Optimal PET-based radiomic signature construction based on the cross-combination method for predicting the survival of patients with diffuse large B-cell lymphoma.

PURPOSE: To develop and externally validate models incorporating a PET radiomics signature (R-signature) obtained by the cross-combination method for predicting the survival of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: A total of 383 patients with DLBCL from two medical centres between 2011 and 2019 were included. The cross-combination method was used on three types of PET radiomics features from the training cohort to generate 49 feature selection-classification candidates based on 7 different machine learning models. The R-signature was then built by selecting the optimal candidates based on their progression-free survival (PFS) and overall survival (OS). Cox regression analysis was used to develop the survival prediction models. The calibration, discrimination, and clinical utility of the models were assessed and externally validated. RESULTS: The R-signatures determined by 12 and 31 radiomics features were significantly associated with PFS and OS, respectively (P<0.05). The combined models that incorporated R-signatures, metabolic metrics, and clinical risk factors exhibited significant prognostic superiority over the clinical models, PET-based models, and the National Comprehensive Cancer Network International Prognostic Index in terms of both PFS (C-index: 0.801 vs. 0.732 vs. 0.785 vs. 0.720, respectively) and OS (C-index: 0.807 vs. 0.740 vs. 0.773 vs. 0.726, respectively). For external validation, the C-indices were 0.758 vs. 0.621 vs. 0.732 vs. 0.673 and 0.794 vs. 0.696 vs. 0.781 vs. 0.708 in the PFS and OS analyses, respectively. The calibration curves showed good consistency, and the decision curve analysis supported the clinical utility of the combined model. CONCLUSION: The R-signature could be used as a survival predictor for DLBCL, and its combination with clinical factors may allow for accurate risk stratification.

Pharmacologic targeting of the P-TEFb complex as a therapeutic strategy for chronic myeloid leukemia.

BACKGROUND: The positive transcription elongation factor b (P-TEFb) kinase activity is involved in the process of transcription. Cyclin-dependent kinase 9 (CDK9), a core component of P-TEFb, regulates the process of transcription elongation, which is associated with differentiation and apoptosis in many cancer types. Wogonin, a natural CDK9 inhibitor isolated from Scutellaria baicalensis. This study aimed to investigate the involved molecular mechanisms of wogonin on anti- chronic myeloid leukemia (CML) cells. MATERIALS AND METHODS: mRNA and protein levels were analysed by RT-qPCR and western blot. Flow cytometry was used to assess cell differentiation and apoptosis. Cell transfection, immunofluorescence analysis and co-immunoprecipitation (co-IP) assays were applied to address the potential regulatory mechanism of wogonin. KU-812 cells xenograft NOD/SCID mice model was used to assess and verify the mechanism in vivo. RESULTS: We reported that the anti-CML effects in K562, KU-812 and primary CML cells induced by wogonin were regulated by P-TEFb complex. We also confirmed the relationship between CDK9 and erythroid differentiation via knockdown the expression of CDK9. For further study the mechanism of erythroid differentiation induced by wogonin, co-IP experiments were used to demonstrate that wogonin increased the binding between GATA-1 and FOG-1 but decreased the binding between GATA-1 and RUNX1, which were depended on P-TEFb. Also, wogonin induced apoptosis and decreased the mRNA and protein levels of MCL-1 in KU-812 cells, which is the downstream of P-TEFb. In vivo studies showed wogonin had good anti-tumor effects in KU-812 xenografts NOD/ SCID mice model and decreased the proportion of human CD45+ cells in spleens of mice. We also verified that wogonin exhibited anti-CML effects through modulating P-TEFb activity in vivo. CONCLUSIONS: Our study indicated a special mechanism involving the regulation of P-TEFb kinase activity in CML cells, providing evidences for further application of wogonin in CML clinical treatment. Video Abstract.

Value of total lesion glycolysis and cell-of-origin subtypes for prognostic stratification of diffuse large B-cell lymphoma patients.

