A characterization for fuzzy strong cut vertices and fuzzy strong cut edges.

Cut vertices and cut edges are valuable for analyzing connectivity problems in classical graph theory. However, they cannot deal with certain fuzzy problems. In order to solve this problem, this paper introduces the definitions of fuzzy strong cut vertices and fuzzy strong cut edges, and characterizes fuzzy strong cut vertices and fuzzy strong cut edges in fuzzy trees, complete fuzzy graphs, and fuzzy cycles. Finally, practical applications verify the effectiveness of the theory in network stability analysis.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

Machine Learning Model Based on Optimized Radiomics Feature from 18F-FDG-PET/CT and Clinical Characteristics Predicts Prognosis of Multiple Myeloma: A Preliminary Study.

OBJECTS: To evaluate the prognostic value of radiomics features extracted from 18F-FDG-PET/CT images and integrated with clinical characteristics and conventional PET/CT metrics in newly diagnosed multiple myeloma (NDMM) patients. METHODS: We retrospectively reviewed baseline clinical information and 18F-FDG-PET/CT imaging data of MM patients with 18F-FDG-PET/CT. Multivariate Cox regression models involving different combinations were constructed, and stepwise regression was performed: (1) radiomics features of PET/CT alone (Rad Model); (2) Using clinical data (including clinical/laboratory parameters and conventional PET/CT metrics) only (Cli Model); (3) Combination radiomics features and clinical data (Cli-Rad Model). Model performance was evaluated by C-index and Net Reclassification Index (NRI). RESULTS: Ninety-eight patients with NDMM who underwent 18F-FDG-PET/CT between 2014 and 2019 were included in this study. Combining radiomics features from PET/CT with clinical data showed higher prognostic performance than models with radiomics features or clinical data alone (C-index 0.790 vs. 0.675 vs. 0.736 in training cohort; 0.698 vs. 0.651 vs. 0.563 in validation cohort; AUC 0.761, sensitivity 56.7%, specificity 85.7%, p < 0.05 in training cohort and AUC 0.650, sensitivity 80.0%, specificity78.6%, p < 0.05 in validation cohort) When clinical data was combined with radiomics, an increase in the performance of the model was observed (NRI > 0). CONCLUSIONS: Radiomics features extracted from the PET and CT components of baseline 18F-FDG-PET/CT images may become an effective complement to provide prognostic information; therefore, radiomics features combined with clinical characteristic may provide clinical value for MM prognosis prediction.

Recombinant human p53 adenovirus injection combined with Bortezomib inhibits proliferation and promotes apoptosis in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a B-cell malignancy characterized by abnormal proliferation of clonal plasma cells in the bone marrow, the incidence of which has further increased in recent years. In multiple myeloma, wild-type functional p53 is often inactivated or dysregulated. Therefore, this study aimed to investigate the role of p53 knockdown or overexpression in multiple myeloma and the therapeutic effect of recombinant adenovirus-p53 (rAd-p53) in combination with Bortezomib. METHODS: SiRNA p53 and rAd-p53 were used to knock down and overexpress p53. RT-qPCR was used to detect gene expression, and western blotting (WB) was used to detect protein expression levels. We also constructed wild-type multiple myeloma cell line-MM1S cell xenograft tumor models and explored the effects of siRNA-p53, rAd-p53, and Bortezomib on multiple myeloma in vivo and in vitro. H&E staining and KI67 immunohistochemical staining were used to assess the anti-myeloma effects of recombinant adenovirus and Bortezomib in vivo. RESULTS: The designed siRNA p53 effectively led to the knockdown of the p53 gene, while rAd-p53 could significantly achieve p53 overexpression. p53 gene inhibited MM1S cell proliferation and promoted apoptosis of wild-type multiple myeloma cell line MM1S. P53 gene inhibited tumor proliferation in vitro by promoting p21 expression and reducing cell cycle protein B1 expression of MM1S. P53 gene overexpression could inhibit tumor growth in vivo. Injection of rAd-p53 in tumor models inhibited tumor development through p21- and cyclin B1-mediated cell proliferation and apoptosis regulation. CONCLUSIONS: We found that overexpression of p53 inhibits MM tumor cell survival and proliferation in vivo and in vitro. Furthermore, the combination of rAd-p53 and Bortezomib significantly improved the efficacy, which provides a new possibility for more effective treatment of MM.

