RESUMO
Given the selection of elderly patients with AML in first complete remission (CR1) the advantage of consolidation with allogeneic hematopoietic cell transplantation (HCT) over chemotherapy is still unclear. Newly diagnosed AML patients in CR1 aged 60-75 years were registered and a donor search initiated. After one consolidation cycle, patients with a matched donor were randomized to HCT with fludarabine/lowdose total body irradiation and cyclosporine/mycophenolate mofetil immunosuppression or conventional non-HCT. Primary outcome was restricted mean leukemia-free survival (RM-LFS) up to five years. Between 2010 and 2017, 245 patients (median age 67 years) were registered at CR1. After one consolidation, 26.9% of patients failed inclusion criteria. Of the 179 (73%) patients still on study, 75.4% had an HLA identical donor. Ten ineligible patients were excluded, and 125 randomized to HCT (n=83) or non-HCT (n=42). The primary outcome RM-LFS up to 5 years was 24.5 months (95%CI:18.9-30.1) in the HCT and 15.6 months (95%CI:10.4-20.8) in the non-HCT arm (p=0.022) due to a decrease in cumulative relapse incidence from 91.1 (95%CI:80.7-100.0) after non-HCT to 37.8 (95%CI:27.2-48.4)% after HCT (p.
Assuntos
Rearranjo Gênico , Histona-Lisina N-Metiltransferase , Proteína de Leucina Linfoide-Mieloide , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Histona-Lisina N-Metiltransferase/genética , Neoplasia Residual/genética , Neoplasia Residual/diagnóstico , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Idoso , Adolescente , PrognósticoRESUMO
The role of autologous-allogeneic tandem stem cell transplantation (alloTSCT) followed by maintenance as upfront treatment for multiple myeloma (MM) is controversial. Between 2008 and 2014 a total of 217 MM patients with a median age of 51 years were included by 20 German centers within an open-label, parallel-group, multi-center clinical trial to compare alloTSCT to auto tandem transplantation TSCT (autoTSCT) followed by a 2-year maintenance therapy with thalidomide (100 mg/d) in both arms with respect to relapse/progression-free survival (PFS) and other relevant outcomes. A total of 178 patients underwent second SCT (allo n = 132 and auto n = 46). PFS at 4 years after the second SCT was 47% (CI: 38-55%) for alloTSCT and 35% (CI: 21-49%) for autoTSCT (p = 0.26). This difference increased to 22% at 8 years (p = 0.10). The cumulative incidences of non-relapse mortality (NRM) and of relapse at 4 years were 13% (CI: 8-20%) and 2% (CI: 0.3-2%) (p = 0.044) and 40% (CI: 33-50%) and 63% (CI: 50-79%) for alloTSCT and autoTSCT (p = 0.04), respectively. The difference for relapse/progression increased to 33% (alloTSCT: 44%, autoTSCT: 77%) at a median follow-up of 82 months (p = 0.002). Four-year OS was 66% (CI: 57-73%) for alloTSCT and 66% (CI: 50-78%) for auto TSCT (p = 0.91) and 8-year OS was 52% and 50% (p = 0.87), respectively. AlloTSCT followed by thalidomide maintenance reduced the rate of recurrence or progression during a follow-up period of up to 10 years but failed to improve PFS significantly.
RESUMO
A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.