BACKGROUND: This study aimed to explore the added prognostic value of baseline metabolic volumetric parameters and cell of origin subtypes to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in nodal diffuse large B-cell lymphoma (DLBCL) patients. METHODS: A total of 184 consecutive de novo nodal DLBCL patients who underwent baseline positron emission tomography/computed tomography (PET/CT) were included in this study. Kaplan-Meier estimates were generated to evaluate the clinical, biological, and PET/CT parameters' prognostic value. The Cox proportional hazards model was performed to examine the potential independent predictors for progression-free survival (PFS) and overall survival (OS). RESULTS: With a median follow-up of 35 months, the 3-year PFS and OS were 65.2% and 73.0%, respectively. In univariate analysis, total lesion glycolysis (TLG), cell-of-origin subtypes, and NCCN-IPI were both PFS and OS predictors. High TLG (≥1,852), non-germinal center B (non-GCB), as well as high NCCN-IPI (≥4), were shown to be independently significantly associated with inferior PFS and OS after multivariate analysis. Based on the number of risk factors (high TLG, non-GCB, and high NCCN-IPI), a revised risk model was designed, and the participants were divided into four risk groups with very different outcomes, in which the PFS rates were 89.7%, 66.2%, 51.7%, and 26.7% (χ2=30.179, P<0.001), and OS rates were 93.1%, 73.8%, 56.7%, and 43.3%, respectively (χ2=23.649, P<0.001), respectively. Compared with the NCCN-IPI alone, the revised risk model showed a stronger ability to reveal further discrimination among subgroups, especially for participants with very unfavorable survival outcomes (PFS: χ2=9.963, P=0.002; OS: χ2=4.166, P=0.041, respectively). CONCLUSIONS: The TLG, cell-of-origin subtypes, and NCCN-IPI are independent prognostic survival factors in DLBCL patients. Moreover, the revised risk model composed of the number of risk factors (high TLG, non-GCB, and high NCCN-IPI) can stratify patients better than the NCCN-IPI, especially for patients at high risk, which suggests its potential integration into decision making for personalized medicine.

Will Baseline Total Lesion Glycolysis Play a Role in Improving the Prognostic Value of the NCCN-IPI in Primary Gastric Diffuse Large B-Cell Lymphoma Patients Treated With the R-CHOP Regimen?

PURPOSE: The aim was to explore whether baseline total lesion glycolysis (TLG) can improve the prognostic value of the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) in primary gastric diffuse large B-cell lymphoma (PG-DLBCL) patients treated with an R-CHOP-like regimen. MATERIALS AND METHODS: Ninety-four PG-DLBCL patients who underwent baseline PET/CT between July 2010 and May 2019 were included in this retrospective study. FDG-avid lesions in each patient were segmented to calculate the SUVmax, total metabolic tumor volume (TMTV), and TLG. Progression-free survival (PFS) and overall survival (OS) were used as end points to evaluate prognosis. RESULTS: During the follow-up period of 5 to 108 months (35.3 ± 23.5 months), high TLG and a high NCCN-IPI were significantly associated with poor PFS and OS. Total lesion glycolysis and the NCCN-IPI were independent predictors of PFS and OS. Patients were stratified into 3 groups according to the combination of TLG and the NCCN-IPI for PFS (P < 0.001) and OS (P < 0.001): high-risk group (TLG > 1159.1 and NCCN-IPI 4-8) (PFS and OS, 57.7% and 61.5%, respectively, n = 42), intermediate-risk group (TLG > 1159.1 or NCCN-IPI 4-8) (PFS and OS, both 76.9%, n = 26), and low-risk group (TLG ≤ 1159.1 and NCCN-IPI 0-3) (PFS and OS, 97.6% and 100.0%, respectively, n = 26). CONCLUSIONS: Both TLG and the NCCN-IPI are independent predictors of PG-DLBCL patient survival. Moreover, the combination of TLG and the NCCN-IPI improved patient risk stratification and might help personalize therapeutic regimens.

Value of 18F-FDG PET/CT for prognostic stratification in patients with primary intestinal diffuse large B cell lymphoma treated with an R-CHOP-like regimen.

