Purpose: Accumulating evidence indicates that intratumor heterogeneity is prevalent in multiple myeloma and that a collection of multiple, genetically distinct subclones are present within the myeloma cell population. It is not clear whether the size of clonal myeloma populations harboring unique cytogenetic abnormalities carry any additional prognostic value.Experimental Design: We analyzed the prognostic impact of cytogenetic aberrations by fluorescence in situ hybridization at different cutoff values in a cohort of 333 patients with newly diagnosed myeloma and 92 patients with relapsed myeloma.Results: We found that nearly all IgH-related arrangements were observed in a large majority of the purified plasma cells; however, 13q deletion, 17p deletion, and 1q21 amplification appeared in different percentages within the malignant plasma cell population. Based on the size of subclones carrying these cytogenetic aberrations, the patients were divided into four groups: 0%-10%, 10.5%-20%, 20.5%-50%, and >50%. Receiver-operating characteristics analysis was applied to determine the optimal cutoff value with the greatest differential survival and showed that the most powerful clone sizes were 10% for 13q deletion, 50% for 17p deletion, and 20% for 1q21 gains, which provided the best possible cutoffs for predicting poor outcomes.Conclusions: Our study indicated that the impact of clone size on prognostic value varies between specific genetic abnormalities. Prognostic value was observed for even a subgroup of plasma cells harboring the cytogenetic aberration of 13q deletion and 1q21 gains; however, 17p deletion displayed the most powerful cutoff for predicting survival only if the predominant clones harbored the abnormality.
ObjectiveTo evaluate the prognosis values of systemic immune–inflammation index (SII) in non-chronic cerebral venous sinus thrombosis (CVST).Methodspatients with CVST, admitted to the First Affiliated Hospital of Zhengzhou University, were retrospectively identified from January 2013 to December 2018. We selected patients in acute/subacute phase from database. Functional outcomes of patients were evaluated with the modified Rankin Scale (mRS)—mRS 3–6 as poor outcomes and mRS 6 as death. The overall survival time was defined as the date of onset to the date of death or last follow-up date. Survival analysis was described by the Kaplan-Meier curve and Cox regression analysis. Multivariate logistic regression analysis assessed the relationship between SII and poor functional outcome. The area under the Receiver Operating Curve curve (AUC) was estimated to evaluate the ability of SII in prediction.ResultsA total of 270 patients were included and their duration of follow-up was 22 months (6–66 months), of whom 31 patients had poor outcomes and 24 patients dead. Cox regression analysis showed that SII (HR=1.304, 95% CI: 1.101 to 1.703, p=0.001) was a predictor of death in non-chronic CVST. Patients with higher SII presented lower survival rates (p=0.003). The AUC of SII was 0.792 (95% CI: 0.695 to 0.888, p=0.040) with a sensitivity of 69.6% and specificity of 80.1%. Subgroups analysis demonstrated that SII was an important predictor of poor outcomes in male (OR=1.303, 95% CI: 1.102 to 1.501, p=0.011) and pregnancy/puerperium female (OR=1.407, 95% CI: 1.204 to 1.703, p=0.034).ConclusionsSII was a potential predictor in the poor prognosis of patients with acute/subacute CVST, especially in male and pregnancy/puerperium female.
Background: Revascularization of the supra-aortic major branches in thoracic endovascular aortic repair (TEVAR) is challenging owing to the complex anatomic configuration of aortic arch pathologies. This study aims to evaluate the feasibility, effectiveness, and safety of three major techniques-chimney, fenestrated, and in-situ fenestration-for patients with aortic arch pathologies. Methods: A retrospective analysis was performed involving 234 patients with aortic arch lesions, who underwent TEVAR with adaptations in technique (chimney, fenestrated, or in-situ fenestration) between January 2016 and December 2017. Results: One hundred and twenty-six patients underwent the chimney technique (98 single chimneys, 24 double chimneys, and four triple chimneys); one hundred and two patients (102/234) were treated with on-the-table fenestration technique (92 single fenestrations, nine double fenestrations, and one double fenestration plus innominate artery chimney); and the remaining six patients underwent in-situ needle fenestration technique. Overall, indications included aortic dissections (99/234), aortic arch aneurysms (60/234), penetrating aortic ulcers (72/234), and re-interventions (3/234). The technical success rates were 99.6%. There were five cases of early all-cause mortality. The patency rates of overall branches were 99.6%.There were 15 cases with type Ia endoleak-14 in the chimney group (11.1%) and one in the on-the-table fenestration group (1%). Five patients underwent re-interventions. The median follow-up time for all patients was 28 (range, 16-41) months. Conclusions: Our experience suggests that chimney, on-the-table fenestration, and in-situ needle fenestration techniques are feasible, effective, and safe treatment options for aortic arch pathologies with encouraging mid-term results. Long-term durability concerns require further evaluation.
