RESUMO
Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of ß2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis.
Assuntos
Células Endoteliais , Vasculite , Quinases da Família src , Humanos , Dasatinibe , Células Endoteliais/metabolismo , Inflamação/metabolismo , Neutrófilos/metabolismo , Fosforilação , Quinases da Família src/genética , Quinases da Família src/metabolismo , Vasculite/genéticaRESUMO
Introduction: We analyzed the incidence, risk factors of central nervous system (CNS) relapse, and outcome of CNS involvement in patients with peripheral T-cell lymphomas (PTCL) from the Czech Lymphoma Study Group Registry NiHiL (Clinical Trial gov. NCT03199066). Materials and Methods: Out of 1,040 patients with PTCL, we identified 29 patients (2.79%) with CNS involvement: 2 patients with primary CNS T cell lymphoma, 11 patients with CNS and systemic disease at diagnosis, and 16 patients (1.54%) at CNS relapse. The most common histology with CNS disease was PTCL, not otherwise specified. Progression-free survival (PFS) was defined as the time interval from diagnosis to progression or death. PFS-2 was defined as the interval from the date of a new relapse until the next relapse. Results: Patients with testicular involvement received intrathecal prophylaxis with methotrexate. High-dose methotrexate-based treatment was administered in 44.8% of patients with CNS disease. Median follow-up was 71.3 months. The difference between the median PFS of 1,027 patients without initial CNS disease (32.6 months) and 11 patients with initial CNS and systemic disease (4.8 months) was significant (p = 0.04). The difference between the median PFS2 in CNS relapses (10.1 months) and 493 relapses outside of CNS (9.1 months) was not significant (p = 0.6). Risk factors for CNS relapses included the following: involvement of more than one extranodal site (p = 0.008), soft tissue involvement (p = 0.003), testicular involvement (p = 0.046), and the presence of B symptoms (p = 0.035). The difference between the median OS of 1,027 patients without initial CNS disease (46.0 months) and 11 patients with initial CNS and systemic disease (18.2 months) was significant (p = 0.02). The median OS2 in CNS relapses was 11.8 months and that in relapses outside of CNS was 21.3 months. CNS involvement was not associated with a significantly worse OS compared to relapsed/refractory patients without CNS involvement (p = 0.1). Conclusions: The incidence of CNS disease at the time of diagnosis and at relapse in PTCL is low and usually associated with other systemic involvement. The prognosis of PTCL with initial CNS involvement is significantly worse when compared to patients without CNS disease at diagnosis. The outcome of CNS relapse is comparable with relapsed PTCL outside of CNS. The optimal treatment is not defined yet.
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Burkitt lymphoma (BL) is a rare subtype of non-Hodgkin's lymphoma with an aggressive course. To refine the individual patient's prognosis, the International Prognostic Index for BL (BL-IPI) was recently developed and 4 risk factors (RF) were determined as optimal prognostic cut-off by multivariate analysis: age ≥40 years, lactate dehydrogenase >3× upper limit of normal, ECOG performance status ≥2, and central nervous system involvement. The BL-IPI distinguishes 3 prognostic groups, low (without RF), intermediate (1 RF), and high risk (2-4 RF), with significant differences in survival. The aim of the current project was to perform an external validation of the BL-IPI in 101 patients from the Registry of Czech Lymphoma Study Group diagnosed between 1999 and 2016 (median age, 45 years). The median follow-up was 50.4 months. The induction treatment included rituximab plus chemotherapy in 82% and chemotherapy alone in 18%. The overall response rate was 78% and the complete remission rate was 73%. According to BL-IPI, low/intermediate/high risk was present in 21/35/45% of patients, showing high similarity to the training BL-IPI US (United States) dataset (18/36/46%). There were significant differences in progression-free survival (PFS) and overall survival (OS) between patients with high vs. intermediate risk (PFS: hazard ratio 0.16, 95% confidence interval 0.08-0.31, p<0.0001; OS: hazard ratio 0.17, 95% confidence interval 0.09-0.35, p<0.0001) but not between patients with low vs. intermediate risk. The 3-year OS probability according to BL-IPI with low/intermediate/high risk was 96/76/59% in the BL-IPI training dataset vs. 95/85/45% in our external validation cohort; the 3-year PFS probability with low/intermediate/high risk was 92/72/53% in the BL-IPI training dataset vs. 95/85/42% in our cohort. In summary, our external validation of the BL-IPI confirmed a good separation of high-risk patients, who have a poor prognosis and for whom the new therapeutic approaches are needed; patients with low and intermediate risk had favorable clinical outcomes, and differences between these groups were not significant, likely due to a small number of patients.
