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Background: A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL. Patients and methods: A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort. Results: Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42-0.79, P = 0.032). Conclusion: Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.
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AIM: This study aimed to evaluate the safety and efficacy of 131 I-rituximab in patients with relapsed or refractory follicular or mantle cell lymphoma. METHODS: Twenty-four patients with relapsed or refractory follicular or mantle cell lymphoma were administered unlabeled rituximab (70 mg) immediately before receiving a therapeutic dose of 131 I-rituximab. Contrast-enhanced 18F-fluorodeoxyglucose positron emission tomography/computed tomography was used a month later to assess tumor response. RESULTS: This study enrolled 24 patients between June 2012 and 2022. Depending on how they responded to radioimmunotherapy (RIT), 131 I-rituximab was administered one to five times. Of the 24 patients, 9 achieved complete response after RIT and 8 achieved partial response. The median progression-free and overall survival was 5.9 and 37.9 months, respectively. During the follow-up period of 64.2 months, three patients were diagnosed with a secondary malignancy. Among treatment-related adverse events, hematologic toxicities were common, and grade 3-4 thrombocytopenia and neutropenia were reported in 66.6% of cases. CONCLUSION: 131 I-rituximab has an effective and favorable safety profile in patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma. This suggests that RIT may also be considered a treatment option for patients with relapsed or refractory follicular lymphoma and mantle cell lymphoma.
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Linfoma Folicular , Linfoma de Células del Manto , Humanos , Adulto , Rituximab/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/radioterapia , Linfoma de Células del Manto/etiología , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/radioterapia , Radioinmunoterapia/efectos adversos , Radioinmunoterapia/métodos , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: This phase II, open-label, multicenter study aimed to investigate the efficacy and safety of a rituximab intensification for the 1st cycle with every 21-day of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP-21) among patients with previously untreated advanced-stage or bulky diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: Ninety-two patients with stage III/IV or bulky DLBCL from 21 institutions were administered 8 cycles of R-CHOP-21 with an additional one dose of rituximab intensification on day 0 of the 1st cycle (RR-CHOP). The primary endpoint was a complete response (CR) rate after 3 cycles of chemotherapy. RESULTS: Among the 92 DLBCL patients assessed herein, the response rate after 3 cycles of chemotherapy was 88.0% (38.0% CR+50.0% partial response [PR]). After the completion of 8 cycles of chemotherapy, the overall response rate was observed for 68.4% (58.7% CR+9.8% PR). The 3-year progression-free survival rate was 64.0%, and the 3-year overall survival rate was 70.4%. Febrile neutropenia was one of the most frequent ï³grade 3 adverse events (40.0%) and 5 treatment-related deaths occurred. Compared with the clinical outcomes of patients who received R-CHOP chemotherapy as a historical control, the interim CR rate was higher in male patients with RR-CHOP (20.5% vs. 48.8%, p=0.016). CONCLUSION: Rituximab intensification on days 0 to the 1st cycle of the standard 8 cycles R-CHOP-21 for advanced DLBCL yielded favorable response rates after the 3 cycles of chemotherapy and acceptable toxicities, especially for male patients. ClinicalTrials.gov ID: NCT01054781.
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Linfoma de Células B Grandes Difuso , Prednisolona , Humanos , Masculino , Rituximab/uso terapéutico , Vincristina , Prednisolona/efectos adversos , Ciclofosfamida , Doxorrubicina , Linfoma de Células B Grandes Difuso/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del TratamientoRESUMEN
Background: Nilotinib is a tyrosine kinase inhibitor approved by the Ministry of Food and Drug Safety for frontline and 2nd line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML). This study aimed to confirm the safety and efficacy of nilotinib in routine clinical practice within South Korea. Methods: An open-label, multicenter, single-arm, 12-week observational post-marketing surveillance (PMS) study was conducted on 669 Korean adult patients with Ph+ CML from December 24, 2010, to December 23, 2016. The patients received nilotinib treatment in routine clinical practice settings. Safety was evaluated by all types of adverse events (AEs) during the study period, and efficacy was evaluated by the complete hematological response (CHR) and cytogenetic response. Results: During the study period, AEs occurred in 61.3% (410 patients, 973 events), adverse drug reactions (ADRs) in 40.5% (271/669 patients, 559 events), serious AEs in 4.5% (30 patients, 37 events), and serious ADRs in 0.7% (5 patients, 8 events). Furthermore, unexpected AEs occurred at a rate of 6.9% (46 patients, 55 events) and unexpected ADRs at 1.2% (8 patients, 8 events). As for the efficacy results, CHR was achieved in 89.5% (442/494 patients), and minor cytogenetic response or major cytogenetic response was achieved in 85.8% (139/162 patients). Conclusion: This PMS study shows consistent results in terms of safety and efficacy compared with previous studies. Nilotinib was well tolerated and efficacious in adult Korean patients with Ph+ CML in routine clinical practice settings.
