time without progression in ENEST-nd, PFS-DASISION, and EFS-MDACC were as previously reported. The EFS-MDACC considered an event any instance of toxicity or death from any cause on or off therapy (if not counted before death as progression/event). RESULTS: Of the 435 patients, 123 (28%) were taken off TKI therapy (resistance/loss of response, n = 33; blastic phase on TKI therapy, n = 6; intolerance/toxicity, n = 29; other causes, n = 55). Thirty-three patients (7.6%) have died; eight patients died on TKI therapy, two patients died within 60 days of being off TKIs, and 23 patients died after being off TKIs for more than 60 days. Of the 33 deaths, 19 deaths (eight deaths on TKI, two deaths within 60 days, and nine deaths off for resistance/relapse/transformation) would be counted as progression/events on the IRIS/ENEST-nd/DASISION studies, whereas 14 deaths would be censored at time off TKI. On the basis of the four definitions used by IRIS, ENEST-nd, DASISION, and MDACC trials, the corresponding 5-year PFS/EFS rates were 96%, 90%, 89%, and 81%. CONCLUSION: Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML.
Assuntos
Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Oncologia/normas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Dasatinibe , Feminino , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiazóis/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Most patients with chronic myelogenous leukemia (CML) harbor residual disease, as evidenced by molecular techniques even after treatment with high-dose imatinib (ie, 800 mg/d). Interferon alpha (IFN α) is efficacious in CML likely due to its immunomodulatory properties, and is synergistic in vitro with imatinib and granulocyte macrophage-colony stimulating factor (GM-CSF). METHODS: A study was undertaken to determine whether adding pegylated (PEG) IFN α-2b and GM-CSF to high-dose imatinib may improve the complete molecular response rate in patients with CML in chronic phase. Ninety-four patients were treated with imatinib 800 mg/d for the first 6 months, then randomly assigned to continue high-dose imatinib alone (n = 49) or in combination with PEG IFN α-2b 0.5 µg/kg/wk and GM-CSF 125 mg/m² 3× weekly (n = 45). RESULTS: The median follow-up for all patients was 54 months (range, 7-70 months). There were no differences in the rates of complete cytogenetic response (87% vs 90%; P = 1.0), or of major (77% vs 77%; P = 1.0) or complete (11% vs 13%; P = 1.0) molecular response (on the international scale) at 12 months between the 2 arms, or at any time during the study. Adverse events led to PEG IFN α-2b discontinuation in all patients. CONCLUSIONS: The addition of PEG IFN α-2b and GM-CSF to high-dose imatinib therapy does not improve significantly the cytogenetic or molecular response rates compared with high-dose imatinib alone. The high dropout rate in the PEG IFN α-2b arm may have compromised its potential immunomodulatory benefit.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Interferon-alfa/administração & dosagem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Piperazinas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Esquema de Medicação , Feminino , Humanos , Mesilato de Imatinib , Interferon alfa-2 , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Pacientes Desistentes do Tratamento , Proteínas RecombinantesRESUMO
We assessed the predictive factors for outcome and response in 123 patients with chronic myeloid leukemia in chronic phase treated with second-generation tyrosine kinase inhibitors (TKIs) after imatinib failure. Better event-free survival rates with second-generation TKI therapy were associated with a previous cytogenetic response to imatinib (P < .001) and a performance status of 0 (P = .001). Patients with 0, 1, or 2 adverse factors had 2-year event-free survival rates of 78%, 49%, and 20% (P < .001), respectively; 2-year overall survival rates of 95%, 85%, and 40%, (P = .002), respectively; and a 12-month probability of achieving a major cytogenetic response of 64%, 36%, and 20% (P = .007), respectively. In conclusion, patients with poor performance status and no previous cytogenetic response to imatinib therapy have a low likelihood of responding to second-generation TKI with poor event-free survival and therefore should be offered additional treatment options. This scoring system could serve to advise patients of their prognosis and treatment options, as well as to evaluate the benefit of newer alternate options.