Assuntos
Leucemia Mieloide Aguda , Mitoxantrona , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Leucemia Mieloide Aguda/tratamento farmacológico , Mitoxantrona/efeitos adversos , Prognóstico , Indução de RemissãoRESUMO
Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20-73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Adulto Jovem , Doença Aguda , Células Dendríticas/patologia , Transtornos Mieloproliferativos/patologia , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/patologia , Condicionamento Pré-Transplante , Resultado do TratamentoRESUMO
Relapse of acute leukemia is a frequent complication with uncertain outcome and poorly defined risk factors. From 1621 patients entered into two prospective clinical trials (AML02; n = 740 and AML04; n = 881), 74.2% reached complete remission (CR) 1 after induction(s) and 59 patients after additional induction ± hematopoietic cell transplantation (HCT). Of the non-refractory patients, 48.4% with a median age of 63 (range 17-85) years relapsed. Relapses occurred within 6 months after CR in 46.5%, between 7 and 18 months in 38.7%, and after 18 months in 14.8% of patients. Relapse treatment resulted in CR2 in 39% of patients depending upon age (54.5% of ≤ 60 and 28.6% of > 60 years), duration of CR1, and treatment of relapse. Overall survival (OS) was 10.9 (7.4-16.2) %, but OS after HCT ± intensive chemotherapy (ICT) was 39.3% (31.8-48.6) at 5 years and not different in younger and older patients. Donor lymphocyte infusion ± chemotherapy and ICT alone resulted only in OS of 15.4% and of 5%, respectively. Independent favorable factors for OS were long CR1 duration, and HCT, while non-monosomal disease was beneficial for OS in elderly patients. Leukemia-free survival [LFS; 24.9 (19.5-31.7) % at 10 years] was affected by similar risk factors. In a competing risk model, the relapse incidence at 5 years was 53.5 ± 3.5% and the non-relapse mortality rate 21.7 ± 2.9%. Lower relapse incidence was observed in patents with HCT, long CR1 duration, and female gender. Risk factors for non-relapse mortality were HCT in younger and type of AML in elderly patients. In conclusion, allogeneic HCT ± IC improved the results in relapsed AML in younger and elderly patients. Increasing CR2 rates and HCT frequency will be the challenge for the next years. Relapse of the disease remains the major problem.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Alemanha/epidemiologia , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Idoso , Bussulfano , Humanos , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Condicionamento Pré-TransplanteRESUMO
Nonmyeloablative (NMA) conditioning regimens facilitate allogeneic stem cell transplantation (alloSCT) in elderly patients and/or in those with comorbidities. The acute leukemia working party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) compared the outcomes of patients ≥60 years with AML in first complete remission (CR1), that had received an alloSCT following NMA conditioning, i.e. either fludarabine/busulfan (FB2) or fludarabine/total-body-irradiation-2Gy (FluTBI2Gy). A total of 1088 patients were included (median age 65 years). Donors were matched siblings (MSD) and matched unrelated donors (MUD) in 47% and 53%, respectively. In vivo T-cell depletion (TCD) was applied to 79% and none (0%) of patients in the FB2 and FluTBI2Gy groups, respectively. In the MSD group we found a trend for less extensive cGVHD in patients receiving FB2 with in vivo TCD, HR: 0.49, p = 0.08, and in those without worse NRM, HR: 2.14, p = 0.04, and a trend for more total cGVHD, HR: 1.61, p = 0.09. Patients transplanted from MUDs had a significantly higher incidence of total cGVHD, extensive cGVHD and a worse GRFS with FluTBI2Gy in comparison to FB2, HR: 2.44; p < 0.0001; HR 4.59; p < 0.00001 and HR: 1.35; p = 0.03, respectively. No differences were observed with respect to LFS, OS, RI, NRM, and aGVHD.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Idoso , Bussulfano , Humanos , Leucemia Mieloide Aguda/terapia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Vidarabina/análogos & derivadosRESUMO