Ruxolitinib as Adjunctive Therapy for Hemophagocytic LymPhohistiocytosis after Liver Transplantation: A Case Report and Literature Review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal hyperinflammatory disorder characterized by dysfunctional cytotoxic T and natural killer cells. Liver transplantation is a predisposing factor for HLH. High mortality rates were reported in 40 cases of HLH following liver transplantation in adults and children. Herein, we describe a case of adult HLH triggered by cytomegalovirus (CMV) infection shortly after liver transplantation. The patient was successfully treated with ruxolitinib combined with a modified HLH-2004 treatment strategy. Our case is the first to report the successful use of ruxolitinib with a modified HLH-2004 strategy to treat HLH in a solid organ transplantation recipient.

Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma.

HDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%-35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

Distinct clinical features and prognostic factors of hepatitis C virus-associated non-Hodgkin's lymphoma: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence suggests that hepatitis C virus (HCV) infection is associated with non-Hodgkin's lymphoma (NHL). However, no clear consensus has been reached about the clinical features and effective treatment of HCV-associated NHL patients. We therefore performed a systematic review and meta-analysis to explore the clinical characteristics and effectiveness of antiviral treatment or rituximab administration among NHL patients with HCV infection. METHODS: Eight electronic databases, including PubMed, OVID, EMBASE, Cochrane Library, ClinicalTrials, WANFANG, CNKI, and VIP, were searched for eligible studies up to July 31, 2021. The hazard ratio (HR) or odds ratio (OR) corresponding to the 95% confidence interval (CI) was calculated to estimate the outcomes. Publication bias was assessed by Egger's and Begg's tests. Statistical analysis was performed with RevMan 5.4 software and Stata version 15. RESULTS: There were 27 shortlisted articles out of a total of 13,368 NHL patients included in the current meta-analysis. Our results demonstrated that NHL patients with HCV infection had a significantly shorter overall survival (OS: HR 1.89; 95% CI 1.42-2.51, P < 0.0001) and progression-free survival (PFS: HR 1.58; 95% CI 1.26-1.98, P < 0.0001), a lower overall response rate (ORR: OR 0.58, 95% CI 0.46-0.73, P < 0.00001) and a higher incidence of hepatic dysfunction during chemotherapy (OR 5.96; 95% CI 2.61-13.62, P < 0.0001) than NHL patients without HCV infection. HCV-positive NHL patients exhibited an advanced disease stage, an elevated level of LDH, a high-intermediate and high IPI/FLIPI risk as well as a higher incidence of spleen and liver involvement. Moreover, antiviral treatment prolonged survival (OS: HR 0.38; 95% CI 0.24-0.60, P < 0.0001), reduced disease progression [PFS/DFS (disease-free survival): HR 0.63; 95% CI 0.46-0.86, P = 0.003] and reinforced the treatment response (ORR: OR 2.62; 95% CI 1.34-5.11, P = 0.005) among the HCV-infected NHL patients. Finally, rituximab administration was associated with a favourable OS, while liver cirrhosis and low levels of albumin predicted a poor OS for HCV-positive NHL patients. CONCLUSIONS: The current study provided compelling evidence about an inferior prognosis and distinct clinical characteristics among HCV-associated NHL patients. Antiviral treatment and rituximab-containing regimens were shown to be efficacious in improving the clinical outcomes of NHL patients with HCV infection.

Screening and identification of a novel FHL2 mutation by whole exome sequencing in twins with familial Waldenström macroglobulinemia.

