Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sam...Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results： The overall response rate （ORR） in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- （defined as more than 25% of cells harbouring a 17p-） had a lower ORR. The median overall survival （OS） in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality （median 162.0 months, P〈0.001）. Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase （LDH）, B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions： These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.展开更多
Skewness(S) and kurtosis(K) of temperature in the surface layer over a grassland are investigated under unstable thermal stratifications. We find that both skewness and kurtosis generally obey Monin–Obukhov similarit...Skewness(S) and kurtosis(K) of temperature in the surface layer over a grassland are investigated under unstable thermal stratifications. We find that both skewness and kurtosis generally obey Monin–Obukhov similarity theory and tend to be constant values(1.5 and 5.3, respectively) when the stability parameter z/L <-2. Quantitative formulas of the similarity functions are proposed. The temperature probability density function(PDF) is close to Gaussian in near neutral stratification and non-Gaussian in unstable stratification. The influence of coherent motions on the PDF behavior is analyzed using the quadrant analysis technique. It shows that PDF behaviors are controlled by ejections and sweeps. The results also indicate that the PDF type of the ejections always follows a Gaussian distribution, while the PDF of the sweeps changes with stability.展开更多
The application of new materials is an important direction for automotive lightweighting.On the basis of ensuring the comprehensive performance of components,the optimization of new material structures through topolog...The application of new materials is an important direction for automotive lightweighting.On the basis of ensuring the comprehensive performance of components,the optimization of new material structures through topology optimization methods can further improve the level of lightweight components.This paper takes the automobile frame as the research object,based on the magnesium alloy,studies the frame topology with the objective function of mass and strength under multiple working conditions,and realizes the lightweight of the automobile frame structure through the multi-objective topology optimization method.According to the topological optimization method of penalty function for solid isotropic materials,the objective function of the quality topology optimization and the objective function of intensity topology optimization under multi-operating conditions are defined by the compromised programming approach.This method avoids the disadvantage that single-target topology optimization cannot consider other factors and is suitable for multi-objective topology optimization of continuum structures.展开更多
Large granular lymphocytic leukemia(LGLL)is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells.Standard first-line immunosuppressive treatments have limitations,achieving complete remissi...Large granular lymphocytic leukemia(LGLL)is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells.Standard first-line immunosuppressive treatments have limitations,achieving complete remission(CR)rates of up to 50%.Immune system dysregulation is implicated in LGLL.Promising results for thalidomide,an immunomodulatory drug,combined with prednisone and methotrexate(TPM),were observed in our pilot study.This multicenter study evaluated the effcacy and safety of a thalidomide,prednisone,and methotrexate(TPM)regimen in 52 symptomatic,methotrexate-and thalidomide-naive LGLL patients from June 2020 to August 2022.Thalidomide(100 mg daily for up to 24 months),prednisone(0.5-1.0 mg/kg every other day,tapered after 3 months),and methotrexate(10 mg/m^(2) weekly for up to 12 months)were administered.The primary objective was to determine the CR rate.The median follow-up duration was 29.0 months(range:4.0-42.0).Forty-seven patients(90.4%)achieved hematological and symptomatic responses.Thirty-nine patients(75.0%)achieved CR.The median time to response was 3.0 months(range:3.0-9.0).The median progression-free survival was 40.0 months(95%confidence interval(Cl):38.0-42.0),and the median duration of response was 39.0 months(95%Cl:36.1-41.9).The most common adverse event was peripheral neuropathy(24.1%),most of which(84.6%)were grades 1-2.Four patients experienced grade≥3 adverse events.In conclusion,the TPM regimen was an effective and safe treatment for symptomatic LGLL patients,with a particularly high CR rate.This trial was registered at www.clinicaltrials.gov(#NCT04453345).展开更多
Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decade...Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together, To predict the time to first treatment （TTFT） in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index （CLL-PI）. Methods： Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region （1GI：tV） in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results： The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages （P 〈 0.001） or with 11q- （P = 0.002）, 17p- （P 〈 0.001）, unmutated IGHV （P 〈 0.001）, negative 13q- （P = 0.007） and elevated lactate dehydrogenase levels （P = 0.001 ） tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified： advanced clinical stage （P = 0.002）, 17p- （P = 0.050） and unmutated 1GHV （P = 0.049）. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize tbur different risk groups （low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]） with significantly different TTFT （median TTFT of not reached （NR）, 65.0 months, 36.0 months and 19.0 months, respectively, P 〈 0.001 ）. Conclusions： This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.展开更多
