RESUMO
ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.
Assuntos
DNA Helicases , Leucemia Mieloide Aguda , Proteínas Nucleares , Proteínas Proto-Oncogênicas , Fatores de Transcrição , Animais , Humanos , Camundongos , Proteínas que Contêm Bromodomínio , Linhagem Celular Tumoral , DNA Helicases/antagonistas & inibidores , DNA Helicases/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleofosmina , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. METHODS: Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. RESULTS: Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n = 34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). CONCLUSION: Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.
RESUMO
BACKGROUND: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax. METHODS: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination. RESULTS: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001). CONCLUSIONS: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Dasatinibe , Sulfonamidas , Humanos , Dasatinibe/administração & dosagem , Dasatinibe/uso terapêutico , Dasatinibe/efeitos adversos , Pessoa de Meia-Idade , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Adulto , Feminino , Idoso , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Adulto Jovem , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/genéticaRESUMO
INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.
RESUMO
BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.
RESUMO
Targeted therapy development for acute myeloid leukaemia (AML) requires an understanding of specific expression profiles. We collected flow cytometry data on 901 AML patients and recorded aberrant CD7 expression on leukaemic blasts. 263 (29.2%) had blasts positive for CD7. CD7+ AML was more likely to be adverse risk (64.6% vs. 55.6%, p = 0.0074) and less likely to be favourable risk (15.2% vs. 24.1%, p = 0.0074) by European LeukemiaNet 2022 criteria. Overall survival was inferior (11.9 [95% CI, 9.7-15.9] vs. 19.0 months [95% CI, 16.1-23.0], p = 0.0174). At relapse, 30.4% lost and 19.0% gained CD7, suggesting moderate instability over time.
Assuntos
Antígenos CD7 , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Antígenos CD7/análise , Antígenos CD7/metabolismo , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Idoso de 80 Anos ou mais , Adulto Jovem , Citometria de Fluxo , Adolescente , Prognóstico , ImunofenotipagemRESUMO
Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.
Assuntos
Eosinofilia , Leucemia Mielogênica Crônica BCR-ABL Positiva , Trombocitose , Humanos , Hibridização in Situ Fluorescente , Leucocitose , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Trombocitose/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Patients with relapsed acute myeloid leukemia (rAML) experience dismal outcomes. We performed a comprehensive analysis of patients with rAML to determine the genetic dynamics and survival predictive factors. We analyzed 875 patients with newly diagnosed AML who received intensive treatment (IT) or low-intensity treatment (LIT). Of these patients, 197 experienced subsequent rAML. Data was available for 164 patients, with a median time from CR/CRi to relapse of 6.5 months. Thirty-five of the 164 patients (21%) experienced relapse after allogeneic hematopoietic stem cell transplantation (alloSCT). At relapse mutations in genes involved in pathway signaling tended to disappear, whereas clonal hematopoiesis-related mutations or TP53 tended to persist. Patients with normal karyotypes tended to acquire cytogenetic abnormalities at relapse. Patients treated with IT had a higher emergence rate of TP53 mutations (16%), compared to patients treated with LIT (1%, P = 0.009). The overall response rates were 38% and 35% for patients treated with salvage IT or LIT, respectively. Seventeen patients (10%) underwent alloSCT after salvage therapy. The median overall survival (OS) duration after relapse was 5.3 months, with a 1-year OS rate of 17.6%. Complex karyotype (hazard ratio [HR] = 2.14, P < 0.001), a KMT2A rearrangement (HR = 3.52, P = 0.011), time in remission < 12 months (HR = 1.71, P = 0.011), and an elevated white blood cell count at relapse (HR = 2.38, P = 0.005) were independent risk factors for OS duration. More effective frontline and maintenance therapies are warranted to prevent rAML.