BACKGROUND: Waldenström macroglobulinemia (WM) is a rare chronic B-cell lymphoma. Familial clustering of WM has been observed over the years. However, little is known about the contribution of inherited genetic variants to familial WM cases. METHODS: The authors performed whole exome sequencing (WES) of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Bioinformatics analysis of public biological databases was used to identify the most relevant familial WM candidate from WES. Transcript expression and protein levels of the familial WM candidate were evaluated in the WM patient and 2 unaffected members of the kindred. RESULTS: Among the 10 shared candidate mutations in the twins, the authors identified a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) as a familial WM-associated mutation. FHL2 appeared to be connected with reported signaling pathways and disease-driving genes such as IL6 and HCK in WM. In addition, the authors found reduced FHL2 messenger RNA and protein expression in peripheral blood samples from the patient with WM in comparison with the healthy siblings. CONCLUSIONS: Taken together, these findings indicate that an FHL2g226a mutation may play an important role in familial WM, and they provide new screening possibilities for familial cases. LAY SUMMARY: Familial clustering in Waldenström macroglobulinemia (WM) has been observed over the years. The authors performed whole exome sequencing of germline DNA samples from twins, one diagnosed with WM and the other diagnosed with immunoglobulin M monoclonal gammopathy of undetermined significance, and their healthy siblings. Among the 10 shared candidate mutations in the twins, a novel heterozygous germline mutation in four and a half LIM domains protein 2 (FHL2; c.G226A, p.V76M) was identified as the most relevant familial WM candidate through bioinformatics analysis of a public database. Also, messenger RNA and protein expression of FHL2 was significantly lower in peripheral blood mononuclear cells of the WM patient in comparison with the healthy siblings, and this suggested that the function of FHL2 was impaired when mutated.

Rhodium-catalyzed synthesis of substituted isoquinolones via a selective decarbonylation/alkyne insertion cascade of phthalimides.

A rhodium-catalyzed decarbonylation/alkyne insertion cascade of phthalimides has been established. The reaction can be carried out in an operationally simple manner and provides expedient access to a series of isoquinolones in moderate to good yields. This reaction proceeded through a sequential decarbonylation/alkyne insertion/intramolecular annulation procedure and featured good functional group tolerance, ample substrate scope, and the construction of C-C and C-N bonds in one pot.

Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta-analysis of clinical trials.

Multiple myeloma (MM) remains incurable primarily due to relapse. Histone deacetylase inhibitors (HDACis) have shown potential application for the treatment of relapsed/refractory multiple myeloma (RRMM). To assess the efficacy and safety of HDACis in RRMM treatment, a systematic review and meta-analysis were conducted based on clinical trial data. A literature search was performed using PubMed, EMBASE, Web of Science and the Cochrane Library databases. Subsequently, 19 trials with 2193 patients treated with one of the three HDACis, panobinostat, ricolinostat and vorinostat, were identified and included in the present study. The efficacy and toxicity of each agent were assessed. The data were pooled using a random effects model in STATA 13.0. The results showed that the overall response rate (ORR) was 0.64 with a 95% confidence interval (CI) of 0.61-0.68 for panobinostat, 0.51 (95% CI, 0.46-0.55) for vorinostat and 0.38 (95% CI, 0.29-0.48) for ricolinostat. Additionally, subgroup analysis revealed an ORR of 0.36 (95% CI, 0.27-0.46) for HDACis-treated bortezomib-refractory MM patients and 0.43 (95% CI, 0.30-0.55) for lenalidomide-refractory patients. The most common grade 3 and 4 hematological adverse events were thrombocytopenia, neutropenia and anemia. Non-hematological adverse events included fatigue/asthenia, diarrhea and nausea. In conclusion, analysis of the pooled data revealed that panobinostat-containing regimens were effective and tolerable for patients with RRMM. Furthermore, lenalidomide-refractory patients may derive greater benefits from these regimens. More clinical and real-world studies are required to validate these results.

The histone methyltransferase Setd2 is indispensable for V(D)J recombination.

The diverse repertoire of T cell receptors (TCR) and immunoglobulins is generated through the somatic rearrangement of respective V, D and J gene segments, termed V(D)J recombination, during early T or B cell development. However, epigenetic regulation of V(D)J recombination is still not fully understood. Here we show that the deficiency of Setd2, a histone methyltransferase that catalyzes lysine 36 trimethylation on histone 3 (H3K36me3) in mice, causes a severe developmental block of thymocytes at the CD4-CD8- DN3 stage. While H3K36me3 is normally enriched at the TCRß locus, Setd2 deficiency reduces TCRß H3K36me3 and suppresses TCRß V(D)J rearrangement by impairing RAG1 binding to TCRß loci and the DNA double-strand break repair. Similarly, Setd2 ablation also impairs immunoglobulin V(D)J rearrangement to induce B cell development block at the pro-B stage. Lastly, SETD2 is frequently mutated in patients with primary immunodeficiency. Our study thus demonstrates that Setd2 is required for optimal V(D)J recombination and normal lymphocyte development.