PURPOSE: The prognostic value of 18F-FDG PET/CT for primary intestinal diffuse large B-cell lymphoma (PI-DLBCL) patients has not been determined. This prompted us to explore the value of 18F-FDG PET/CT for prognostic stratification in patients with PI-DLBCL treated with an R-CHOP-like regimen. MATERIALS AND METHODS: Seventy-three PI-DLBCL patients who underwent baseline PET/CT between January 2010 and May 2019 were included in this retrospective study. Total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG) were computed using the 41% SUVmax thresholding method. Progression-free survival (PFS) and overall survival (OS) were used as endpoints to evaluate prognosis. RESULTS: During the follow-up period of 3-117 months (29.0 ± 25.5 months), high TLG, non-germinal center B-cell-like (non-GCB) and high National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) were significantly associated with inferior PFS and OS. TLG, cell-of-origin and NCCN-IPI were independent predictors of PFS, and both TLG and NCCN-IPI were independent predictors of OS. The grading system was based on the number of risk factors (high TLG, non-GCB, high NCCN-IPI) and patients were divided into 4 risk groups (PFS: χ2 = 33.858, P < 0.001; OS: χ2 = 29.435, P < 0.001): low-risk group (none of the 3 risk factors, 18 patients); low-intermediate risk group (1 risk factor, 24 patients); high-intermediate risk group (2 risk factors, 16 patients); and high-risk group (all 3 risk factors, 15 patients). CONCLUSIONS: High TLG, non-GCB and high NCCN-IPI can identify a subset of PI-DLBCL patients with inferior survival outcomes. Furthermore, the grading system can identify PI-DLBCL patient groups with markedly different prognoses, which might contribute to the adjustment of the therapeutic regime.

Fast-track multidisciplinary treatment versus conventional treatment for colorectal cancer: a multicenter, open-label randomized controlled study.

BACKGROUND: Laparoscopic surgery, fast-track perioperative treatment and XELOX chemotherapy are effective strategies for shortening the duration of hospital stay for cancer patients. This trial aimed to clarify the safety and efficacy of the fast-track multidisciplinary treatment (FTMDT) model compared to conventional surgery combined with chemotherapy in Chinese colorectal cancer patients. METHODS: This trial was a prospective randomized controlled study with a 2 × 2 balanced factorial design and was conducted at six hospitals. Patients in group 1 (FTMDT) received fast-track perioperative treatment and XELOX adjuvant chemotherapy. Patients in group 2 (conventional treatment) received conventional perioperative treatment and mFOLFOX6 adjuvant chemotherapy. Subgroups 1a and 2a had laparoscopic surgery and subgroups 1b and 2b had open surgery. The primary endpoint was total length of hospital stay during treatment. RESULTS: A total of 374 patients were randomly assigned to the four subgroups, and 342 patients were finally analyzed, including 87 patients in subgroup 1a, 85 in subgroup 1b, 86 in subgroup 2a, and 84 in subgroup 2b. The total hospital stay of group 1 was shorter than that of group 2 [13 days, (IQR, 11-17 days) vs. 23.5 days (IQR, 15-42 days), P = 0.0001]. Compared to group 2, group 1 had lower surgical costs, fewer in-hospital complications and faster recovery (all P < 0.05). Subgroup 1a showed faster surgical recovery than that of subgroup 1b (all P < 0.05). There was no difference in 5-year overall survival between groups 1 and 2 [87.1% (95% CI, 80.7-91.5%) vs. 87.1% (95% CI, 80.8-91.4%), P = 0.7420]. CONCLUSIONS: The FTMDT model, which integrates laparoscopic surgery, fast-track treatment, and XELOX chemotherapy, was the superior model for enhancing the recovery of Chinese patients with colorectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01080547 , registered on March 4, 2010.

A Data Mining-Based Analysis of Medication Rules in Treating Bone Marrow Suppression by Kidney-Tonifying Method.

