Correlation of distribution characteristics and dynamic changes of gut microbiota with the efficacy of immunotherapy in EGFR-mutated non-small cell lung cancer.

BACKGROUND: The effects of gut microbiota and metabolites on the responses to immune checkpoint inhibitors (ICIs) in advanced epidermal growth factor receptor (EGFR) wild-type non-small cell lung cancer (NSCLC) have been studied. However, their effects on EGFR-mutated (EGFR +) NSCLC remain unknown. METHODS: We prospectively recorded the clinicopathological characteristics of patients with advanced EGFR + NSCLC and assessed potential associations between the use of antibiotics or probiotics and immunotherapy efficacy. Fecal samples were collected at baseline, early on-treatment, response and progression status and were subjected to metagenomic next-generation sequencing and ultra-high-performance liquid chromatography-mass spectrometry analyses to assess the effects of gut microbiota and metabolites on immunotherapy efficacy. RESULTS: The clinical data of 74 advanced EGFR + NSCLC patients were complete and 18 patients' fecal samples were dynamically collected. Patients that used antibiotics had shorter progression-free survival (PFS) (mPFS, 4.8 vs. 6.7 months; P = 0.037); probiotics had no impact on PFS. Two dynamic types of gut microbiota during immunotherapy were identified: one type showed the lowest relative abundance at the response time point, whereas the other type showed the highest abundance at the response time point. Metabolomics revealed significant differences in metabolites distribution between responders and non-responders. Deoxycholic acid, glycerol, and quinolinic acid were enriched in responders, whereas L-citrulline was enriched in non-responders. There was a significant correlation between gut microbiota and metabolites. CONCLUSIONS: The use of antibiotics weakens immunotherapy efficacy in patients with advanced EGFR + NSCLC. The distribution characteristics and dynamic changes of gut microbiota and metabolites may indicate the efficacy of immunotherapy in advanced EGFR + NSCLC.

Development of a Silicone Rubber Mold with an Innovative Waterfall Cooling Channel.

A conformal cooling channel (CCC) follows the mold core or cavity profile to carry out uniform cooling in the cooling stage. However, the significant pressure drop along the cooling channels is a distinct disadvantage of the CCC. In this study, an innovative waterfall cooling channel (WCC) was proposed and implemented. The WCC cools the injected products via surface contact, replacing the conventional line contact to cool the injected products. The WCC was optimized using numerical simulation software. Silicone rubber molds with two kinds of cooling channels were designed and implemented. The cooling time of the molded part was evaluated using a low-pressure wax injection molding machine. The experimental results of the cooling time of the molded part were compared with the simulation results from numerical simulation software. The results showed that the optimal mesh element count was about 1,550,000 with a mesh size of 1 mm. The simulation software predicted the filling time of the water cup injection-molded product to be approximately 2.008 s. The cooling efficiency for a silicone rubber mold with a WCC is better than that of the silicone rubber mold with a CCC since the core and cavity cooling efficiency is close to 50%. The pressure drop of the WCC is smaller than that of the CCC, which reduces the pressure drop by about 56%. Taking a water cup with a mouth diameter of 70 mm, a height of 60 mm, and a thickness of 2 mm as an example, the experimental results confirmed that the use of the WCC can save the cooling time of the product by about 265 s compared with the CCC. This shows how a WCC can increase cooling efficiency by approximately 17.47%.

Effects of Rotational Speed on Joint Characteristics of Green Joining Technique of Dissimilar Polymeric Rods Fabricated by Additive Manufacturing Technology.

Friction welding (FW) FW of dissimilar polymer rods is capable of manufacturing green products swiftly and economically. In this study, a green manufacturing technique of joining dissimilar polymer rods was proposed, and the effects of rotational speed on the joint characteristics of friction-welded dissimilar polymer rods fabricated by the fused deposition modeling process were investigated experimentally. The shore surface hardness test, impact test, three-point bending test, and differential scanning calorimetry analysis were carried out on the weld joints. The impact energy for FW of polylactic acid (PLA) and PLA, PLA and acrylonitrile butadiene styrene (ABS), PLA and PLA filled with glass fiber (GF), PLA and PLA filled with carbon fiber (CF), PLA and polycarbonate (PC), and PLA and polyamide (PA) rods can be increased by approximately 1.5, 1.5, 1.3, 1.3, 2.1, and 1.5 times by increasing the rotational speed from 330 rpm to 1350 rpm. The bending strength for FW of PLA and PLA, PLA and ABS, PLA and PLA filled with GF, PLA and PLA filled with CF, PLA and PC, and PLA and PA rods can be increased by approximately 1.3, 1.7, 1.3, 1.2, 1.2, and 1.2 times by increasing the rotational speed from 330 rpm to 1350 rpm. However, the surface hardness of the weld bead is not proportional to the rotational speed. The average surface hardness of the weld bead was increased by approximately 5% compared to the surface hardness of the welding base materials.