RESUMO
Incidence of potential targetable genetic abnormalities by age in AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/epidemiologiaRESUMO
Here we report on the first prospective study evaluating the safety and long-term survival when an escalating dose of inotuzumab ozogamicin (INO) (0.6, 1.2, or 1.8 mg/m2 on day 13) was added to one alkylator-containing conditioning regimen in patients with relapsed CD22 (+) lymphoid malignancies who were candidates for hematopoietic stem cell transplantation (HSCT). Twenty-six patients were enrolled. Six (23%) of these patients entered the phase 1 study: four were treated at an INO dose of 0.6 mg/m2 and two at dose of 1.2 mg/m2. None of these patients experienced dose-limiting toxicities. The remaining 20 (77%) patients entered the phase 2 part of the study at the maximum dose of 1.8 mg/m2. One patient developed VOD; this patient had received nivolumab immediately before HSCT while simultaneously experiencing hyperacute graft-vs-host disease (GVHD). Treatment-related mortality (TRM) at 5 years was 12%. With a median follow-up of 48.7 months, the 5-year overall survival (OS) and progression-free survival (PFS) rates were 84% and 80%, respectively. Compared with a historical cohort who received same conditioning for HSCT but without INO (n = 56), the INO group showed no significant differences in incidence of liver toxicity, engraftment time, TRM, or risk of acute GVHD. Patients with lymphoma who received INO had a trend for a better 5-year OS (93% versus 68%) and PFS (93% versus 58%) than those in the control group. In conclusion, our results showed that INO is safe with no increased risk of VOD when combined with one alkylator-containing regimen of HSCT.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Inotuzumab Ozogamicina , Estudos Prospectivos , Recidiva , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Alquilantes , Condicionamento Pré-Transplante/métodosRESUMO
PURPOSE: To evaluate the effectiveness and safety of pre-emptive transcatheter arterial embolization (P-TAE) for aortic side branches (ASBs) to prevent Type 2 endoleaks (EL2) before endovascular aneurysm repair (EVAR) using the Excluder stent-graft system (Excluder). MATERIALS AND METHODS: In this prospective, multicenter study, 80 patients (mean age, 79.1 years [SD ± 6.7]; 85.0% were men; mean aneurysmal sac diameter, 48.4 mm [SD ± 7.4]) meeting the eligibility criteria were prospectively enrolled from 9 hospitals. Before EVAR, P-TAE was performed to embolize the patent ASBs originating from the abdominal aortic aneurysm. Contrast-enhanced computed tomography (CT) was performed at 1 month and 6 months after EVAR. The primary endpoint was EL2 incidence at 6 months, and the secondary endpoints were aneurysmal sac diameter changes at 6 and 12 months, P-TAE outcomes, adverse events related to P-TAE, reintervention, and aneurysm-related mortality. RESULTS: All patients successfully underwent P-TAE without serious. Coil embolization was successful in 81.6% of ASBs. EL2 incidence at 6 months was identified in 18 of 70 (25.7%) patients. Aneurysmal sac diameter shrinkage (≥5 mm) was observed in 30.0% of patients at 6 months and in 40.9% at 12 months. Only 1 patient required reintervention for EL2 within 1 year of EVAR; aneurysm-related deaths were not observed. CONCLUSIONS: P-TAE for ASBs before EVAR using Excluder is a safe and effective strategy. It aids in achieving early aneurysmal sac shrinkage and reduces EL2 reintervention at 1 year after EVAR.
Assuntos
Aneurisma da Aorta Abdominal , Implante de Prótese Vascular , Prótese Vascular , Angiografia por Tomografia Computadorizada , Embolização Terapêutica , Endoleak , Procedimentos Endovasculares , Desenho de Prótese , Stents , Humanos , Feminino , Masculino , Idoso , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Estudos Prospectivos , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/cirurgia , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/instrumentação , Resultado do Tratamento , Idoso de 80 Anos ou mais , Endoleak/etiologia , Endoleak/terapia , Endoleak/diagnóstico por imagem , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/instrumentação , Fatores de Tempo , Aortografia , Fatores de Risco , Japão , Correção Endovascular de AneurismaRESUMO
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.