Assuntos
Linfoma de Burkitt , Linfoma Difuso de Grandes Células B , Humanos , Pessoa de Meia-Idade , Adulto , Linfoma de Burkitt/tratamento farmacológico , Prognóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Estudos Retrospectivos , República Tcheca/epidemiologia , Sistema de Registros , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Relapsing diffuse large B cell lymphomas (rDLBCL) represent a heterogeneous disease. This heterogeneity should be recognized and reflected, because it can deform the interpretation of clinical trial results. DLBCL patients with the first relapse and without CNS involvement were identified in the Czech Lymphoma Study Group (CLSG) database. Interval-to-therapy (ITT) was defined as the time between the first manifestation of rDLBCL and the start of any treatment. The overall survival (OS) of different ITT cohorts (< 7 vs. 7-21 vs. > 21 days) was compared. In total, 587 rDLBCLs (51.8% males) progressed with a median of 12.8 months (range 1.6 to 152.3) since the initial diagnosis (2000-2017). At the time of relapse, the median age was 67 years (range 22-95). First-line therapy was administered in 99.3% of the patients; CHOP and anti-CD20 were given to 69.2% and 84.7% of the patients, respectively. The salvage immune/chemotherapy was administered in 88.1% of the patients (39.2% platinum-based regimen). The median ITT was 20 days (range 1-851), but 23.2% of patients initiated therapy within 7 days. The 5-year OS was 17.4% (range 10-24.5%) vs. 20.5% (range 13.5-27.4%) vs. 42.2% (range 35.5-48.8%) for ITT < 7 vs. 7-21 vs. > 21 days (p < 0.001). ITT was associated with B symptoms (p 0.004), ECOG (p < 0.001), stage (p 0.002), bulky disease (p 0.005), elevated LDH (p < 0.001), and IPI (p < 0.001). The ITT mirrors the real clinical behavior of rDLBCL. There are patients (ITT < 7 days) with aggressive disease and a poor outcome. Conversely, there are rDLBCLs with ITT ≥ 21 days who survive for a long time.
Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Tempo para o Tratamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Coortes , Ciclofosfamida/uso terapêutico , República Tcheca/epidemiologia , Bases de Dados Factuais , Progressão da Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/epidemiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Terapia Neoadjuvante/estatística & dados numéricos , Prednisona/uso terapêutico , Prognóstico , Recidiva , Estudos Retrospectivos , Rituximab/administração & dosagem , Tempo para o Tratamento/estatística & dados numéricos , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND CNS involvement in Hodgkin lymphoma is rare. Despite various treatment options, median overall survival is only 13 months after diagnosis of CNS involvement in relapsed/refractory HL. CASE REPORT A 29-year-old woman with classical HL (mixed cellularity) in clinical stage IIB was treated with multilineage chemotherapy and radiotherapy without achieving a sustained complete remission. Systemic and CNS progression of HL occurred at the age of 32 years and the patient received 2 cycles of brentuximab vedotin with bendamustine alternating with 2 cycles of high-dose methotrexate-based treatment and achieved partial remission. She then underwent autologous stem cell transplantation followed by brentuximab vedotin consolidation. The disease progressed and the patient died 6 months after the last dose of brentuximab vedotin. CONCLUSIONS We demonstrated a durable response to brentuximab vedotin-based chemotherapy in a patient with refractory Hodgkin lymphoma with CNS involvement. Prognosis of these patients is poor and new treatment options are needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Progressão da Doença , Doença de Hodgkin/fisiopatologia , Doença de Hodgkin/terapia , Adulto , Evolução Fatal , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Prognóstico , Terapia de Salvação/métodos , Transplante AutólogoRESUMO
Twenty percent of patients with high-tumor-burden (HTB) follicular lymphoma (FL) develop progression/relapse of disease (POD) within 24 months of frontline immunochemotherapy. Unfortunately, about 50% of these patients die within 5 years since POD event. Rituximab maintenance was proven to reduce relapse rate in responding FL, but its role on preventing POD was not defined. We analyzed 1360 HTB-FL patients from the Czech Lymphoma Study Group registry treated with frontline rituximab-containing regimen. Of those, 950 cases received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and achieved complete or partial remission: 712 patients received rituximab maintenance (MAINT) and 238 were a historical observational cohort (OBS). We have proposed a modified POD24 (mPOD24) endpoint for the chemosensitive patients calculated from the end-of-induction (EOI). Survival rates since EOI were as follows: 5-year overall survival (OS) 86.2% versus 94.5% in the OBS and MAINT groups, respectively (P < .001) and 5-year progression-free survival 58.5% (OBS) and 75.4% (MAINT) (P < .001). The Cox proportional hazards model showed a decrease in mPOD24 incidence in the MAINT group with the overall hazard rate reduced by 56% (hazard ratio = 0.44; P < .001). The cumulative incidence of mPOD24 was reduced from 24.1% in OBS to 10.1% in MAINT (P < .001). Comparison of non-mPOD24 cases showed OS similar to that in the general population. Rituximab maintenance given after R-CHOP resulted in a 2.4-fold reduction in mPOD24 incidence. Once the non-POD24 status is achieved, FL does not shorten the patients' life expectancy.
RESUMO
Background: A histopathological examination was conducted on vein samples from six patients who had undergone great saphenous vein sealing with Histoacryl and Lipiodol to treat chronic venous insufficiency of the superficial venous system. Patients and methods: In each patient a sample of the complete vein including the surrounding tissue was obtained through a minor incision under perioperative sonographic monitoring. Each patient had signed an informed consent form. Samples were taken at the following intervals: six days, six weeks, six months, one year, two years, and three years after treatment. Results: N-butyl-2-cyanoacrylate with Lipiodol induces a thrombotic reaction in the acute phase and endothelium is destroyed but no significant inflammation or substantial vascular wall damage is present. In the subsequent period, a foreign body giant cell reaction emerges accompanied by only moderate chronic inflammation that does not extend to the vascular wall or the surrounding tissue. The thrombus is organized with minimal recanalization. The foreign material is gradually degraded, and it is no longer detectable after three years. The vessel wall showed slight sclerotization. Conclusions: N-butyl-2-cyanoacrylate that has been applied gradually degrades over the course of three years accompanied by a giant cell reaction, mild chronic inflammation and cicatrices, but there is minimal recanalization of the obturated section.
