RESUMO
ABSTRACT: Posttransplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation, and cytotoxic chemotherapy is associated with treatment-related morbidity and mortality. Current treatment takes a sequential, risk-stratified approach, and patients with low-risk disease after initial immunotherapy can avoid escalation to immunochemotherapy. TIDaL is a prospective, single-arm phase 2 trial investigating the activity and tolerability of ibrutinib combined with risk-stratified therapy for first-line treatment of PTLD. Eligible patients were adults with newly diagnosed CD20+ B-cell PTLD after solid organ transplant and performance status 0 to 2. Initial treatment comprised 49 days of ibrutinib 560 mg once daily, with 4 doses of weekly rituximab. Treatment response on interim scan and baseline International Prognostic Index were used to allocate patients to either a low-risk arm (who continued ibrutinib, alongside 4 further doses of 3-weekly rituximab) or high-risk (escalation to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] immunochemotherapy, with ibrutinib continuing in patients aged <65 years). The primary outcome was complete response on interim scan, achieved by 11 of 38 patients (29%; 95% confidence interval [CI], 15-46). This did not reach the prespecified threshold for clinically significant activity. Secondary outcomes included allocation to the low-risk arm (41% of patients), 2-year progression-free survival (58%; 95% CI, 44-76), and 2-year overall survival (76%; 95% CI, 63-91). Adverse events were mostly hematological, gastrointestinal, and infective. Although TIDaL does not support adding ibrutinib into first-line treatment of PTLD, increasing the proportion of patients who can be treated without cytotoxic chemotherapy remains an important aim of future research. This trial was registered at www.clinicaltrials.gov as #ISRCTN32667607.
Assuntos
Adenina , Protocolos de Quimioterapia Combinada Antineoplásica , Transtornos Linfoproliferativos , Piperidinas , Rituximab , Humanos , Piperidinas/uso terapêutico , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Pessoa de Meia-Idade , Feminino , Masculino , Adenina/análogos & derivados , Adenina/uso terapêutico , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Idoso , Adulto , Rituximab/efeitos adversos , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante de Órgãos/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Doxorrubicina/administração & dosagem , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Prospectivos , Pirazóis/uso terapêutico , Pirazóis/efeitos adversos , Pirazóis/administração & dosagemRESUMO
We investigated the effects of transcriptional intermediary factor 1γ (TIF1γ) and SMAD4 on the proliferation and liver metastasis of colorectal cancer (CRC) cells through knockdown of TIF1γ and/or SMAD4 and knockdown of TIF1γ and/or restoration of SMAD4 expression. Furthermore, we examined TIF1γ and SMAD4 expression in human primary CRC and corresponding liver metastatic CRC specimens. TIF1γ promoted but SMAD4 inhibited the proliferation of CRC cells by competitively binding to activated SMAD2/SMAD3 complexes and then reversely regulating c-Myc, p21, p27, and cyclinA2 levels. Surprisingly, both TIF1γ and SMAD4 reduced the liver metastasis of all studied CRC cell lines via inhibition of MEK/ERK pathway-mediated COX-2, Nm23, uPA, and MMP9 expression. In patients with advanced CRC, reduced TIF1γ or SMAD4 expression was correlated with increased invasion and liver metastasis and was a significant, independent risk factor for recurrence and survival after radical resection. Patients with advanced CRC with reduced TIF1γ or SAMD4 expression had higher recurrence rates and shorter overall survival. TIF1γ and SMAD4 competitively exert contrasting effects on cell proliferation but act complementarily to suppress the liver metastasis of CRC via MEK/ERK pathway inhibition. Thus, reduced TIF1γ or SMAD4 expression in advanced CRC predicts earlier liver metastasis and poor prognosis.
Assuntos
Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteína Smad4 , Fatores de Transcrição/metabolismoRESUMO
Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.
Assuntos
Receptor gp130 de Citocina , Interleucina-11 , Síndrome de Job , Humanos , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Citocinas/genética , Citocinas/metabolismo , Interleucina-11/metabolismo , Interleucina-6/metabolismo , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Fator de Transcrição STAT3/metabolismoRESUMO
Regardless of their age, adult patients with Wiskott-Aldrich syndrome should be considered for hematopoietic stem cell transplantation if clinically indicated.