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In the phase 3 study RERISE, patients with newly diagnosed chronic myeloid leukaemia in chronic phase demonstrated significantly faster and higher rates of major molecular response (MMR) with twice-daily radotinib 300 mg (n = 79) or 400 mg (n = 81) than with once-daily imatinib 400 mg (n = 81) after 12 months. With ≥48 months' follow-up, MMR was higher with radotinib 300 mg (86%) or 400 mg (83%) than with imatinib (75%). Among patients with BCR-ABL1 ≤ 10% at three months, MMR and molecular response 4·5 (MR4·5 ) were achieved within 48 months by more radotinib-treated patients (300 mg: 84% and 52%, respectively; 400 mg: 74% and 44%, respectively) than imatinib-treated patients (71% and 44%, respectively). Estimated overall and progression-free survival rates at 48 months were not significantly different between imatinib (94% and 94%, respectively) and radotinib 300 mg (99% and 97%, respectively) or 400 mg (95% and 93%, respectively). The treatment failure rate was significantly higher with imatinib (19%) than with radotinib 300 mg (6%; P = 0·0197) or 400 mg (5%; P = 0·0072). Safety profiles were consistent with previous reports; most adverse events occurred within 12 months. Radotinib continues to demonstrate robust, deep molecular responses, suggesting that treatment-free remission may be attainable.
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Antineoplásicos/uso terapéutico , Benzamidas/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/complicaciones , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirazinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Benzamidas/farmacología , Femenino , Humanos , Mesilato de Imatinib/farmacología , Masculino , Persona de Mediana Edad , Pirazinas/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
The aim of this study was to investigate the efficacy of nilotinib (NIL) versus high-dose imatinib (IM) versus sustained standard-dose IM for patients with chronic myeloid leukemia (CML) with suboptimal molecular response to first-line IM therapy. Patients with CML who achieved complete cytogenetic response (CCyR) but not major molecular response (MMR) after 18-24 months on first-line IM therapy were enrolled and divided into three treatment cohorts: NIL 800â¯mg/day (Cohort 1, nâ¯=â¯28) and IM 800â¯mg/day (Cohort 2, nâ¯=â¯28) in the RE-NICE study, and sustained IM 400â¯mg/day (Cohort 3, nâ¯=â¯52) in clinical practice. The primary efficacy variable of cumulative rate of MMR by 12 months was not different among the three cohorts. However, the cumulative incidence of MMR by 36 months was significantly higher in Cohort 1 than Cohort 3 (83.1% vs. 57.1%, Pâ¯=â¯0.021), but there were no significant differences in Cohort 1 vs. 2 (Pâ¯=â¯0.195) and Cohort 2 vs. 3 (Pâ¯=â¯0.297). Different profile for adverse events was observed between NIL and high-dose IM therapy. In conclusion, our data suggested that switching to NIL may provide more effective long-term response than sustaining standard-dose IM for patients with suboptimal molecular response to first-line IM.
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Antineoplásicos/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adolescente , Adulto , Anciano , Biomarcadores de Tumor , Análisis Citogenético , Femenino , Humanos , Leucemia Mieloide de Fase Crónica/diagnóstico , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Retratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.