Chinese consensus on management of tyrosine kinase inhibitor-associated side effects in gastrointestinal stromal tumors.

Tyrosine kinase inhibitors (TKIs) have improved the overall survival of patients with gastrointestinal stromal tumors (GISTs), but their side effects can impact dose intensity and, consequently, the clinical benefit. To date, no guideline or consensus has been published on the TKI-associated adverse reactions. Therefore, the Chinese Society of Surgeons for Gastrointestinal Stromal Tumor of the Chinese Medical Doctor Association organized an expert panel discussion involving representatives from gastrointestinal surgery, medical oncology, cardiology, dermatology, nephrology, endocrinology, and ophthalmology to consider the systemic clinical symptoms, molecular and cellular mechanisms, and treatment recommendations of GISTs. Here, we present the resultant evidence- and experience-based consensus to guide the management of TKI-associated side events in clinical practice.

Subclinical Anthracycline-Induced Cardiotoxicity in the Long - Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis.

BACKGROUND: Anthracycline generates progressive left ventricular dysfunction associated with a poor prognosis. OBJECTIVES: The purpose of this study was to evaluate whether layer-specific strain analysis could assess the subclinical left ventricular dysfunction after exposure to anthracycline. METHODS: Forty-two anthracycline-treated survivors of large B-cell non-Hodgkin lymphoma, aged 55.83 ± 17.92 years (chemotherapy group) and 27 healthy volunteers, aged 51.39 ± 13.40 years (control group) were enrolled. The cumulative dose of epirubicin in chemotherapy group was 319.67 ± 71.71mg/m2. The time from last dose of epirubicin to the echocardiographic examination was 52.92 ± 22.32 months. Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), subendocardial, mid and subepicardial layer of longitudinal (LS-ENDO, LS-MID, LS-EPI) and circumferential strain (CS-ENDO, CS-MID, CS-EPI) values were analyzed. Transmural strain gradient was calculated as differences in peak systolic strain between the subendocardial and subepicardial layers. A value of p < 0.05 was considered significant. RESULTS: Conventional parameters of systolic and diastolic function showed no significant difference between two groups. Compared with controls, patients had significantly lower GCS and GLS. Multi-layer speckle tracking analysis showed significant reduction of circumferential strain of subendocardial layer, transmural CS gradient and longitudinal strain of all three layers. In contrast, the two groups did not differ in transmural longitudinal strain gradient and radial strains. CONCLUSIONS: It proved the preferential impairment of subendocardial deformation in long-term survivors after exposure to anthracycline. Multi-layer speckle tracking echocardiography might facilitate the longitudinal follow-up of this at-risk patient cohort.

A case of ureteral myeloid sarcoma post-renal transplantation.

BACKGROUND: Significant attention has been directed toward the high incidence of malignant tumours that occur post-transplantation. However, there are few reports of myeloid sarcomas (MSs) following renal transplantation. CASE PRESENTATION: This case report describes a 26-year-old male patient who presented with repeatedly high creatinine levels and hydronephrosis six months post-renal transplantation. Surgical pathology revealed ureteral MS; however, the tumour recurred following resection. Bone marrow biopsy indicated that the patient also had acute promyelocytic leukaemia. The tumour was treated with local radiotherapy, and the leukaemia was treated with systemic chemotherapy. The patient's conditions were satisfactory at the one-year follow-up. CONCLUSIONS: This report is the first to describe a ureteral MS post-renal transplantation. Our findings suggest that surgical resection combined with radiotherapy and chemotherapy can help control the status of patients with this condition.