Assuntos
Anemia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Macaca fascicularis , Inibidores de Prolil-Hidrolase , Animais , Anemia/tratamento farmacológico , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Administração Oral , Humanos , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/química , Inibidores de Prolil-Hidrolase/síntese química , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Estrutura-Atividade , Estrutura Molecular , Eritropoetina , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese químicaRESUMO
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.
Assuntos
Anemia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Inibidores de Prolil-Hidrolase , Animais , Ratos , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Anemia/tratamento farmacológico , Inibidores de Prolil-Hidrolase/farmacologia , Inibidores de Prolil-Hidrolase/química , Humanos , Administração Oral , Relação Estrutura-Atividade , Insuficiência Renal Crônica/tratamento farmacológico , Descoberta de Drogas , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Relação Dose-Resposta a DrogaRESUMO
Patients with chronic myeloid leukemia in chronic phase (CML-CP) can have a normal life expectancy when treated with the BCR::ABL1 tyrosine kinase inhibitors. In recent years, treatment discontinuation and treatment-free remission (TFR) emerged as the new goal of therapy in patients with CML-CP. Deep and sustained molecular remissions for more than 3 to 5 years are associated with higher chances of a successful TFR. However, although uncommon, some patients may still experience molecular or hematological relapse after treatment discontinuation, even after a prolonged duration of remission. In this case series, we report the outcome of four patients with CML-CP who were treated with tyrosine kinase inhibitors and achieved a deep molecular response for ≥8 years, but eventually experienced disease relapse after treatment discontinuation. We discuss the importance of regular monitoring after treatment discontinuation as well as future strategies to increase the chances of TFR in patients with CML-CP.
Assuntos
Aberrações Cromossômicas , Leucemia Mielogênica Crônica BCR-ABL Positiva , Cromossomo Filadélfia , Indução de Remissão , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , IdosoAssuntos
Imidazóis , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Piridazinas , Recidiva , Humanos , Piridazinas/uso terapêutico , Piridazinas/efeitos adversos , Piridazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Imidazóis/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversosRESUMO
In cone-beam computed tomography (CBCT) for image-guided radiation therapy (IGRT) of the head, we evaluated the exposure dose reduction effect to the crystalline lens and position-matching accuracy by narrowing one side (X2) of the X-ray aperture (blade) in the X-direction. We defined the ocular surface dose of the head phantom as the crystalline lens exposure dose and measured using a radiophotoluminescence dosimeter (RPLD, GD-352 M) in the preset field (13.6 cm) and in each of the fields when blade X2 aperture was reduced in 0.5 cm increments from 10.0 to 5.0 cm. Auto-bone matching was performed on CBCT images acquired five times with blade X2 aperture set to 13.6 cm and 5.0 cm at each position when the head phantom was moved from - 5.0 to + 5.0 mm in 1.0 mm increment. The maximum reduction rate in the crystalline lens exposure dose was - 38.7% for the right lens and - 13.2% for the left lens when blade X2 aperture was 5.0 cm. The maximum difference in the amount of position correction between blade X2 aperture of 13.6 cm and 5.0 cm was 1 mm, and the accuracy of auto-bone matching was similar. In CBCT of the head, reduced blade X2 aperture is a useful technique for reducing the crystalline lens exposure dose while ensuring the accuracy of position matching.