OBJECTIVE: To investigate the rule of kidney-tonifying method in Chinese medicine for the treatment of bone marrow suppression (BMS), in order to provide evidence and references for the clinical application of herbs and formulae. DESIGN: Collecting and sorting the information about the treatment of BMS related to kidney-tonifying (Bushen) method in Chinese medicine literatures on databases including Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM), establishing a database of BMS treating formulae after radiotherapy and chemotherapy with traditional Chinese medicine (TCM) kidney-tonifying method, and finally applying the relevant theories and techniques of data mining to analyze the medication rules of it. RESULTS: A total of 239 formulae and 202 herbs were included in this database, in which the herbs occurred 2,602 times in general. The high frequency herbs included Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizoma (Baizhu), and Ligustri Lucidi Fructus (Nvzhenzi). The main herb categories were deficiency-tonifying herbs, blood-activating herbs, dampness-draining diuretic herbs, heat-clearing herbs, and digestant herbs. Deficiency-tonifying herbs accounted for 64.60% of the total number. A total of 8 clustering formulae are summarized according to cluster analysis and 26 herb suits association rules are identified by Apriori algorithm. CONCLUSION: The treatment of BMS is mainly based on the method of invigorating the spleen and tonifying the kidney and liver to strengthen healthy qi, supplementing with blood-activating herbs, and dampness-draining diuretic herbs to eliminate pathogenic factors.

Oroxylin A, a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells.

Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the upregulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation. The present study demonstrates that oroxylin A, a natural compound isolated from Scutellariae radix, sensitizes leukemia cells to TNFα and markedly enhances TNFα-induced growth inhibition and differentiation of AML cell including human leukemia cell lines and primary AML cells. Activation of PI3K/AKT pathway could be inhibited by oroxylin A through inhibiting expression of tRXRα in NB4 and HL-60-resistant cells. Furthermore, we found that oroxylin A inhibited the activation of NF-κB and the DNA binding activity by TNFα proved by EMSA in these two AML cell lines. Moreover, in vivo studies showed that treatment with oroxylin A in combination with TNFα decreased AML cell population and prolonged survival in NOD/SCID mice with xenografts of primary AML cells. Overall, our results indicate that oroxylin A is able to inhibit the negative effects of TNFα for AML therapy, suggesting that combination of oroxylin A and TNFα have the potential to delay growth or eliminate the abnormal leukemic cells, thus representing a promising strategy for AML treatment.

Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma.

PURPOSE: To evaluate whether the addition of two biological markers (MYC and BCL-2 protein overexpression) improves the stratification of high-risk patients with diffuse large B-cell lymphoma (DLBCL). METHOD: Seven risk factors were identified at diagnosis, and a maximum of 7 points were assigned to each patient. The patients were classified according to four risk groups: low (0-1), low-intermediate (2-3), high-intermediate (4), and high (5-7). Only high-risk patients with DLBCL were included in this analysis. We retrospectively examined 20 cases from 2008 to 2013 at the Nanjing Drum Tower Hospital. RESULTS: The median expression of MYC protein was 60%, and 17 of 20 (65%) evaluable cases overexpressed MYC. The median expression of BCL-2 protein was also 60%. Eighteen of 20 (90%) evaluable cases showed BCL-2 overexpression. Additionally, 12 out of 20 cases (60%) demonstrated coexpression of MYC and BCL-2 proteins. The percentages of overall survival and progression-free survival at the median follow-up time (36 months) were 33.3%±16.1% and 16.9%±13.5%, respectively. By comparison, nine, four, and 20 patients were classified as high risk based on the International Prognostic Index (IPI), National Comprehensive Cancer Network(NCCN)-IPI, and revised IPI criteria, respectively. According to the IPI and NCCN-IPI stratification, the risk groups demonstrated closely overlapping survival curves. In addition, four out of 20 cases were identified as low-intermediate risk according to the NCCN-IPI criteria. CONCLUSION: The addition of MYC and BCL-2 protein expression to the IPI could identify a subset of DLBCL patients with high-risk clinicopathological characteristics and poor clinical outcome.

Anticancer Effect and Apoptosis Induction of Gambogic Acid in Human Leukemia Cell Line K562 In Vitro.