Second Primary Malignancy Risk in Multiple Myeloma from 1975 to 2018.

As the survival times for multiple myeloma (MM) patients continue to extend, the risk of a second primary malignancy (SPM) among MM survivors has become a topic of increasing concern within the medical community. The Surveillance, Epidemiology, and End Results (SEER) 9 Registry Database was used to evaluate the risk and survival of SPM among MM survivors from 1975 to 2018. The standardized incidence ratio (SIR), absolute excess risk (AER), and cumulative incidence (CMI) of SPM for MM risk were calculated. Survival and the CMI were estimated by using hazard ratios (HRs). Subgroup analyses were performed according to race, sex, age, time of myeloma diagnosis, and the SPM site. A total of 43,825 cases were recorded with the initial diagnosis of MM from 1975 to 2018. A total of 3101 (7.1%) patients developed 3407 SPMs. Solid tumors were decreased in patients with MM (SIR = 0.93; 95% CI = 0.90-0.97) compared to the general population, whereas the risk of hematological malignancy was increased (SIR = 1.90; 95% CI = 1.72-2.10). Taking death as a competing event, the CMI of SPM in the whole population was 7.38% at 10 years (6.11% solid and 1.27% hematologic). Factors associated with SPM occurrence were age, sex, race, and time of MM diagnosis. The survival of SPM patients from MM diagnosis was longer than that of patients without SPM (HR = 0.67, 95% CI = 0.58-0.63). The median survival time was 17 months from SPM diagnosis and 34 months from MM diagnosis (HR = 1.4, 95% CI = 1.35-1.46). Age, race, and sex were important factors for the risk of SPM. Site- and time-specific surveillance strategies should be recommended to monitor SPM in high-risk MM patients.

Weld Strength of Friction Welding of Dissimilar Polymer Rods Fabricated by Fused Deposition Modeling.

Friction welding (FRW) is a promising method for joining cylindrical components of dissimilar and similar polymers or metals. In particular, FRW is capable of generating defect-free welds. Fused deposition modeling (FDM) has been widely employed in the automotive industry, ranging from lightweight tools, testing models, and functional parts. Conventionally, dissimilar parts fabricated by FDM are joined by glue. However, distinct disadvantages of this approach include both low joining strength and low joining efficiency. Hitherto, little has been reported on the characterizations of weld strength of FRW of dissimilar parts fabricated by FDM. In addition, FRW of dissimilar polymeric materials is a difficult task because different polymers have different physical, rheological, and mechanical properties. In this study, the effects of welding revolution on the weld strength of friction welding dissimilar parts fabricated by FDM are investigated experimentally. It was found that the average flexural strength of dissimilar polymer rods fabricated by FRW is about 1.52 times that of dissimilar polymer rods fabricated by gluing. The highest flexure strength can be obtained by FRW using polylactic acid (PLA) and PC (polycarbonate) rods. The average impact strength of dissimilar polymer rods fabricated by FRW is about 1.04 times that of dissimilar polymer rods joined by gluing. The highest impact strength can be obtained by FRW using PLA to PLA rods.