We performed serial measurable residual disease (MRD) monitoring in bone marrow (BM) and peripheral blood (PB) samples of 155 intensively treated patients with RUNX1-RUNX1T1+ AML, using a qRT-PC-based assay with a sensitivity of up to 10-6. We assessed both reduction of RUNX1-RUNX1T1 transcript levels (TLs) and achievement of MRD negativity (MRD-) for impact on prognosis. Achievement of MR2.5 (>2.5 log reduction) after treatment cycle 1 and achievement of MR3.0 after treatment cycle 2 were significantly associated with a reduced risk of relapse (P = .034 and P = .028, respectively). After completion of therapy, achievement of MRD- in both BM and PB was an independent, favorable prognostic factor in cumulative incidence of relapse (4-year cumulative incidence relapse: BM, 17% vs 36%, P = .021; PB, 23% vs 55%, P = .001) and overall survival (4-year overall survival rate BM, 93% vs 70%, P = .007; PB, 87% vs 47%, P < .0001). Finally, during follow-up, serial qRT-PCR analyses allowed prediction of relapse in 77% of patients exceeding a cutoff value of 150 RUNX1-RUNX1T1 TLs in BM, and in 84% of patients exceeding a value of 50 RUNX1-RUNX1T1 TLs in PB. The KIT mutation was a significant factor predicting a lower CR rate and inferior outcome, but its prognostic impact was outweighed by RUNX1-RUNX1T1 TLs during treatment. Virtually all relapses occurred within 1 year after the end of treatment, with a very short latency from molecular to morphologic relapse, necessitating MRD assessment at short intervals during this time period. Based on our data, we propose a refined practical guideline for MRD assessment in RUNX1-RUNX1T1+ AML.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Proteínas de Fusão Oncogênica/análise , Adolescente , Adulto , Idoso , Subunidade alfa 2 de Fator de Ligação ao Core/análise , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Proteínas de Fusão Oncogênica/genética , Prognóstico , Proteína 1 Parceira de Translocação de RUNX1/análise , Proteína 1 Parceira de Translocação de RUNX1/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Translocação Genética , Adulto JovemRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for many malignant high-risk hematological diseases. The Graft-vs.-Tumor (GvT) effect is the major hallmark of this treatment approach. However, disease relapse remains a major limitation. Boosting the GvT effect by checkpoint inhibitors (CI) is an attractive option in this desperate situation although potentially triggering Graft-vs.-Host Disease (GvHD). Early reports in patients with Hodgkin's lymphoma support the idea that CI therapy after HSCT is feasible and effective. We have retrospectively analyzed CI therapy for treatment of disease recurrence after allo-HSCT other than Hodgkin's lymphoma including 21 patients from eight German transplant centers. The median follow-up was 59 days. The overall response rate (ORR) was 43%. Patients receiving donor lymphocyte infusion (DLI) in combination with CI had superior response (ORR 80%). Severe acute GvHD grade III-IV and moderate to severe chronic GvHD were observed in 29% of all patients. Taken together, CI therapy in relapsed patients after HSCT, especially in combination with DLI, is effective but induces severe GvHD in a considerable proportion of patients. Thus, prospective trials or EBMT registry-based validation of different dosing and application schedules including immunosuppressive regimens in those patients are urgently needed.
Assuntos
Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transplante Homólogo/métodos , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Busulfan/fludarabine (BuFlu) is a widely used conditioning regimen for patients with myeloid malignancies. The sequential FLAMSA (fludarabineâ¯+â¯Ara-Câ¯+â¯amsacrine chemotherapy) protocol followed by either cyclophosphamide and total body irradiation (FLAMSA-TBI) or cyclophosphamide and busulfan (FLAMSA-Bu) has shown remarkable activity in high-risk acute myelogenous leukemia (AML) patients. Here we compare the outcomes of AML patients transplanted in first complete remission (CR1) or second complete remission (CR2) after conditioning with BuFlu or FLAMSA. Eligible patients had their first allogeneic stem cell transplantation for AML in CR1 or CR2 between January 2005 and June 2016. Donors were matched related or unrelated with up to 1 mismatch. Conditioning consisted of either BuFlu or FLAMSA. Propensity score matching was applied and comparisons were performed using weighted Cox regression. BuFlu conditioning was used in 1197 patients, whereas FLAMSA-TBI and FLAMSA-Bu were used in 258 and 141 patients, respectively. Median follow-up of survivors was 24.72 months. In univariate analysis, relapse incidence (RI) was 30.3%, 21.9%, and 23.1% in the BuFlu, FLAMSA-TBI, and FLAMSA-Bu groups, respectively (P < .01), and nonrelapse mortality at 2 years was 16.1%, 16.4%, and 26.7%, respectively (P < .01). Leukemia-free survival (LFS) at 2 years was 53.6%, 61.6%, and 50.1%, respectively (P = .03). Weighted Cox regression revealed that FLAMSA-TBI compared with BuFlu was associated with lower RI (hazard ratio [HR], .64; 95% confidence interval [CI], .42 to .98; P = .04) and a trend for better LFS (HR, .72; 95% CI, .49 to 1.06; P = .09). These results suggest that compared with BuFlu, conditioning with FLAMSA-TBI leads to reduced RI at 2 years in AML patients transplanted in CR1 or CR2.