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Análise Citogenética , Dasatinibe , Intervalo Livre de Doença , Feminino , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mieloide de Fase Crônica/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Tiazóis/uso terapêutico , Falha de Tratamento , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known. METHODS: Data from 87 patients with MDS (n=67) and chronic myelomonocytic leukemia (n=.20) after failure of decitabine regimens were reviewed. RESULTS: After a median follow-up of 21 months from decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12-month survival rate was 28%. The estimated 12-month survival rates were 27%, 33%, and 33%, respectively, for patients with high-risk, intermediate-2-risk, and intermediate-1-risk disease (P=.99) by the International Prognostic Scoring System. The estimated 12-month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P=.01). CONCLUSIONS: The outcome of patients after decitabine failure is poor and appears to be predictable after decitabine failure.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Azacitidina/uso terapêutico , Decitabina , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Falha de Tratamento , Resultado do TratamentoRESUMO
We assessed the long-term efficacy of imatinib dose escalation in 84 patients with chronic myeloid leukemia in chronic phase who met the criteria of failure to standard-dose imatinib. Twenty-one patients with hematologic failure and 63 with cytogenetic failure had their imatinib dose escalated from 400 to 800 mg daily (n = 72) or from 300 to 600 mg daily (n = 12). After a median follow-up of 61 months from dose escalation, 69% remained alive. Complete cytogenetic responses were achieved in 40%; including 52% of patients with cytogenetic failure and 5% of those with hematologic failure. The estimated 2- and 3-year event-free survival and overall survival rates were 57% and 47%, and 84% and 76%, respectively. Responses were long-lasting; 88% of patients with major cytogenetic response sustained their response beyond 2 years. Treatment was well tolerated, with 76% of patients, at 12 months, continuing to receive imatinib at 100% of the intended dose. In conclusion, imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic failure and a previous cytogenetic response to standard-dose imatinib.
Assuntos
Antineoplásicos/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Piperazinas/efeitos adversos , Prognóstico , Pirimidinas/efeitos adversos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resultado do TratamentoRESUMO
To determine when patients with incomplete responses on second-line tyrosine kinase inhibitor (2TKI) therapy should consider alternative treatment, we analyzed the outcome of 113 patients receiving nilotinib (n = 43) or dasatinib (n = 70) after imatinib failure. After 12 months of 2TKI therapy, patients achieving a major cytogenetic response (12MMCyR) had a significant survival advantage over patients in minor cytogenetic response or complete hematologic response, with a projected one-year survival of 97% and 84% respectively (P = .02). Projected 1-year progression to hematologic failure, accelerated phase, or blast phase was also significantly different (3% vs 17%, P = .003). Early cytogenetic response was strongly predictive of achievement of 12MMCyR, with less than 10% of patients showing no cytogenetic response at 3 to 6 months eventually attaining the target of 12MMCyR. These results suggest that patients receiving 2TKI with no cytogenetic response at 3 to 6 months should be considered for alternative therapies.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Pirimidinas/administração & dosagem , Tiazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Análise Citogenética , Dasatinibe , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Pessoa de Meia-Idade , Piperazinas , Inibidores de Proteínas Quinases/uso terapêutico , Indução de Remissão , Análise de Sobrevida , Falha de TratamentoRESUMO
BACKGROUND: Topoisomerase I inhibitors, like topotecan, have activity in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). 9-Nitro-camptothecin (9-NC) is a new oral topoisomerase inhibitor with a good safety profile. The aims of the current study were to evaluate the activity and safety of 9-NC in MDS and CMML. METHODS: Adults with a diagnosis of MDS (n = 12) and CMML (n = 32) received 9-NC 2 mg/m(2) orally daily 5 days a week, every 4 to 6 weeks. RESULTS: Overall, 5 (11%) patients achieved complete response (CR), 7 (16%) had a partial response (PR), and 6 (14%) had hematologic improvement (HI), for an overall response rate of 41%. The response rate was similar in MDS and CMML. Severe (Grade 3-4) side effects included nausea and vomiting (7%), diarrhea (18%), other gastrointestinal toxicities (5%), and genitourinary toxicities (12%). CONCLUSIONS: 9-NC is active in MDS and CMML. The paucity of available therapies in CMML makes 9-NC a good candidate for further studies as a single agent, or in combination with decitabine, 5-azacitidine or cytarabine.