Primary central nervous system lymphoma in the United States, 1975-2017.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) has received more attention because of an inferior prognosis. Less is known about the incidence rate, histological type, and survival rate of PCNSL, especially in the 2010s. METHODS: Data of PCNSL from the Surveillance, Epidemiology, and End Results (SEER) registry database (SEER 9 registries and SEER 18 registries) were used. Incidence was estimated by age, gender, race, site, and histological type. Trends were analyzed using joinpoint regression and described as annual percent change (APC) and average annual percent change (AAPC). Five-year overall survival estimates were compared using log-rank tests. RESULTS: Most PCNSL occurred in the brain, followed by the spinal cord. The most frequent histological type of PCNSL was diffuse large B-cell lymphoma, followed by marginal zone lymphoma. Incidence rate increased from 0.1/100,000 to 0.5/100,000 with an AAPC of 5.3% from 1975 to 2017. Incidence rates varied greatly between the younger and older age population. The 5-year overall survival rates in SEER 9 registries and SEER 18 registries were 30.5% and 37.4%, respectively. Even though the 5-year overall survival rate significantly increased from 27.9% for the 1975-1979 time period to 44.8% for the 2010-2017 time period, survival benefit could not be expected for patients ⩾60 years. The 5-year survival rate for elderly patients was about 30% in the 2010s. CONCLUSION: With aging, the incidence of PCNSL in the elderly is increased. Over the past decade, no advances have been made in the treatment of elderly PCNSL. Prospective trials with PCNSL are warranted to improve the survival of elderly patients.

Effects of Different Mold Materials and Coolant Media on the Cooling Performance of Epoxy-Based Injection Molds.

Metal additive manufacturing techniques are frequently applied to the manufacturing of injection molds with a conformal cooling channel (CCC) in order to shorten the cooling time in the injection molding process. Reducing the cooling time in the cooling stage is essential to reducing the energy consumption in mass production. However, the distinct disadvantages include higher manufacturing costs and longer processing time in the fabrication of injection mold with CCC. Rapid tooling technology (RTT) is a widely utilized technology to shorten mold development time in the mold industry. In principle, the cooling time of injection molded products is affected by both injection mold material and coolant medium. However, little work has been carried out to investigate the effects of different mold materials and coolant media on the cooling performance of epoxy-based injection molds quantitatively. In this study, the effects of four different coolant media on the cooling performance of ten sets of injection molds fabricated with different mixtures were investigated experimentally. It was found that cooling water with ultrafine bubble is the best cooling medium based on the cooling efficiency of the injection molded parts (since the cooling efficiency is increased further by about 12.4% compared to the conventional cooling water). Mold material has a greater influence on the cooling efficiency than the cooling medium, since cooling time range of different mold materials is 99 s while the cooling time range for different cooling media is 92 s. Based on the total production cost of injection mold and cooling efficiency, the epoxy resin filled with 41 vol.% aluminum powder is the optimal formula for making an injection mold since saving in the total production cost about 24% is obtained compared to injection mold made with commercially available materials.

LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2α-ATF4-CHOP axis.

Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1-25 µM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50 values of around 10 µM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK-eIF2α-ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. In NOD/SCID mice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.

Comparison of Antifungal Prophylaxis Drugs in Patients With Hematological Disease or Undergoing Hematopoietic Stem Cell Transplantation: A Systematic Review and Network Meta-analysis.

Importance: Several antifungal drugs are available for antifungal prophylaxis in patients with hematological disease or who are undergoing hematopoietic stem cell transplantation (HSCT). Objective: To summarize the evidence on the efficacy and adverse effects of antifungal agents using an integrated comparison. Data Sources: Medline, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials were searched to collect all relevant evidence published in randomized clinical trials that assessed antifungal prophylaxis in patients with hematological disease. Sources were search from inception up to October 2019. Study Selection: Studies that compared any antifungal agent with a placebo, no antifungal agent, or another antifungal agent among patients with hematological disease or undergoing HSCT were included. Of 39 709 studies identified, 69 met the criteria for inclusion. Data Extraction and Synthesis: The outcome from each study was estimated using the relative risk (RR) with 95% CIs. The Mantel-Haenszel random-effects model was used. The reliability and validity of the networks were estimated by addressing inconsistencies in the evidence from comparative studies of different treatments. Data were analyzed from December 2019 to February 2020. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses for Network Meta-analysis (PRISMA-NMA) guideline. Main Outcomes and Measures: The primary outcomes were invasive fungal infections (IFIs) and mortality. The secondary outcomes were fungal infections, proven IFIs, invasive candidiasis, invasive aspergillosis, fungi-related death, and withdrawal owing to adverse effects of the drug. Results: We identified 69 randomized clinical trials that reported comparisons of 12 treatments with at total of 14 789 patients. Posaconazole was the treatment associated with the best probability of success against IFIs (surface under the cumulative ranking curve, 86.7%; mean rank, 2.5). Posaconazole treatment was associated with a significant reduction in IFIs (RR, 0.57; 95% CI, 0.42-0.79) and invasive aspergillosis (RR, 0.36; 95% CI, 0.15-0.85) compared with placebo. Voriconazole was associated with a significant reduction in invasive candidiasis (RR, 0.15; 95% CI, 0.09-0.26) compared with placebo. However, posaconazole was associated with a higher incidence of withdrawal because of the adverse effects of the drug (surface under the cumulative ranking curve, 17.5%; mean rank, 9.2). In subgroup analyses considering efficacy and tolerance, voriconazole might be the best choice for patients undergoing HSCT, especially allogenic HSCT; however, posaconazole was ranked as the best choice for patients with acute myeloid leukemia or myelodysplastic syndrome. Conclusions and Relevance: These findings suggest that voriconazole may be the best prophylaxis option for patients undergoing HSCT, and posaconazole may be the best prophylaxis option for patients with acute myeloid leukemia or myelodysplastic syndrome.