Assuntos
Bussulfano/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Indução de Remissão/métodos , Vidarabina/análogos & derivados , Bussulfano/farmacologia , Europa (Continente) , Feminino , Humanos , Incidência , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vidarabina/farmacologia , Vidarabina/uso terapêuticoRESUMO
In this phase Ib/IIa study (ClinicalTrials.gov Identifier: NCT00850382) of the German-Austrian AML Study Group (AMLSG) the multikinase inhibitor dasatinib was added to intensive induction and consolidation chemotherapy and administered as single agent for 1-year maintenance in first-line treatment of adult patients with core-binding factor (CBF) acute myeloid leukemia (AML). The primary combined end point in this study was safety and feasibility, and included the rates of early (ED) and hypoplastic (HD) deaths, pleural/pericardial effusion 3°/4° and liver toxicity 3°/4°, and the rate of refractory disease. Secondary end points were cumulative incidence of relapse (CIR) and death in complete remission (CID), and overall survival (OS). Eighty-nine pts [median age 49.5 years, range: 19-73 years; t(8;21), n = 37; inv (16), n = 52] were included. No unexpected excess in toxicity was observed. The rates of ED/HD and CR/CRi were 4.5% (4/89) and 94% (84/89), respectively. The 4-year estimated CIR, CID, and OS were 33.1% [95%-CI (confidence interval), 22.7-43.4%], 6.0% (95% CI, 0.9-11.2%), and 74.7% (95% CI, 66.1-84.5%), respectively. On the basis of the acceptable toxicity profile and favorable outcome in the AMLSG 11-08 trial, a confirmatory randomized phase III trial with dasatinib in adults with CBF-AML is ongoing (ClinicalTrials.gov Identifier: NCT02013648).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Fatores de Ligação ao Core/metabolismo , Dasatinibe/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Recidiva , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematodermic neoplasm which typically presents with skin infiltrates with or without lymphadenopathy and bone marrow involvement. No standard of care exists for this aggressive disease and prognosis is particularly poor. Here, we present our experience with nine BPDCN patients diagnosed at our institution between 2005 and 2012. BPDCN patients were identified in the databases at the Department of Hematology and Oncology, the Department of Dermatology, and the Institute of Pathology at the Otto-von-Guericke-University Magdeburg. There were six male and three female patients with a median age at diagnosis of 66 years. Sites involved were skin (five cases), lymph nodes (five cases), and bone marrow (five cases). Treatments varied from single agent chemotherapy to polychemotherapy and allogeneic stem cell transplantation for consolidation. The three patients that were treated with acute leukemia-type induction therapy followed by allogeneic stem cell transplantation (one after standard conditioning and two after reduced intensity conditioning using fludarabine in combination with thiotepa) achieved sustained remissions and are alive with a follow-up of 8, 35, and 41 months. In contrast, median survival in the less intensively treated patients was only 9.5 (range 1 to 29) months.
Assuntos
Células Dendríticas/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Neoplasias Cutâneas/terapia , Doadores não Relacionados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND & AIMS: In this study, adenoviral vectors encoding an antisense RNA complementary to the 5' non-coding region (5'NCR) of the HCV-genome were generated to inhibit HCV-RNA gene expression in cell culture and in vivo. METHODS: First and second-generation (with E4-deletion) adenoviruses encoding the HCV5'NCR in antisense direction (Ad-NCRas and Ad-E4del-NCRas) were generated. Inhibition of HCV gene expression was analyzed in hepatoma cells stably transfected with the HCV5'NCR cDNA fused to the firefly luciferase gene (NCRluc), as well as in the HCV subgenomic replicon (genotypes 1b and 2a) and the fully infectious HCV JFH-1 cell culture systems. For in vivo experiments, an adenovirus encoding the NCRluc-gene was injected intravenously to achieve a NCR-dependent luciferase-expression in the liver of C3H/HeNcrl-mice. RESULTS: Forty eight hours after transduction with GFP-encoding adenoviruses, >85% of HepG2-, CCL13-and Huh7-cells expressed GFP. Surprisingly, GFP-expression of E4-deleted adenoviruses was considerably reduced at the same MOI. Using antisense first-generation adenoviruses (Ad-NCRas), a significant inhibition of the 5'NCR-dependent HCV-gene expression (54±19% in HepG2-cells and 66.2±15% in Huh7-cells) was achieved 48h after transduction. In Huh7-cells containing the HCV subgenomic replicons and in infectious HCV JFH-1 cell cultures, adenovirus-mediated transcription of antisense 5'NCR significantly blocked HCV-replication (40% and 76%, respectively). Corresponding to low transgene expression, the maximal inhibition reached with Ad-delE4-NCRas was 30%. In vivo, antisense adenoviral vectors also showed a significant inhibition (40%) of NCR-dependent luciferase expression compared to control adenoviruses (p<0.05). CONCLUSIONS: The data indicate that HCV gene expression can be inhibited by antisense RNA encoding adenoviruses in the tested settings.
Assuntos
Vetores Genéticos , Hepacivirus/genética , RNA Antissenso/genética , Regiões 5' não Traduzidas , Adenoviridae/genética , Animais , Linhagem Celular , Expressão Gênica , Genes Virais , Hepacivirus/fisiologia , Hepatite C Crônica/terapia , Hepatite C Crônica/virologia , Técnicas In Vitro , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos C3H , Replicon , Transdução Genética , Replicação Viral/genéticaRESUMO
Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFRalpha) gene. Both PDGFRalpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTs significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.