Assuntos
Veia Safena , Varizes , Insuficiência Venosa , Embucrilato , Humanos , Resultado do TratamentoRESUMO
Peripheral T cell lymphomas (PTLs) have a globally poor prognosis. The CHOP regimen shows insufficient efficacy; first-line consolidation with autologous stem cell transplantation (auto-SCT) is a promising strategy but has never been confirmed by randomized data. We analyzed retrospectively 906 patients diagnosed with PTL between 1999 and 2015. Chemotherapy was given to 862 patients, and 412 of them were < 60 years. In this subset, we compared induction with CHOP (n = 113) vs. CHOEP (n = 68) and tested auto-SCT (n = 79) vs. no SCT (n = 73) in the intent-to-treat analysis. The median age of the whole cohort at diagnosis was 60 years (range; 18-91); the median follow-up was 4.3 years (range; 0.1-17.8). A shorter overall survival (OS) was associated with the male gender, age ≥ 60 years, stage III/IV, performance status ≥ 2, bulky tumor ≥ 10 cm, and elevated LDH. CHOEP induction showed a better 5-year PFS (25.0% vs. 32.9%; p.001), and 5-year OS (65.6% vs. 47.6%; p.008) than CHOP. Auto-SCT compared to no SCT brought a 5-year OS of 49.2% vs. 59.5% (p.187). Auto-SCT did not influence the OS in low-risk or low-intermediate risk PTLs. The high-intermediate and high-risk IPIs displayed a worse 5-year OS in auto-SCT arm (17.7% vs.46.2%; p.049); however, 73.9% of the patients never received planned auto-SCT. Our population-based analysis showed the superiority of CHOEP over CHOP in first-line treatment. We confirm the 5-year OS of around 50% in PTLs undergoing auto-SCT. However, the intended auto-SCT could not be given in 73.9% of the high-risk PTLs.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Progressão da Doença , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Autólogo , Vincristina/uso terapêuticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/terapia , Rituximab/uso terapêutico , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma de Célula do Manto/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Indução de Remissão/métodos , Análise de Sobrevida , Transplante AutólogoAssuntos
Hipertensão Portal/etiologia , Neoplasias Pancreáticas/diagnóstico , Plasmocitoma/diagnóstico , Choque Hemorrágico/etiologia , Endossonografia , Evolução Fatal , Humanos , Hipertensão Portal/diagnóstico , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Pâncreas/patologia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/patologia , Plasmocitoma/complicações , Plasmocitoma/patologia , Choque Hemorrágico/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
We analyzed 495 MCL patients from the Czech Lymphoma Study Group data registry. With the median follow-up of 4.4 years, 51.7% patients progressed or relapsed and 34.1% died. Five-year overall survival reached 65.3% and five-year progression free survival 44.1% of the patients. Maintenance rituximab (MR) after first line therapy improved overall and progression free survival compared to the patients under observation only (both p < .001). Elevated beta-2-microglobulin (p = .003), presence of systemic symptoms (p = .002), ECOG >0 (p = .003), age (p = .014), and MIPI (p < .001) were associated with MR failure. Patients who did not achieve complete remission have had two-fold higher risk of MR failure (p < .001). Autologous stem cell transplant reduced the risk of MR failure by 69% (p < .001). The MIPI and the beta-2-microglobulin were identified as independent predictors of MR failure (p = .02 and p = .03, respectively). Patients who relapsed/progressed on MR reached shorter OS calculated from the MR start compared to patients without failure (HR = 15.0; p < .001).