Autologous Cytokine-Induced Killer Cell Immunotherapy for Patients with High-Risk Diffuse Large B Cell Lymphoma After the First Complete Remission.

PURPOSE: To evaluate whether autologous cytokine-induced killer (CIK) cell immunotherapy improves the prognosis of patients with high-risk diffuse large B cell lymphoma (DLBCL) after the first complete remission (CR). PATIENTS AND METHODS: Peripheral blood mononuclear cells (PBMCs) were extracted from 20 patients with high-risk DLBCL (IPI≥3) after the first CR. Twenty CR patients who were age- and sex-matched during the same period were selected as controls. PBMCs were cultured with IFN-γ, IL-2 and anti-CD3 mAb to generate CIK cells. These obtained cells were then transfused back into the patients; the transfusion was repeated every 3 months up to a total of four courses. Changes in peripheral blood lymphocyte subgroups and survival were assessed. RESULTS: Compared with the baseline proportions, the proportion of CD3+ T cells, CD3+CD8+ T cells, and NK cells in the peripheral blood were significantly higher after transfusions (p<0.05). The 5-year DFS was improved from 45.0 ± 11.1% to 79.3 ± 9.2% in the CIK group (HR favoring CIK, 0.29; 95% CI, 0.09 to 0.92; p = 0.035), and the 5-year OS was estimated at 90 ± 6.7% for CIK versus 55 ± 11.1% for control (HR favoring CIK, 0.20; 95% CI, 0.04 to 0.93; p = 0.040). No severe side effects were observed related to CIK treatment. CONCLUSION: Autologous CIK cell immunotherapy has emerged as a safe and efficacious option to improve the prognosis of patients with high-risk DLBCL after the first CR.

Genomic and Transcriptomic Characterization of Natural Killer T Cell Lymphoma.

Natural killer/T cell lymphoma (NKTCL) is an aggressive and heterogeneous entity of non-Hodgkin lymphoma, strongly associated with Epstein-Barr virus (EBV) infection. To identify molecular subtypes of NKTCL based on genomic structural alterations and EBV sequences, we performed multi-omics study on 128 biopsy samples of newly diagnosed NKTCL and defined three prominent subtypes, which differ significantly in cell of origin, EBV gene expression, transcriptional signatures, and responses to asparaginase-based regimens and targeted therapy. Our findings thus identify molecular networks of EBV-associated pathogenesis and suggest potential clinical strategies on NKTCL.

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.

Prognostic role of pretreatment neutrophil-lymphocyte ratio in patients with diffuse large B-cell lymphoma treated with RCHOP.

This study aims to investigate whether neutrophil to lymphocyte ratio (NLR) is an independent predictor in newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients in the rituximab era. Data from newly diagnosed DLBCL patients at Nanjing Drum Tower Hospital from 2006 to 2015 were retrospectively reviewed. We used the receiver operating characteristic (ROC) curve analysis to generate the optimal cutoff value for NLR. Among those 156 patients enrolled, the NLR was < 3.0 in 46.8% (73/156) of the patients, and the remaining 53.2% (83/156) had an NLR ≥ 3.0. Patients with higher pretreatment NLR were found to correlate with poorer OS and PFS than these with lower NLR (hazard ratio [HR] = 2.66, 95% confidence interval [CI] = 1.43-4.97, P = 0.002 and HR = 1.79, 95% CI = 1.05-3.07, P = 0.034, respectively). The multivariate Cox proportional hazard model analysis further showed that high NLR was found independently predictive of poor OS (HR = 0.40; CI = 0.19-0.84, P = 0.015) and PFS (HR = 0.57; CI = 0.33-0.98, P = 0.042). Consequently, pretreatment NLR was an independent prognostic predictor in patients with DLBCL in the rituximab era.