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Benzamidas/administración & dosificación , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/efectos adversos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Peso Molecular , Pirazinas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Purpose: Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) approved in Korea for chronic phase chronic myeloid leukemia (CML-CP) in patients newly diagnosed or with insufficient response to other TKIs. This study was conducted to evaluate the efficacy and safety of radotinib as first-line therapy for CML-CP.Experimental Design: This multinational, open-label study assigned patients (1:1:1) to one of two twice-daily radotinib doses, or imatinib daily. The primary endpoint was major molecular response (MMR) by 12 months.Results: Two hundred forty-one patients were randomized to receive radotinib 300 mg (n = 79) or 400 mg twice-daily (n = 81), or imatinib 400 mg daily (n = 81). MMR rates by 12 months were higher in patients receiving radotinib 300 mg (52%) or radotinib 400 mg twice-daily (46%) versus imatinib (30%; P = 0.0044 and P = 0.0342, respectively). Complete cytogenetic response (CCyR) rates by 12 months were higher for radotinib 300 mg (91%) versus imatinib (77%; P = 0.0120). Early molecular response at 3 months occurred in 86% and 87% of patients receiving radotinib 300 mg and radotinib 400 mg, respectively, and 71% of those receiving imatinib. By 12 months, no patients had progression to accelerated phase or blast crisis. Most adverse events were manageable with dose reduction.Conclusions: Radotinib demonstrated superiority over imatinib in CCyR and MMR in patients newly diagnosed with Philadelphia chromosome-positive CML-CP. This trial was registered at www.clinicaltrials.gov as NCT01511289 Clin Cancer Res; 23(23); 7180-8. ©2017 AACR.
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Benzamidas/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Pirazinas/uso terapéutico , Adulto , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Esquema de Medicación , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/administración & dosificación , Mesilato de Imatinib/efectos adversos , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Inducción de Remisión , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
OBJECTIVES: MRI of bone marrow of the axial skeleton is recommended for evaluation of multiple myeloma. The impact of bone marrow involvement pattern on MRI for determining progression-free survival (PFS) and overall survival (OS) is not yet clear. METHODS: We performed a meta-analysis of research on the prognostic significance of MRI patterns for OS and PFS using a random effects model. Databases searched without language restriction were MEDLINE, EMBASE, and the Cochrane Library (January 1976 to April 2014). Manual searches were also conducted. RESULTS: Of 10,953 citations identified in the original search, 10 cohort studies for a total of 2015 patients met the inclusion criteria. Nine of the 10 included studies are from three research groups. Pooled hazard ratios were 1.80 (95 % confidence interval [CI] 1.32-2.46; P < 0.001) for OS and 2.30 (95 % CI 1.65-3.20; P < 0.001) for PFS for focal lesions on MRI; and 1.70 (95 % CI 1.30-2.21; P < 0.001) for OS and 1.74 (95 % CI 1.07-2.85; P = 0.03) for PFS for diffuse infiltration on MRI. No significant heterogeneity was observed among studies. CONCLUSIONS: This meta-analysis demonstrated an association between focal lesions and diffuse infiltration and poor prognosis in this population. KEY POINTS: ⢠MRI findings of multiple myeloma include normal, focal, variegated and diffuse infiltration ⢠Focal lesions and diffuse infiltration on MRI were poor prognostic factors ⢠Bone marrow involvement pattern on MRI can help physicians assess prognosis.
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Enfermedades de la Médula Ósea/patología , Mieloma Múltiple/patología , Anciano , Enfermedades de la Médula Ósea/mortalidad , Supervivencia sin Enfermedad , Humanos , Imagen por Resonancia Magnética , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
Complement-C1q/tumor necrosis factor-α related protein 1 (CTRP1) is a 35-kDa glycoprotein that is secreted from various tissues. Although CTRP1 is highly increased in patients with type II diabetes and obesity, the metabolic roles of CTRP1 remain largely unknown. To unveil the physiological roles of CTRP1 in vivo, CTRP1 transgenic (TG) mice were challenged by a high-fat diet (HFD) and a high-sucrose drink (HS). Homeostatic model assessment-estimated insulin resistance values were decreased in HFD- or HS-fed CTRP1 TG mice compared with wild-type control mice. In this context, CTRP1 stimulated glucose uptake through the glucose transporter GLUT4 translocation to the plasma membrane and also increased glucose consumption by stimulating glycolysis. To analyze the roles of CTRP1 in lipid metabolism, acetyl-CoA carboxylase (ACC) and hormone-sensitive lipase levels were determined in CTRP1 TG mice, and the effect of CTRP1 on fatty acid oxidation was assessed in C2C12 myotubes. CTRP1 was found to inhibit ACC by phosphorylation and to stimulate fatty acid oxidation in C2C12 myotubes. Taken together, CTRP1 performs active catabolic roles in vivo. Therefore, CTRP1 seems to perform a defensive function against nutritional challenges.