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Antineoplásicos Imunológicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/epidemiologia , Rituximab/efeitos dos fármacos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Combinada , Ciclofosfamida , República Tcheca/epidemiologia , Doxorrubicina , Feminino , Seguimentos , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/mortalidade , Quimioterapia de Manutenção , Masculino , Prednisona , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Análise de Sobrevida , Falha de Tratamento , Resultado do Tratamento , VincristinaRESUMO
The rituximab maintenance (RM) therapy for follicular lymphoma is effective and clinically well tolerated, however there is limited data regarding this from the elderly segment of the population. This analysis was performed to evaluate the efficacy of RM in elderly patients 65 years of age and older and to assess the influence of the induction therapy with immunochemotherapy (R-CHEMO) on the treatment outcome in a real world setting. A total of 232 consecutive patients treated with first-line R-CHEMO and RM (RM1 group; n = 158) or observation (RM0 group; n = 74) were analyzed. The effect of which induction therapy (R-CHOP vs. R-CVP) and the response of the patients to the first-line therapy were also evaluated. The addition of RM improved the treatment results in elderly patients. The 5- year overall survival rate in patients receiving R-CHEMO + RM1 compared to patients receiving R-CHEMO + RM0, was 83.7% (95% CI 76.1-89%) and 64.3% (95% CI 51.8-74.3%), respectively, p = 0.0012. The induction therapy with R-CHOP was found to be more effective than R-CVP but it is necessary to point out higher age of patients in the R-CVP arm. The 5- year overall survival rate in patients using R-CHOP ± RM and R-CVP ± RM was 84.9% (95% CI 77.5-90%), and 65.0% (95% CI 50.1-76.4%), respectively, p = 0.0008. The patients who achieved CR + uCR after having received first-line therapy had better outcomes compared to patients in PR. The 5- year overall survival rate in uCR + CR patients treated with R-CHEMO + RM1 and PR patients treated with R-CHEMO + RM1 was 90.6% and 68.3%, respectively, p = 0.0019. Rituximab maintenance treatment in patients 65 years and older yielded improved survival rates in a real world clinical setting. The R-CHOP regimen seems to be a more effective induction agent than R-CVP but the outcome of less intensively treated patients with R-CVP + RM is also acceptable. The achievement of uCR + CR after first-line therapy is associated with a better outcome.
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Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Quimioterapia de Manutenção , Rituximab/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , República Tcheca/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
We report on the case of a 39-year old man who underwent a thyroidectomy and a parathyroidectomy with misdiagnosed medullary carcinoma of the thyroid in 2013. During the operation the thyroid gland and parathyroid glands were artificially damaged due to the complicated surgical access to the glands because of the obesity of the patient as well as the deep placement of the enlarged parathyroid glands. Three years later, the neck ultrasound showed bilateral nodules on the neck, suspected to be metastases of the medullary carcinoma. Microscopically, the nodules were found to be focuses of parathyromatosis, and there was also an infiltrating carcinoma. This lesion was reclassified after clinico-pathological correlation and immunohistochemical examination as nonfunctioning parathyroid carcinoma. This article discusses morphological and immunohistochemical features of parathyromatosis and parathyroid carcinoma and its separation from lesions with which it may be misdiagnosed.
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Hiperparatireoidismo , Neoplasias das Paratireoides , Adulto , Humanos , Hiperparatireoidismo/complicações , Hiperparatireoidismo/diagnóstico , Masculino , Glândulas Paratireoides , Neoplasias das Paratireoides/complicações , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , TireoidectomiaRESUMO
The aim of this study is to assess the incidence, risk factors, and outcome of biopsy-proven transformation in follicular lymphoma (FL) patients in the rituximab era. Transformation was analyzed in 1233 patients with initially diagnosed FL grades 1-3A, identified between 2002 and 2012 in the prospectively maintained Czech Lymphoma Study Group database. Only patients with histologically proven transformation (HT) were included. HT occurred in 58 cases at a median of 3.0 years from the initial FL diagnosis; the HT rate was 4% at 5 years. Transformation occurred most frequently at the first relapse (84% patients). Median OS from the HT was 2.5 years (95% CI 0.4-4.6) and 6-year OS with HT was shorter compared to all FLs (60 vs. 83.9%; 95% CI). A bulky tumor (≥ 10 cm), increased lactate dehydrogenase, age ≥ 60 years, and International Prognostic Index (intermediate/high risk), but not Follicular Lymphoma International Prognostic Index, were associated with transformation (p < 0.05). In the first line, 70% of patients received rituximab (including 36% rituximab maintenance), 57% CHOP-like regimens, and 2.6% of patients were treated with fludarabine-based therapy, whereas 11% of patients were watched only. The patients treated with R-CHOP in the first line (n = 591) showed the transformation rate at 5 years of 4.23% (95% CI 2.52-5.93); subsequent rituximab maintenance (n = 276) vs. observation (n = 153) was associated with a lower transformation rate (p.033; HR 3.29; CI 1.10-9.82). The transformation rate seems to be lower than in previous series, which may be influenced by broad use of rituximab, but prognosis of HT developed during therapy continues to be poor.