MYC and BCL-2 adjusted-International Prognostic Index (A-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.

The International Prognostic Index (IPI) has been the basis for determining prognosis in patients with diffuse large B-cell lymphoma (DLBCL) for the past 20 years. The utility of the IPI must be reassessed in the era of immunochemotherapy. Seven risk factors at diagnosis were identified, and a maximum of 7 points were assigned to each patient. Four risk groups were created: low (0-1), low-intermediate (2-3), high-intermediate (4), and high (5-7). Using MYC and BCL-2 clinical data from the Drum Tower Hospital collected during the rituximab era, we performed a retrospective analysis of patients with DLBCL treated with R-CHOP and built an biological markers adjusted IPI with the goal of improving risk stratification.Clinical features from 60 adults with de novo DLBCL diagnosed from 2008-2013 were assessed for their prognostic significance. The IPI remains predictive, but it cannot identify the high-risk subgroup. Compared with the IPI, the MYC and BCL-2 adjusted-IPI (A-IPI) better discriminated patients in the high-risk subgroup (4-year overall survival [OS]: 33.3%) than did the IPI (4 year OS: 48.0%). In the era of R-CHOP treatment, MYC and BCL-2 adjusted-IPI is more powerful than the IPI for helping guide treatment planning and interpretation of clinical trials.

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.

[Mutations of FBXW7 in Adult T-Cell Acute Lymphocytic Leukemia].

BACKGROUD: F-Box and WD40 domain containing protein 7 gene (FBXW7) is part of the E3 ubiquitin ligase complex that controls the turnover of various proteins including NOTCH1, c-MYC and Cyclin E. OBJECTIVE: To investigate the mutations of FBXW7 gene in adult T-cell acute lymphoblastic leukemia (T-ALL). METHODS: Exon 5-12 of FBXW7 were amplified, cloned and sequenced in 54 adult T-ALL patients; the frequency, position and types of FBXW7 mutation were analyzed; the co-existing of mutations with NOTCH1 and their relevant prognostic significance were explored as well. RESULTS: FBXW7 mutations were identified in 11.1% of adult T-ALL patients. A total of 4 types of point mutations (R465H, R465L, R479P and R505C) and 1 deletion/insertion mutation were observed, and all of them located in WD40 domain of FBXW7. In addition, co-existing mutations with NOTCH1 were identified in 83.3% of patients with FBXW7 mutation. Notably, the co-existed NOTCH1 mutations, including 3 point mutations (L1574P, L1596H and L1600P) and 2 deletion/insertion mutations located in HD domain. Furthermore, patients with FBXW7 mutation only had significantly longer overall survival compared with those without mutation (P=0.049). CONCLUSION: FBXW7 mutations may play an important role in NOTCH1 mediated pathogenesis in T-ALL.

[Mutation and expression of PAX5 gene in adult acute lymphoblastic leukemia].

PAX5 is an important transcription factor of paired-box(PAX) family. The aim of this study was to investigate the mutations and expression of PAX5 and its clinical significance in adult patients with acute lymphoblastic leukemia (ALL). Reverse transcription polymerase chain reaction (RT-PCR) and genomic PCR were performed to detect the deletions of PAX5 and point mutations of PAX5 exon 2-10 in 101 cases of adult ALL and were confirmed by cloning and sequencing. In addition, quantitative PCR (qPCR) was performed to evaluate the expression of PAX5. Furthermore, the correlations of mutations and expression of PAX5 with clinical parameters were analyzed, and the prognostic significance was evaluated as well. The results showed that PAX5 mutations were observed in 8 of 101 (7.9%) patients with B-ALL. A total of 9 types of mutations were detected, including 4 types of deletions, 4 types of point mutations and 1 insertion mutation; percentage of patients with age ≥ 50 years was higher in PAX5 mutation group than in wide-type group (62.5% vs 21.5%,P = 0.031) . The statistical differences were observed in B-cell subtype, initial platelet count and immunophenotypes between high and low expression of PAX5 (P < 0.05) . In addition, patients with high expression of PAX5 had higher first complete remission rate (86.7% vs 62.5%, P = 0.030) and 6-month overall survival rate (75.0% vs 50.0%, P = 0.034) compared with patients with low expression of PAX5. It is concluded that deletion/insertion/point mutations and aberrant expression of PAX5 can be observed in adult patients with B-ALL. Mutations and aberrant expression of PAX5 correlated with clinical parameters and have important clinical significance.