Assuntos
Tumores do Estroma Gastrointestinal/tratamento farmacológico , Mutação/efeitos dos fármacos , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Benzamidas , Análise Mutacional de DNA , Feminino , Tumores do Estroma Gastrointestinal/genética , Tumores do Estroma Gastrointestinal/patologia , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Homologia de Sequência de AminoácidosRESUMO
Gastrointestinal stromal tumors (GISTs) are often associated with activating KIT mutations, affecting regulatory domains of the KIT tyrosine kinase. Sporadic mastocytosis in adults is usually also caused by KIT mutations that, however, activate KIT by affecting the intracellular enzymatic site of the molecule. Most GISTs respond to KIT inhibitors that bind to the enzymatic site; in most cases of mastocytosis, however, the modified enzymatic site is not affected by these drugs. We present a kindred with both familial GISTs and mastocytosis that express a novel germline KIT mutation in exon 8, resulting in deletion of codon 419 and affecting the extracellular domain of KIT. This mutation activates KIT, and the mutant KIT is inhibited by the tyrosine kinase inhibitor imatinib mesylate. Our studies identify a new regulatory region in the KIT molecule and strongly suggest that patients with extracellular KIT mutations respond to tyrosine kinase inhibitors.
Assuntos
Tumores do Estroma Gastrointestinal/genética , Mutação em Linhagem Germinativa , Mastocitose/genética , Proteínas Proto-Oncogênicas c-kit/genética , Adulto , Criança , Feminino , Tumores do Estroma Gastrointestinal/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Deleção de SequênciaAssuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/genética , Pirimidinas/uso terapêutico , Idoso , Benzamidas , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Mutação , Metástase NeoplásicaRESUMO
BACKGROUND/AIMS: In this study we established an orthotopic tumour model for hepatocellular carcinoma and evaluated a non-invasive high resolution ultrasound technique for diagnosis and follow-up of intrahepatic HCC. METHODS: Orthotopic liver tumours were induced by intrahepatic tumour cell injection of 10(5) Hepa129 hepatoma cells. Tumour establishment and growth were assessed by explorative laparotomy, ultrasound technique and hepatectomy one and two weeks after tumour cell implantation. Tumour establishment was confirmed histologically in liver sections. RESULTS: Our results show that the Hepa129 hepatoma cell line is suitable for orthotopic tumour establishment and that tumours can be diagnosed correctly by ultrasound imaging in all cases as confirmed by explorative laparotomy, hepatectomy and cross-sections. Tumour diameters obtained by explorative laparotomy correlated significantly with diameters assessed by ultrasound (r=0.7; P<0.0001). Tumour burden was slightly overestimated (1.2-fold) by ultrasound one week after tumour induction and relative tumour extensions increased 1.7-fold and 1.8-fold within one week as determined by subsequent explorative laparotomy or ultrasound imaging, respectively. CONCLUSIONS: These data demonstrate in a systematic study that ultrasound imaging can be used as a reliable tool to detect and to follow up orthotopic liver tumours in this tumour model in mice.
Assuntos
Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos C3H , Transplante de Neoplasias , Fatores de Tempo , Ultrassonografia/métodosRESUMO
Gastrointestinal stromal tumors (GISTs) typically express high levels of the Kit-receptor. The majority of GISTs carry mutations in the c-kit protooncogene clustering in exon 11. The significance of c-kit mutations for the biological behavior of GISTs is still under discussion. We evaluated 55 sporadic GISTs with available follow-up data for c-kit mutations in the juxtamembrane domain and detected mutations in 35 cases (63.6%). We found a mutational hotspot in codons 557 (tryptophan) and 558 (lysine) preferentially in histomorphologically malignant tumors. In the group of GISTs carrying c-kit mutations, 16 of 21 malignant, but only 3 of 8 benign GISTs and 3 of 6 lesions with uncertain malignant potential, carried mutations of Trp-557 and/or Lys-558. We investigated whether mutations in these 2 amino acids had an impact on biological behavior. Trp-557 and/or Lys-558 were mutated in all 15 metastatic GISTs carrying c-kit mutations but only in a minority of nonmetastatic tumors. A combined deletion of Trp-557 and Lys-558 occurred exclusively in 8 metastatic GISTs. We conclude that in addition to histomorphological evaluation determination of mutations in exon 11 may be an additional parameter for predicting the metastatic risk of GISTs and may be important for the decision that patients will need close clinical follow-up or further adjuvant treatment with kit antagonists.