BACKGROUND: The aim of this study was to investigate the anticancer effect and related mechanisms of gambogic acid (GA), a traditional Chinese medicine, on human leukemia cell line K562, together with the effect on bone marrow mononuclear cells (MNCs). MATERIAL AND METHODS: K562 cells and MNCs were treated with various concentrations and treatment times of GA. Inhibitory rate was detected by use of the Cell Counting Kit-8 (CCK-8) assay. Apoptosis was analyzed by morphological detection, Annexin-V/PI doubling staining, and TUNEL assays. The expression changes of pivotal proteins were evaluated by Western blotting. RESULTS: GA not only suppressed cell proliferation, but also induced apoptosis of K562 cells in a dose-dependent manner. While it did not significantly inhibit cell proliferation of MNCs, it did induce apoptosis in a dose-dependent manner. CCK-8 assay revealed that the proliferation of K562 cells was significantly inhibited when the concentration of GA was more than 0.5 µM. Morphological detection showed the nuclei became denser and more intense orange in K562 cells after GA treatment compared with the untreated group. The expression levels of BCL-2, nuclear factor-κB (NF-κB), c-myc, phosphatidylinositol3-kinase (PI3K), and phosphorylation of serine-threonine kinase (p-AKT) were down-regulated by GA. CONCLUSIONS: GA significantly suppressed the proliferation of K562 cells, but has less effect on MNCs. The inhibition of K562 cells proliferation and apoptosis induced by GA might be related to the down-regulation of BCL-2, NF-κB, c-myc, PI3K, and p-AKT.

Antihyperglycemic and antioxidant activity of water extract from Anoectochilus roxburghii in experimental diabetes.

The hypoglycemic and antioxidant effects of the water extract from Anoectochilus roxburghii in alloxan-induced diabetic mice were examined. Compared with untreated diabetic mice, the daily oral administration of the water extract from A. roxburghii at 0.5 or 2 g/kg for 14 days caused a significant decrease (p<.05) in blood glucose levels with similar effect but no evidence of dose-related effect. Simultaneously, the alteration in lipid metabolism was partially attenuated as evidenced by decreased serum total cholesterol and triglyceride levels and by increased high-density lipoprotein cholesterol concentration in diabetic mice (p<.05) but no dose-related effect was observed. In addition, the water extract from A. roxburghii caused a significant increase (p<.05) in the activities of enzymic antioxidants and the levels of vitamin E in liver and kidney of diabetic mice. Our results suggest that water extract from A. roxburghii possesses hypoglycemic and antioxidant properties after oral administration to mice showing alloxan-induced diabetes.

[Observation of clinical efficacy of acupuncture for cerebral vasospasm after embolization of ruptured aneurysms].

OBJECTIVE: To observe the improvement of acupuncture in cerebral vasospasm (CVS) after embolization of ruptured aneurysms. METHODS: Sixty cases were randomly divided into two groups, an acupuncture-medication group and a conventional treatment group, 30 cases in each one. The cases of CVS in conventional treatment group were treated with Nimodipine. In acupuncture-medication group, on the basis of the treatment as conventional treatment group, Baihui (GV 20) and Fengchi (GB 20) were selected as the main acupoints in the treatment of CVS. The treatment lasted for 3 weeks. Hunt-Hess scale for the standard assessment was adopted to determine the severity of disease before and after treatment and compare the efficacy between two groups. The transcranial Doppler (TCD) was conducted on the 1st, 4th, 7th, 10th, 14th and 21st days successively after operation, and the average flow velocity of 3 pairs of vessels (ACA, MCA, and PCA) was recorded. CT perfusion (CTP) was taken to test cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) on the 1st, 7th, 14th and 21st days successively. RESULTS: The improvement of Hunt-Hess scale in acupuncture-medication group was superior to that in conventional treatment group (P < 0.05). The analysis of variance (ANOVA) was adopted in the comparison of ACA, MCA, PCA, CBF, CBV and MTT between two groups. The results showed that the therapy in either group achieved the effect on CVS (all P < 0.05). But, the improvements in the above mentioned indices in acupuncture-medication group were superior to those in conventional treatment group (all P < 0.05). CONCLUSION: Acupuncture at Baihui (GV 20) and Fengchi (GB 20) down-regulates the peak values or upregulates the valley values. It releases the peak of CVS effectively, improves the clinical prognosis significantly and is the effective therapy for CVS after subarachnoid hemorrhage.