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Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Transformação Celular Neoplásica/patologia , Estudos de Coortes , República Tcheca/epidemiologia , Feminino , Seguimentos , Humanos , Incidência , Linfoma Folicular/epidemiologia , Linfoma Folicular/patologia , Linfoma Folicular/prevenção & controle , Quimioterapia de Manutenção/efeitos adversos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Estudos Retrospectivos , Rituximab/efeitos adversos , Prevenção Secundária , Análise de SobrevidaRESUMO
Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first-line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R-CHOP and R-cytarabine for newly diagnosed transplant-ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography-computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression-free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography-negativity independently correlated with progression-free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R-CHOP and R-cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/farmacologia , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ciclofosfamida/farmacologia , Ciclofosfamida/uso terapêutico , Citarabina/farmacologia , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/farmacologia , Prednisona/uso terapêutico , Rituximab , Vincristina/farmacologia , Vincristina/uso terapêuticoRESUMO
BACKGROUND: The high incidence of mutations and cytogenetic abnormalities in patients with myelodysplastic syndrome (MDS) suggests that defects in DNA repair mechanisms. We monitored DNA repair pathways in MDS and their alterations during disease progression. METHODS: Expression profiling of DNA repair genes was performed on CD34+ cells, and paired samples were used for monitoring of RAD51 and XRCC2 gene expression during disease progression. Immunohistochemical staining for RAD51 was done on histology samples. RESULTS: RAD51 and XRCC2 showed differential expression between low-risk and high-risk MDS (P<.0001), whereas RPA3 was generally decreased among the entire cohort (FC=-2.65, P<.0001). We demonstrated that RAD51 and XRCC2 expression gradually decreased during the progression of MDS. Down-regulation of XRCC2 and RAD51 expression was connected with abnormalities on chromosome 7 (P=.0858, P=.0457). Immunohistochemical staining revealed the presence of RAD51 only in the cytoplasm in low-risk MDS, while in both the cytoplasm and nucleus in high-risk MDS. The multivariate analysis identified RAD51 expression level (HR 0.49; P=.01) as significant prognostic factor for overall survival of patients with MDS. CONCLUSIONS: Our study demonstrates that the expression of DNA repair factors, primarily RAD51 and XRCC2, is deregulated in patients with MDS and presents a specific pattern with respect to prognostic categories.
Assuntos
Regulação da Expressão Gênica , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Reparo de DNA por Recombinação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Medula Óssea/patologia , Aberrações Cromossômicas , Reparo do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Adulto JovemRESUMO
Optimal frontline treatment in younger high tumor-burden risk follicular lymphoma patients remains a challenge given the reduced efficacy of standard immunochemotherapy (R-CHOP) in widespread disease and unclear role of intensive induction. The retrospective non-randomized pair-matched (1:3) analysis compared 48 intermediate/high Follicular Lymphoma International Prognostic Index (FLIPI) patients receiving intensive rituximab sequential chemotherapy (R-SQ) with 144 random controls (R-CHOP) matched for age, FLIPI score, and maintenance delivery. Complete response rates were 91.7% and 74.1%, respectively (p = .038). After a median follow-up of 8.8 (R-SQ) and 6.5 years (R-CHOP), 5-year time to treatment failure, progression-free survival, and overall survival were 80.9%, 83.2%, and 100% and 57.5%, 60.3%, and 92.1% (p = .0044; p = .0047; p = .22), respectively. Intensive treatment was accompanied by higher acute hematologic toxicity and infections, comparable non-hematologic toxicity, and incidence of secondary malignancies. Intensive induction demonstrates superior long-term disease control compared to R-CHOP, with higher acute hematologic toxicity, but without acute treatment-related mortality. Further studies are needed to define ultra-high-risk FL patients benefiting most from treatment intensity.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/mortalidade , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , República Tcheca/epidemiologia , Feminino , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/epidemiologia , Quimioterapia de Manutenção , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Vigilância da População , Indução de Remissão , Resultado do Tratamento , Carga TumoralRESUMO