RESUMO
BACKGROUND: A new quality assurance and control method for electrometers using a new current source, different from the method published in the guidelines for electrometers, has been reported. This current source uses dry batteries and exhibits excellent performance in terms of voltage, temperature, and time characteristics. The electrometer sensitivity coefficient can be calculated by comparing the sensitivity of one electrometer with that of another on the electrometer calibration coefficient that has been calibrated by a calibration laboratory in advance in both methods. The guideline method requires two or more sets of ionization chambers and electrometers in the facility. In contrast, our method does not use ionization chambers; therefore, the sensitivity ratio of the electrometer can be measured in any facility. This study compared the uncertainty of the electrometer sensitivity factor calculated using the new current source method (current method) with that calculated using a linear accelerator (LINAC) and ionization chambers (LINAC method) described in the electrometer guidelines. METHOD: In this study, we used a current source that we invented previously by Kawaguchi Electric Works in Japan. The sensitivity ratios of the electrometers were measured with three manufacture's electrometers. The electrometer sensitivity factor was calculated by multiplying the electrometer calibration coefficient. The ionization chamber was 30013 (PTW), and the current source was the current obtained from 10 MV TrueBeam X-rays under calibration conditions. The mean value, standard deviation, and coefficient of variation were calculated. The time required to set up the ionization chamber for calculating the sensitivity ratio of the electrometer was also measured. The accuracy was confirmed by calculating the expanded uncertainty of the electrometer sensitivity coefficients. RESULTS: The LINAC method had a maximum coefficient of variation of 0.072%. The gross time of the LINAC method was approximately 110 min. The current method had a maximum coefficient of variation of 0.0055% and took less than half the time taken by the LINAC method (35 min) because there was no waiting time for the ionization chamber to be set up and the applied voltage to stabilize under calibration conditions. The expanded uncertainties of the electrometer calibration coefficients were 0.36% and 0.36%, respectively. CONCLUSION: The new cross-comparison method for electrometer sensitivity factors using a current source is more efficient and useful than the linear accelerator method described in the guidelines; furthermore, this method ensured accuracy for quality assurance and control of electrometers.
Assuntos
Dosímetros de Radiação , Incerteza , Calibragem , Guias como Assunto , Radiometria/instrumentação , Radiometria/métodos , Aceleradores de PartículasRESUMO
We report a case of a life-threatening ruptured renal angiomyolipoma (AML) that did not meet the criteria for prophylactic treatment (tumor >4 cm or intratumoral aneurysm >5 mm) during follow-up. A woman in her 70s was followed up for a 2.5-cm AML with a rich vascular component. An intratumoral aneurysm >5 mm was not identified for 2 years. She complained of a sudden abdominal pain with hypotension, and contrast-enhanced computed tomography revealed a retroperitoneal hematoma with contrast media extravasation from an intratumoral aneurysm. Emergency transcatheter arterial embolization was successfully performed using N-butyl cyanoacrylate glue. Rupture can occur in small AMLs or in AMLs not identified with intratumoral aneurysms during follow-up. AMLs with a rich vascular component at the kidney surface are more likely to rupture.
RESUMO
BACKGROUND: Lenalidomide is an immunomodulatory therapy used to treat multiple hematologic malignancies. The incidence of eosinophilia and hypereosinophilia during lenalidomide therapy, and the requirement for high-dose steroids are not well-defined PATIENTS AND METHODS: We retrospectively reviewed 44 patients with myelodysplastic syndromes who were treated with lenalidomide therapy from August 2006 and March 2023. RESULTS: Eosinophilia (0.5-1.5 × 109/L) and hypereosinophilia (>1.5 × 109/L) were observed in 6 patients (14%) and 4 patients (9%), respectively. The median duration of lenalidomide therapy was 6.5 months. Backward multivariate ordinary logistic regression identified higher absolute eosinophil count (OR, 4759.986; 95% CI, 11.223-2018772.073; P = .006) and longer duration of lenalidomide therapy (OR, 1.148; 95% CI, 1.012-1.302; P = .032) as independent prognostic factors for the incidence of eosinophilia and hypereosinophilia. There was a trend for a higher use of high-dose steroids with hypereosinophilia. The median time to develop the first occurrence hypereosinophilia was 0.5 months. Steroids were used in 40% of patients with eosinophilia or hypereosinophilia. All events resolved with discontinuation of lenalidomide and/or use of steroids. No long-tern lasting adverse effects were recorded. CONCLUSION: Lenalidomide may induce or worsen existing eosinophilia which may lead to the need for steroids within a month of therapy.