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Adipoquinas/fisiología , Dieta , Ácidos Grasos/metabolismo , Hiperglucemia/prevención & control , Células 3T3-L1 , Animales , Dieta Alta en Grasa , Metabolismo Energético , Glucólisis , Hiperglucemia/etiología , Ratones , Músculo Esquelético/metabolismo , Oxidación-ReducciónRESUMEN
A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient's body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45, p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259 versus 83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively.
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Antineoplásicos/farmacología , Benzamidas/farmacología , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Adulto , Anciano , Antineoplásicos/uso terapéutico , Pueblo Asiatico , Benzamidas/uso terapéutico , Superficie Corporal , Peso Corporal , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Resistencia a Antineoplásicos , Femenino , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
Recently, reactive thrombosis or platelet to lymphocyte ratio has been reported as a strong predictor of poor prognosis in various types of cancer. However, a study investigating the relationship between platelet counts and thrombopoietic cytokines suggested that low platelet could be important in multiple myeloma (MM), which means platelet count decreased in advanced International Staging System (ISS) stage. Therefore, we developed inverse platelet to lymphocyte ratio (iPLR) and assessed the prognostic value of iPLR in patients with MM. We retrospectively analyzed 283 patients who were treated up front with a novel agent-containing regimen. Patients were classified into three groups based on hazard ratio (HR) according to iPLR: low iPLR (group 1), middle iPLR (group 2), and high iPLR (group 3). Over a median follow-up of 34.8 months, staging by iPLR group had predictive value for progression-free survival (PFS) and overall survival (OS). In addition, staging by iPLR group was a reliable method to predict for survival in patients who presented with renal failure (eGFR<60 mL/min/1.73 m2) and in elderly patients. Multivariate analyses demonstrated that staging by iPLR group was associated with PFS and OS in patients with MM. In conclusion, this study suggested that iPLR is a simple and reliable inflammatory prognostic factor in the era of novel agents.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Plaquetas/metabolismo , Linfocitos/metabolismo , Mieloma Múltiple/sangre , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Recuento de Plaquetas/métodos , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia/tendencias , Resultado del TratamientoRESUMEN
Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).
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Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Benzamidas/efectos adversos , Benzamidas/uso terapéutico , Femenino , Estudios de Seguimiento , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crónica/genética , Leucemia Mieloide de Fase Crónica/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazinas/efectos adversos , Pirazinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Inducción de Remisión , Resultado del Tratamiento , Adulto JovenRESUMEN
Substituted 2-pyrones are important structural sub-units present in a number of natural products having broad range of biological activity. However, little is known about the anti-cancer effect of 2-pyrone derivatives including leukemia. Therefore, this present study was undertaken to investigate the effect of 2-pyrone derivatives in human acute myeloid leukemia (AML). Among 23 synthesized derivatives, 5-bromo-3-(3-hydroxyprop-1-ynyl)-2H-pyran-2-one (code name; pyrone 9) showed the most potent antileukemic activity with 5 × 10(-6) M to 5 × 10(-5) M of IC(50) in various AML cell lines as well as primary leukemic blasts from AML patients, while normal peripheral blood mononuclear cells was not affected by pyrone 9. Flow cytometric analysis indicated that pyrone 9 induced the G1 and G2 phase dual arrest of the cell cycle in HL-60 cells. To address the mechanism of the antileukemic effect of pyrone 9, we examined the effect of pyrone 9 on cell cycle-related proteins in HL-60 cell. The levels of CDK2, CDK4, CDK6, CDK1, cyclin B1 and cyclin E were decreased; in contrast, cyclin A was not altered. In addition, pyrone 9 not only increased the p27 level but also enhanced its binding to with CDK2, CDK4 and CDK6 which resulted in the reduction of CDK2-, CDK4- and CDK6-associated kinase activities. Pyrone 9 also induced the apoptosis in HL-60 cells. The apoptotic process of HL-60 cells was associated with increased Bax, decreased Bcl-2 and activation of caspase-8, -9, -3 and PARP. Antileukemic effect of pyrone 9 was associated