Assuntos
Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Inibidores da Topoisomerase I , Administração Oral , Adulto , Idoso , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Desacetyl alpha-MSH predominates over alpha-MSH during development, but whether it is biologically active and has a physiological role is unclear. We compared the effects of 0.3 microg.g(-1).day(-1) desacetyl alpha-MSH with that of 0.3 microg.g(-1).day(-1) alpha-MSH on postnatal body growth by administering the peptides subcutaneously daily for postnatal days 0-14 and also used a two-dimensional gel electrophoresis gel-based proteomic approach to analyze protein changes in hypothalami, the relay center for body weight and growth regulation, after 14 days of treatment. We found that the growth rate between days 1 and 10 was significantly decreased by desacetyl alpha-MSH but not by alpha-MSH, but by day 14, a time reported for development of a mature pattern of hypothalamic innervation, both peptides had significantly increased neonatal growth compared with PBS-treated control rats. Desacetyl alpha-MSH significantly increased spleen weight, but alpha-MSH had no effect. alpha-MSH significantly decreased kidney weight, but desacetyl alpha-MSH had no effect. Both desacetyl alpha-MSH and alpha-MSH significantly decreased brain weight. By 14 days, both peptides significantly changed expression of a number of hypothalamic proteins, specifically metabolic enzymes, cytoskeleton, signaling, and stress response proteins. We show that peripherally administered desacetyl alpha-MSH is biologically active and induces responses that can differ from those for alpha-MSH. In conclusion, desacetyl alpha-MSH appears to be an important regulator of neonatal rat growth.
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Crescimento/efeitos dos fármacos , Hipotálamo/metabolismo , Proteínas do Tecido Nervoso/biossíntese , alfa-MSH/farmacologia , Animais , Animais Recém-Nascidos , Peso Corporal/efeitos dos fármacos , Cromatografia Líquida , Eletroforese em Gel de Poliacrilamida , Hipotálamo/efeitos dos fármacos , Injeções Subcutâneas , Espectrometria de Massas , Tamanho do Órgão/efeitos dos fármacos , RatosRESUMO
BACKGROUND: Several staging classification systems, all of which were designed in the preimatinib era, are used for chronic myeloid leukemia (CML). The World Health Organization (WHO) recently proposed a new classification system that has not been validated clinically. The authors investigated the significance of the WHO classification system and compared it with the classification systems used to date in imatinib trials ("standard definition") to determine its impact in establishing the outcome of patients after therapy with imatinib. METHODS: In total, 809 patients who received imatinib for CML were classified into chronic phase (CP), accelerated phase (AP), and blast phase (BP) based on standard definitions and then were reclassified according to the new WHO classification system. Their outcomes with imatinib therapy were compared, and the value of individual components of these classification systems was determined. RESULTS: With the WHO classification, 78 patients (10%) were reclassified: 45 patients (6%) were reclassified from CP to AP, 14 patients (2%) were reclassified from AP to CP, and 19 patients (2%) were reclassified from AP to BP. The rates of complete cytogenetic response for patients in CP, AP, and BP according to the standard definition were 72%, 45%, and 8%, respectively. After these patients were reclassified according to WHO criteria, the response rates were 77% (P = 0.07), 39% (P = 0.28), and 11% (P = 0.61), respectively. The 3-year survival rates were 91%, 65%, and 10%, respectively, according to the standard classification and 95% (P = 0.05), 63% (P = 0.76), and 16% (P = 0.18), respectively, according to the WHO classification. Patients who had a blast percentage of 20-29%, which is considered CML-BP according to the WHO classification, had a significantly better response rate (21% vs. 8%; P = 0.11) and 3-year survival rate (42% vs. 10%; P = 0.0001) compared with patients who had blasts > or = 30%. CONCLUSIONS: Different classification systems had an impact on the outcome of patients, and some prognostic features had different prognostic implications in the imatinib era. The authors believe that a new, uniform staging system for CML is warranted, and they propose such a system.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/classificação , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Organização Mundial da SaúdeRESUMO