Subclinical Anthracycline-Induced Cardiotoxicity in the Long - Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis / Cardiotoxicidade Subclínica Induzida por Antraciclina no Seguimento a Longo Prazo de Sobreviventes de Linfoma: Uma Análise Speckle Tracking Multi-Layer

Abstract Background: Anthracycline generates progressive left ventricular dysfunction associated with a poor prognosis. Objectives: The purpose of this study was to evaluate whether layer-specific strain analysis could assess the subclinical left ventricular dysfunction after exposure to anthracycline. Methods: Forty-two anthracycline-treated survivors of large B-cell non-Hodgkin lymphoma, aged 55.83 ± 17.92 years (chemotherapy group) and 27 healthy volunteers, aged 51.39 ± 13.40 years (control group) were enrolled. The cumulative dose of epirubicin in chemotherapy group was 319.67 ± 71.71mg/m2. The time from last dose of epirubicin to the echocardiographic examination was 52.92 ± 22.32 months. Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), subendocardial, mid and subepicardial layer of longitudinal (LS-ENDO, LS-MID, LS-EPI) and circumferential strain (CS-ENDO, CS-MID, CS-EPI) values were analyzed. Transmural strain gradient was calculated as differences in peak systolic strain between the subendocardial and subepicardial layers. A value of p < 0.05 was considered significant. Results: Conventional parameters of systolic and diastolic function showed no significant difference between two groups. Compared with controls, patients had significantly lower GCS and GLS. Multi-layer speckle tracking analysis showed significant reduction of circumferential strain of subendocardial layer, transmural CS gradient and longitudinal strain of all three layers. In contrast, the two groups did not differ in transmural longitudinal strain gradient and radial strains. Conclusions: It proved the preferential impairment of subendocardial deformation in long-term survivors after exposure to anthracycline. Multi-layer speckle tracking echocardiography might facilitate the longitudinal follow-up of this at-risk patient cohort.

Resumo Fundamentos: A antraciclina gera uma disfunção ventricular esquerda progressiva associada a um prognóstico ruim. Objetivos: O propósito deste estudo foi avaliar se a análise layer específico de strain poderia avaliar disfunção ventricular esquerda subclínica após exposição a antraciclina. Métodos: Foram inscritos quarenta e dois sobreviventes tratados com antraciclina por linfoma não Hodgkin de células B grandes, de 55,83 ± 17,92 anos (grupo de quimioterapia) e 27 voluntários saudáveis, de 51,39 ± 13,40 anos (grupo controle). A dose cumulativa de epirrubicina no grupo de quimioterapia foi de 319,67 ± 71,71 mg/m2. O tempo desde a última dose de epirrubicina até o exame ecocardiográfico foi de 52,92 ± 22,32 meses. Analisaram-se o strain longitudinal global (GLS), o circunferencial (GCS) e o strain radial (GRS), os valores das camadas subendocárdica, média e subepicárdica so strain longitudinal (LS-ENDO, LS-MID, LS-EPI) e do strain circunferencial (CS-ENDO, CS-MID, CS-EPI). O gradiente de strain transmural foi calculado como a diferença no strain sistólico pico entre as camadas subendocárdicas e subepicárdicas. Um valor de p < 0,05 foi considerado significativo. Resultados: Os parâmetros convencionais da função sistólica e diastólica não mostraram diferenças significativas entre dois grupos. Comparados aos controles, os pacientes apresentaram GCS e GLS significativamente menores. A análise de speckle tracking multi-layer mostrou uma redução significativa no strain circunferencial da camada subendocárdica, o gradiente transmural CS e o strain longitudinal das três camadas. Em contraste, os dois grupos não diferiram no gradiente de strain longitudinal transmural e de strain radiais. Conclusões: Provou-se a deterioração preferencial do strain subendocárdico em sobreviventes de longa duração após exposição à antraciclina. O ecocardiograma de speckle tracking multi-layer pode facilitar o acompanhamento longitudinal dessa coorte de pacientes em risco. (Arq Bras Cardiol. 2018; 110(3):219-228)

Correlation of pretreatment 18F-FDG uptake with clinicopathological factors and prognosis in patients with newly diagnosed diffuse large B-cell lymphoma.