We have investigated whether the addition of rituximab to methotrexate, procarbazine, vincristine, radiotherapy and cytarabine was associated with improved outcome of primary central nervous system lymphomas (PCNSL). Of 164 patients, 49 received rituximab. Median age was 63 years, median Karnofsky performance score (KPS) was 60 and median follow-up of living patients was 59.5 months. 1- and 2-year PFS were 49.7 and 37.9%, 1- and 2-year OS were 57.0 and 45.3%. Median progression-free survival (PFS), but not overall survival (OS) was significantly better for patients treated with rituximab (22.9 vs. 10.9 months, p = 0.037). In multivariate analysis, age ≤70 years and KPS ≥90 were predictive for PFS and OS, rituximab was an independent prognostic factor for PFS only. In landmark analyses, rituximab was not found beneficial for long-term survivors and no group particularly benefited from rituximab. In conclusion, addition of rituximab was associated with improved PFS, but not OS in this unselected cohort of PCNSL patients.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Biópsia , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/mortalidade , República Tcheca , Feminino , Humanos , Linfoma/diagnóstico , Linfoma/mortalidade , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Sistema de Registros , Estudos Retrospectivos , Rituximab/administração & dosagem , Resultado do TratamentoRESUMO
GATA-2 deficiency was recently described as common cause of overlapping syndromes of immunodeficiency, lymphedema, familiar myelodysplastic syndrome or acute myeloid leukemia. The aim of our study was to analyze bone marrow and peripheral blood samples of children with myelodysplastic syndrome or aplastic anemia to define prevalence of the GATA2 mutation and to assess whether mutations in GATA-2 transcription factor exhibit specific immunophenotypic features. The prevalence of a GATA2 mutation in a consecutively diagnosed cohort of children was 14% in advanced forms of myelodysplastic syndrome (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and myelodysplasia-related acute myeloid leukemia), 17% in refractory cytopenia of childhood, and 0% in aplastic anemia. In GATA-2-deficient cases, we found the most profound B-cell lymphopenia, including its progenitors in blood and bone marrow, which correlated with significantly diminished intronRSS-Kde recombination excision circles in comparison to other myelodysplastic syndrome/aplastic anemia cases. The other typical features of GATA-2 deficiency (monocytopenia and natural killer cell lymphopenia) were less discriminative. In conclusion, we suggest screening for GATA2 mutations in pediatric myelodysplastic syndrome, preferentially in patients with impaired B-cell homeostasis in bone marrow and peripheral blood (low number of progenitors, intronRSS-Kde recombination excision circles and naïve cells).
Assuntos
Linfócitos B/metabolismo , Fator de Transcrição GATA2/deficiência , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Células Precursoras de Linfócitos B/metabolismo , Adolescente , Anemia Aplástica/diagnóstico , Anemia Aplástica/etiologia , Biomarcadores , Medula Óssea/metabolismo , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Criança , Pré-Escolar , Diagnóstico Diferencial , Humanos , Imunofenotipagem , Lactente , Contagem de Linfócitos , Linfopenia/diagnóstico , Mutação , Células Mieloides/metabolismo , Fenótipo , Curva ROC , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto JovemRESUMO
Controversies still exist regarding definition of the thrombotic risks in Ph- (BCR/ABL1-) myeloproliferative disorders with thrombocythemia (MPD-T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD-T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 × 10(9)/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2(V617F) mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V 'Leiden' and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7-fold) and arterial events (1.8-fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value.