with activation of mitogen-activated protein kinase (MAPK) pathway, as evidenced by activation of p-ERK and p38 MAPK. In addition, pyrone 9 was influenced PI3 kinase pathway. Expressions of p-Akt (ser473), p-Raf, and p-PDK were down-regulated; in contrast, those of PTEN and p-PTEN were up-regulated. Furthermore, pyrone 9 suppressed NF-κB pathway signaling. To gain insights into the antileukemic activity of pyrone 9 in vivo, BALB/c mouse leukemic model was established using intraperitoneal inoculation of syngeneic WEHI-3BD(+) mouse leukemic cells. Pyrone 9 inhibited in vitro and in vivo the growth of WEHI-3BD(+) cells, and ultimately, prolonged the survival of pyrone 9-treated mice. These findings suggest that the pyrone 9 inhibits the cell proliferation of human AML cell line, HL-60, through MAPK and PI3 kinase pathway as well as induction of cell cycle arrest. In particular, pyrone 9 prolonged the survival of pyrone 9-treated leukemic mice.
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Antineoplásicos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Pironas/farmacología , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Células HL-60 , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Ratones , Ratones Endogámicos BALB C , Pironas/uso terapéuticoRESUMEN
Pure red cell aplasia is characterized as a normocytic anemia associated with reticulocytopenia and the absence of erythroblasts in the bone marrow. Pure red cell aplasia can be induced by various causes such as thymoma, connective tissue disease, viral infection, lymphoma, and adverse drug reactions. There have been only a few reports of pure red cell aplasia associated with acute viral hepatitis A. In Korea, no case of pure red cell aplasia caused by acute hepatitis A has yet been reported. We recently experienced a case of acute viral hepatitis A complicated by pure red cell aplasia. The patient was successfully treated with corticosteroids. Here we report this case and review the literature.
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BACKGROUND/AIMS: Stomach cancer can be easily diagnosed via endoscopy, but also possible to be missed. The aim of this study was to investigate the clinical and endoscopic characteristics of advanced gastric cancers that were not diagnosed based on endoscopic examination. METHODS: We evaluated patients who had newly diagnosed advanced gastric cancer that was undetected via endoscopy within the last six months. RESULTS: Sixteen patients were included in this study. The locations of the cancers were the cardia in six cases, the greater curvature side of the body in eight cases and the antrum in two cases. The histological findings were tubular type adenocarcinoma in 11 cases, with ten cases of moderately to poorly differentiated adenocarcinoma and five cases of signet ring cell type adenocarcinoma. CONCLUSIONS: Even advanced gastric cancer lesions may not be detected during endoscopy. If a patient continues to complain of upper gastrointestinal symptoms, even though endoscopy does not find abnormal findings, repeated endoscopy and/or additional diagnostic studies should be considered.
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Adenocarcinoma/diagnóstico , Neoplasias Gástricas/diagnóstico , Adenocarcinoma/patología , Adulto , Anciano , Cardias/patología , Errores Diagnósticos , Femenino , Gastroscopía , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Antro Pilórico/patología , Neoplasias Gástricas/patologíaRESUMEN
To investigate the correlation of trough imatinib mesylate (IM) levels with cytogenetic or molecular responses, we measured trough IM levels in patients with chronic myeloid leukemia, chronic phase (CML-CP), at 6 months of treatment with a standard dose of IM. Eighty-seven newly diagnosed patients with CML-CP were prospectively enrolled. Seventy-eight patients (89.7%) showed an optimal response (complete or partial cytogenetic response) at 6 months. Trough IM levels were 1378â±â725 ng/mL. When categorized into two groups, there was a statistically significant difference in numbers of patients with optimal and suboptimal responses at 6 months (group withâ <1000: 80.6% vs. 19.4%; â≥ 1000: 94.6% vs. 5.4%; pâ=â0.032), and in numbers of patients with early major molecular response (early-MMR) and without MMR at 6 months (group withâ <1000: 3.2% vs. 96.8%;â ≥ 1000: 21.4% vs. 78.6%; pâ=â0.047). In conclusion, the incidence of optimal cytogenetic response or early-MMR in patients with CML-CP treated with IM for 6 months was significantly higher in those with a trough level ofâ ≥ 1000 compared with those with a level ofâ<1000. Dose escalation of IM can be one option in patients with CML showing suboptimal response or resistance to the standard dose of IM, especially with low trough plasma IM levels (<1000 ng/mL).