OBJECTIVES: The aim of this study is to determine the correlation of pretreatment fluorine-18 fluorodeoxyglucose uptake with clinicopathological factors and its prognostic value in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: A cohort of 162 patients with newly diagnosed DLBCL who had undergone pretreatment PET/computed tomography was retrospectively reviewed. The relationship of pretreatment maximum standard uptake value (SUVmax) with clinical factors, molecular markers, and efficacy was evaluated. The value of SUVmax in predicting progression-free survival (PFS) and overall survival was analyzed. RESULTS: In all, 72.9% of the patients received R-CHOP treatment; the rest received CHOP chemotherapy. The median follow-up duration was 30 months (range, 4-124 months). The median SUVmax was 12.2 (range, 1.7-42.7). SUVmax between groups differed significantly with respect to each of International Prognostic Index (IPI) factors, except for age and performance status. High SUVmax was associated with high Ki-67 and Glut-3 protein expression, but not with Glut-1. Complete remission rate differed significantly between the low (SUVmax≤9.0) and the high SUVmax (SUVmax>9.0) groups (91.7 vs. 61.1%, P=0.000). Patients with low SUVmax showed favorable survival (3-year PFS: 92.2 vs. 63.6%, P=0.000; 3-year overall survival: 95.5 vs. 78.3%, P=0.003). On multivariate analyses, SUVmax predicted PFS independent of revised-IPI (SUVmax: P=0.011, hazard ratio 4.784; revised-IPI: P=0.004, hazard ratio 2.551). CONCLUSION: Pretreatment SUVmax was associated with clinicopathological factors, efficacy, and survival outcome. A novel prognostic model on the basis of IPI score/pretreatment SUVmax might be useful for risk stratification of patients with newly diagnosed DLBCL Video abstract: http://links.lww.com/NMC/A55.

RUNX1-Evi-1 fusion gene inhibited differentiation and apoptosis in myelopoiesis: an in vivo study.

BACKGROUND: Acute myeloid leukemia (AML) 1-Evi-1 is a chimeric gene generated by the t (3; 21) (q26; q22) translocation, which leads into malignant transformation of hematopoietic stem cells by unclear mechanisms. This in vivo study aimed to establish a stable line of zebrafish expressing the human RUNX1-Evi-1 fusion gene under the control of a heat stress-inducible bidirectional promoter, and investigate its roles in hematopoiesis and hematologic malignancies. METHODS: We introduced human RUNX1-Evi-1 fusion gene into embryonic zebrafish through a heat-shock promoter to establish Tg(RE:HSE:EGFP) zebrafish. Two males and one female mosaic F0 zebrafish embryos (2.1%) were identified as stable positive germline transgenic zebrafish. RESULTS: The population of immature myeloid cells and hematopoietic blast cells were accumulated in peripheral blood and single cell suspension from kidney of adult Tg(RE:HSE:EGFP) zebrafish. RUNX1-Evi-1 presented an intensive influence on hematopoietic regulatory factors. Consequently, primitive hematopoiesis was enhanced by upregulation of gata2 and scl, while erythropoiesis was downregulated due to the suppression of gata1. Early stage of myelopoiesis was flourishing with the high expression of pu.1, but it was inhibited along with the low expression of mpo. Microarray analysis demonstrated that RUNX1-Evi-1 not only upregulated proteasome, cell cycle, glycolysis/gluconeogenesis, tyrosine metabolism, drug metabolism, and PPAR pathway, but also suppressed transforming growth factor ß, Jak-STAT, DNA replication, mismatch repair, p53 pathway, JNK signaling pathway, and nucleotide excision repair. Interestingly, histone deacetylase 4 was significantly up-regulated. Factors in cell proliferation were obviously suppressed after 3-day treatment with histone deacetylase inhibitor, valproic acid. Accordingly, higher proportion of G1 arrest and apoptosis were manifested by the propidium iodide staining. CONCLUSION: RUNX1-Evi-1 may promote proliferation and apoptosis resistance of primitive hematopoietic cell, and inhibit the differentiation of myeloid cells with the synergy of different pathways and factors. VPA may be a promising choice in the molecular targeting therapy of RUNX1-Evi-1-related leukemia.