Introduction The majority of acute promyelocytic leukemia (APL) cases are characterized by PML-RARα fusion gene. Although PML-RARα fusion gene can be detected in more than 98% of APL cases, RARα is also found to be fused with other partner genes, which are also related to ATRA-dependent transcriptional activity and cell differentiation. In this study, we identified a novel RARα fusion gene, TBLR1-RARα, in a rare case of APL with a t(3;17)(q26;q21),t(7;17)(q12;q21) complex chromosomal rearrangement. The structure, pathogenesis and response to drug therapy of the novel fusion gene were investigated to illustrate the characteristics, pathogenesis and the therapeutic effect in this variant APL. Methods To identify and amplify the novel chimeric fusion transcript, 5’ RACE and RT-PCR was performed. The TBLR1-RARα expression vector was constructed and transfected into 293T cell line by Lipofectamine2000 reagent. When the transfected 293T cell line was treated with or without ATRA, the expression level and the subcellular localization of TBLR1-RARα were investigated by Western blot and immunofluorescence analysis, and then coimmunoprecipitation and immunofluorescence analysis were performed to investigate the formation of homodimer and the recruitment of the corepressors by TBLR1-RARα. Dual-luciferase assay was used to clarify the transcriptional activity of TBLR1-RARα. Then, a lentiviral vector of TBLR1-RARα was constructed and infected the HL-60 cell line. The HL-60 cells which highly expressed TBLR1-RARα were sorted by flow cytometry. Colony formation assay and flow cytometry analysis were performed to detect the differentiation status in the TBLR1-RARα highly expressed HL-60 cells. Results In our study, the novel TBLR1-RARα fusion gene was cloned from an APL patient who demonstrated the typical clinical features of APL, such as bleeding tendency, leukocytosis, hypergranular promyelocytes accumulated in the bone marrow, coagulopathy. However, RT-PCR analysis and FISH studies failed to detect PML-RARα fusion gene in this case, while karyotype analysis revealed a rare complex translocation, t(3;17)(q26;q21),t(7;17)(q12;q21). When treated with ATRA, As2O3 and chemotherapeutic drugs, this patient achieved complete remission. After three courses of consolidation therapies, the patient relapsed with leukocytosis and the bone marrow karyotype analysis displayed a recurring chromosomal rearrangement, 46,xy,t(3;17)(q26;q21),t(7;17)(q12;q21),5q+,6q-,10q+,11p-, which was more complex in comparison with the karyotype at diagnosis. There have been nine RARα fusion genes reported so far. Like other RARα fusion genes, TBLR1-RARα contains the exon 3 and the 3’ sequence of RARα. TBLR1-RARα oncoprotein contains the LisH domain from TBLR1 and the B-F domains from RARα. TBLR1-RARα diffusely locates in nucleus and cytoplasm. Like other RARα fusion protein, TBLR1-RARα can form homodimer and recruit corepressors to inhibit the transcription of the RARα target gene. TBLR1-RARα inhibits the RARα transcriptional activation in a dominant-negative manner and the transcriptional inhibition can be rescued by overexpression of wild-type RARα. In the presence of pharmacological doses of ATRA, TBLR1-RARα could be degraded and its homodimerization was abrogated. Moreover, when treated with ATRA, TBLR1-RARα could mediate the dissociation and degradation of transcriptional corepressors and consequently transactivated transcription of RARα target genes and induced cell differentiation in a dose- and time- dependent manner. Finally, TBLR1-RARα was also detected in another two cases of APL with t(3;17) chromosomal translocation. Conclusions In this study, we discovered a novel RARα fusion gene TBLR1-RARα from a APL patient with t(3;17) chromosomal translocation, and investigated its function, pathogenesis and response to drug treatment. Unlike wild-type RARα, TBLR1-RARα can form homodimer, recruit more corepressors to inhibit the transcription of RARα target gene and play a role in APL pathogenesis. The transcriptional inhibition of TBLR1-RARα can be rescued by overexpression of RARα and ATRA treatment and finally leads to cell differentiation. Disclosures: Wang: Bristol Myers Squibb: Consultancy; Novartis: Consultancy.
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