PURPOSE: To determine the clinical significance of molecular response and relapse among patients with chronic myelogenous leukemia (CML) treated with imatinib. EXPERIMENTAL DESIGN: We analyzed the results of quantitative PCR in 280 patients with CML in chronic phase who achieved complete cytogenetic remission with imatinib (117 after IFN-alpha failure and 163 previously untreated). Median follow-up was 31 months (range, 3-52 months). RESULTS: Median BCR-ABL/ABL ratio before the start of therapy was 39.44 (range, 0.252-170.53). A major molecular response (BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%), and transcripts became undetectable (complete molecular response) in 95 (34%). By multivariate analysis, only treatment with high-dose imatinib (P = 0.02) was associated with achievement of a major molecular response. Nine of 166 (5%) patients who achieved a major molecular response lost their cytogenetic remission, compared with 25 of 68 (37%) among those who did not achieve this response (P < 0.0001). Patients achieving a major molecular response 12 months after the start of therapy had significantly better complete cytogenetic remission duration than others. A >1-log reduction in transcript levels after 3 months of therapy predicted for an improved probability of achieving a major molecular response at 24 months. Increasing levels of BCR-ABL transcripts predicted for a loss of cytogenetic remission only among patients who did not achieve a major molecular response. CONCLUSIONS: Achieving a major molecular response, particularly within the first year of therapy, is predictive of a durable cytogenetic remission and may be the future goal of therapy in CML.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas , Criança , Pré-Escolar , Aberrações Cromossômicas/efeitos dos fármacos , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Pessoa de Meia-Idade , Prognóstico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/genética , Indução de Remissão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Resultado do TratamentoRESUMO
The functional significance of N-terminal acetylation of ACTH[1-13]NH(2) is unknown. N-terminal acetylation of ACTH[1-13]NH(2) (known as desacetyl-alpha-MSH) to produce alpha-MSH enhances some activities of ACTH[1-13]NH(2) and virtually eliminates others. To determine whether alpha-MSH and desacetyl-alpha-MSH diverge in their coupling to melanocortin receptors in vitro, we measured the sensitivity of MC1, MC3, MC4, and MC5 receptors stably expressed in HEK293 cells to these peptides, functionally coupling them to adenylyl cyclase and a calcium signaling pathway. alpha-MSH and desacetyl-alpha-MSH similarly coupled these overexpressed receptors to both signaling pathways. In contrast, we discovered that alpha-MSH significantly increased primary rat osteoblast proliferation while for desacetyl-alpha-MSH there was only a trend to do the same. Osteoblast cells expressing very low levels of endogenous melanocortin receptors, in contrast with transfected HEK293 cells overexpressing a single melanocortin receptor, may provide an in vitro model for differentiating between alpha-MSH and desacetyl-alpha-MSH signaling.
Assuntos
Fragmentos de Peptídeos/metabolismo , Receptores da Corticotropina/metabolismo , Transdução de Sinais/fisiologia , alfa-MSH/análogos & derivados , alfa-MSH/metabolismo , Adenilil Ciclases/metabolismo , Proteína Relacionada com Agouti , Animais , Cálcio/metabolismo , Linhagem Celular , Ingestão de Alimentos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Osteoblastos/metabolismo , Pigmentação/fisiologia , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Proteínas/metabolismo , Receptores da Corticotropina/química , Receptores de MelanocortinaRESUMO
We treated 261 patients with Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML) in chronic phase after failure of IFN-alpha with the Bcr-Abl tyrosine kinase inhibitor imatinib mesylate (400 mg/day given p.o.) and analyzed hematological and cytogenetic responses, long-term prognosis, factors associated with achievement of major cytogenetic response and survival, and comparative survival in similar patients treated with other regimens. Median patient age was 55 years; 34% were 60 years or older, and median chronic-phase duration was 33 months. Overall, 94% achieved a complete hematological response, and 71% had a cytogenetic response [major (Ph+ cells <35%) in 62% and complete in 45%]. At a median follow-up of 17 months, 241 patients (92%) were still taking imatinib mesylate; estimated 18-month freedom from progression and survival rates were 93 and 96%. Multivariate analysis of factors associated with major cytogenetic response identified long chronic phase, marrow basophilia, high percentage of Ph+ cells before therapy, and prior hematological resistance to IFN-alpha as being adverse factors. This model was used to generate good-, intermediate- and poor-risk subgroups who had estimated major cytogenetic response rates of 93, 53, and 34%, respectively. Univariate analysis in terms of survival identified leukocytosis, high percentages of peripheral and marrow blasts, marrow basophilia, and the presence of cytogenetic clonal evolution as being adverse factors. Achieving a cytogenetic response at 3 or 6 months of therapy was associated with prolonged survival. In a subset analysis, survival rates among 161 patients with Ph-positive CML after hematological or cytogenetic failure after IFN-alpha who had been treated with imatinib mesylate were better than those for similar patients treated previously with other regimens. In summary, imatinib mesylate is highly effective in chronic-phase CML after IFN-alpha failure. We identified pretreatment and treatment-associated factors that were associated with higher major cytogenetic response rates and with improved survival.