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Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Leucemia Mieloide de Fase Crónica/genética , Piperazinas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Benzamidas , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib , Modelos Logísticos , Masculino , Neutropenia/inducido químicamente , Piperazinas/sangre , Piperazinas/farmacocinética , Estudios Prospectivos , Pirimidinas/sangre , Pirimidinas/farmacocinética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Trombocitopenia/inducido químicamente , Factores de Tiempo , Transcripción Genética/efectos de los fármacos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: We investigated response rates to and toxicities of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL). PATIENTS AND METHODS: Patients with recurrent or refractory diffuse large B-cell lymphoma or mantle cell lymphoma (DLBCL) were eligible for enrollment in this study. Treatment consisted of gemcitabine 1,000 mg/m(2) intravenously (i.v.) on Days 1 and 8, ifosfamide 2,000 mg/m(2) i.v. on Day 1, dexamethasone 40 mg orally on Days 1-4, and oxaliplatin 130 mg/m(2) i.v. on Day 2, every 21 days. The primary goal of treatment was to establish a response rate after three cycles. Afterwards, patients could proceed to high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) or receive up to six treatment cycles. RESULTS: Twenty-seven eligible patients were evaluated for toxicity and response. The median age of the patients was 54 years (range, 18-75 years), and most had DLBCL. After three cycles, there were four CR (15%) and 10 PR (37%) for an overall response rate (RR) of 52%. Among a total of 88 GIDOX cycles, grade 3 and 4 neutropenia occurred in 33% and 16% of the cycles, respectively. Likewise, grade 3 and 4 thrombocytopenia occurred in 14% and 16% of the cycles, respectively. Two patients (2%) experienced febrile neutropenia, while seven patients (26%) proceeded to HDC-ASCT. CONCLUSIONS: GIDOX is an active salvage regimen for aggressive B-cell NHL and can be tolerated by patients with acceptable toxicity.
Asunto(s)
Linfocitos B/patología , Desoxicitidina/análogos & derivados , Dexametasona/uso terapéutico , Ifosfamida/uso terapéutico , Linfoma no Hodgkin/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Terapia Recuperativa , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Ifosfamida/administración & dosificación , Ifosfamida/efectos adversos , Linfoma no Hodgkin/patología , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Resultado del Tratamiento , Adulto Joven , GemcitabinaRESUMEN
Bortezomib (VELCADE), thalidomide and dexamethasone (VTD), as well as melphalan, prednisolone, and thalidomide (MPT) therapy, are highly effective in patients with multiple myeloma. We evaluated the responses and survival times of 35 patients treated with VTD followed by MPT. All patients were newly diagnosed and non-transplantation candidates. Patients received six cycles of VTD, which were followed by eight cycles of MPT. Approximately 97% of patients exhibited early responses to therapy, as early as the second cycle of VTD. Thirty percent of the responses were high quality, which was defined as a complete response (CR), a near-CR or a very good partial response. High-risk patients were defined as patients with any of the following aberrations: del(13), t(4;14), or del(17p). The remaining patients were defined as standard risk. Eleven high-risk patients showed 100% response rates, including 91% high-quality responses. In contrast, 13 standard-risk patients exhibited 92% response rates, including 61% high-quality responses. The overall 2-year survival rates were 60% in high-risk patients and 85% in standard-risk patients, which was not significantly different. As a first-line therapy, VTD followed by MPT has the potential to provide high-quality responses with durable remission among elderly and high-risk patients (clinicaltrials.gov identifier: NCT00320476).