[Mutation and expression of LEF1 in adult acute lymphocytic leukemia and their clinical significance].

Lymphoid enhancer factor 1 (LEF1) is a key transcription factor in Wingless-type (Wnt) pathway. The present study was aimed to explore the genetic mutation and expression of LEF1, and their clinical significance in adult patients with acute lymphocytic leukemia (ALL). Genomic DNA was amplified and sequenced to detect the mutation of LEF1 in 131 newly diagnosed adult patients with ALL. Quantitative PCR (qPCR) was performed to detect the expression of LEF1. Moreover, the correlations between mutations and expression of LEF1 with clinical characteristics were analyzed. The results showed that the frequency of LEF1 mutation in adult ALL was 3.1% (4/131) and all of them were point mutations located in exon 2 and 3; the median white blood cell count and median percentage of blasts at diagnosis were significantly higher in LEF1 high expression group than in low expression group (70.6 × 109/L vs 26.2 × 109/L)(P = 0.010); (81.0% vs 57.0%) (P = 0.014); in addition, the percentage of patients with Philadelphia chromosome positive and patients in high-risk group significantly increased in LEF1 high expression group compared with that in low expression group (66.7% vs 36.5%) (P = 0.038); (79.2% vs 56.2%) (P = 0.044). It is concluded that high expression of LEF1 may play an important role on development of adult ALL.

MYC protein expression is associated with poor prognosis in diffuse large B cell lymphoma patients treated with RCHOP chemotherapy.

This study aims to investigate the prognostic significance of the MYC protein expression in diffuse large B cell lymphoma (DLBCL) patients treated with RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). A total of 60 patients with DLBCL from 2008 to 2013 were included. Formalin-fixed, paraffin-embedded DLBCL samples were analyzed for MYC protein expression and divided into high or low MYC group. The MYC protein expression and the international prognostic variables were evaluated. The high MYC protein expression predicted a shorter 3-year estimated overall survival (OS) and progression-free survival (PFS) versus the low MYC protein expression (57 % vs. 96 %, P < 0.001 and 50 % vs. 96 %, P = 0.001, respectively). Multivariate analysis confirmed the prognostic significance of the MYC protein expression for both OS (HR, 11.862; 95 % CI, 1.462-96.218; P = 0.021) and PFS (HR, 6.073; 95 % CI, 1.082-34.085; P = 0.040). MYC protein expression with International Prognostic Index (IPI) score distinguished patients into three risk groups with different 3-year OS rates (χ (2) 23.079; P < 0.001) and distinct 3-year PFS rates (χ (2) 15.862; P < 0.001). This study suggests that the MYC protein expression is an important inferior prognostic factor for survival in patients with DLBCL treated with RCHOP. The combinative model with IPI score and MYC protein expression could stratify DLBCL patients into prognostically relevant subgroups more effectively than either the IPI or the MYC alone.

Methylenetetrahydrofolate reductase gene polymorphisms association with the risk of diffuse large B cell lymphoma: a meta-analysis.

To date, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) and diffuse large B cell lymphoma (DLBCL) have provided either controversial or inconclusive results. To clarify the effect of MTHFR on the risk of diffuse large B cell lymphoma, a meta-analysis of all case-control observational studies was performed. The fixed effects and random effects model showed that the C677T polymorphism was associated with a risk of DLBCL among East Asian populations, and A1298C polymorphism was not associated with a risk of DLBCL among Caucasian and East Asian populations. Our pooled data suggest evidence for a major role of MTHFR C677T polymorphism in the carcinogenesis of DLBCL among East Asian populations.