To the Editor:As a rare indolent B cell non-Hodgkin lymphoma,lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia(LPL/WM)has unique clinical and biological characteristics.[1]However,due to the difficulties in...To the Editor:As a rare indolent B cell non-Hodgkin lymphoma,lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia(LPL/WM)has unique clinical and biological characteristics.[1]However,due to the difficulties in obtaining tumor metaphase for karyotyping and slow cell proliferation,only very few studies have detected the cytogenetic aberration of LPL/WM.[2,3]In addition,6q deletion is the most common cytogenetic aberration in WM,with an incidence rate of about 50%.[2]Nevertheless,other cytogenetic aberrations remain largely unclear,and the prognostic role of cytogenetic aberrations needs to be further explored.In the present study,we systematically analyzed 305 LPL/WM cases in China,focusing on the characteristics and cytogenetic aberrations in Chinese patients.展开更多
To the Editor:Diffuse large B-cell lymphoma(DLBCL)exhibits clinical significance and biological diversity.Over the last two decades,rituximab with cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)has sub...To the Editor:Diffuse large B-cell lymphoma(DLBCL)exhibits clinical significance and biological diversity.Over the last two decades,rituximab with cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)has substantially improved outcomes for DLBCL patients.However,approximately one-third of DLBCL cases continue to experience disease progression,resulting in long-term survival ranging from 50%to 60%.[1]Efforts to improve DLBCL patient outcomes by modifying R-CHOP dosing schedules have yielded limited success,and the addition of new drugs has benefited only specific patient subgroups.Nevertheless,intensive immunochemotherapy(IIC)has demonstrated promise and cost-effectiveness in recent years.The regimen of dose-adjusted etoposide.展开更多
Waldenstrom macroglobulinemia(WM)is a type of incurable,indolent B-cell lymphoma that is prone to relapse.Over time,treatment strategies have progressed from cytotoxic drugs to rituximab(R)-or bortezomib(V)-based regi...Waldenstrom macroglobulinemia(WM)is a type of incurable,indolent B-cell lymphoma that is prone to relapse.Over time,treatment strategies have progressed from cytotoxic drugs to rituximab(R)-or bortezomib(V)-based regimens,and have now entered into an era of Bruton tyrosine kinase inhibitor(BTKi)-based regimens.However,the optimal treatment for the relapsed patients is still unclear.Herein,we analyzed the outcomes of the first-and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy.After a median follow-up of 45.4 months,89 patients received second-line therapy,and 53 patients were evaluated for response.The major response rates(MRR)of first-and second-line treatment were 65.1%and 67.9%(P=0.678).The median progression-free survival(PFS)for the second-line therapy(PFS2)was shorter than that for the first-line therapy(PFS1)(56.3 vs 40.7 months,P=0.03).However,PFS2 in targeted drugs group(R-/V-/BTKi-based regimens)was comparable to PFS1(60.7 months vs 44.7 months,respectively,P=0.21).Regarding second-line therapy,patients who underwent sequential treatment escalation—such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens(escalation group)—had higher MRR(80.6%vs 47.1%,respectively,P=0.023)and longer PFS2(50.4 vs 23.5 months,respectively,P<0.001)compared to the non-escalation group.Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group(median,not reached vs 50.7 months,respectively,P=0.039).Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.展开更多
基金supported by grants from the National Nature Science Foundation of China (No. 81200395, 81370632)the National Science and Technology supporting Program (No. 2014BAI09B12)+1 种基金the Fundamental Application and Advanced Technology Research Program of Tianjin (No. 15JCYBJC27900)the National Public Health Grand Research Foundation (No. 201202017)
文摘Objective： This study aims to evaluate the natural history of patients with chronic lymphocytic leukemia （CLL） and a 17p deletion （17p-） and identify the predictive factors within this subgroup. Methods： The sample of patients with CLL were analyzed by fluorescence in situ hybridization for deletions in chromosome bands 1 lq22, 13q14 and 17p13; trisomy of bands 12q13; and translocation involving band 14q32. The data from 456 patients with or without a 17p- were retrospectively collected and analyzed. Results： The overall response rate （ORR） in patients with a 17p- was 56.9%, and patients with a high percentage of 17p- （defined as more than 25% of cells harbouring a 17p-） had a lower ORR. The median overall survival （OS） in patients with a 17p- was 78.0 months, which was significantly shorter than the OS in patients without this genetic abnormality （median 162.0 months, P〈0.001）. Within the subgroup with a 17p-, the progression-free survival was significantly shorter in patients at Binet stage B-C and patients with elevated lactate dehydrogenase （LDH）, B symptoms, unmutated IGHVand a high percentage of 17p-. Conclusions： These results indicated that patients with a 17p- CLL have a variable prognosis that might be predicted using simple clinical and laboratory characteristics.
基金supported by the National Key Research and Development Program of China (2017YFC0209605)the National Natural Science Foundation of China (Grant Nos. 11472272, 41605010 and 41675012)
文摘Skewness(S) and kurtosis(K) of temperature in the surface layer over a grassland are investigated under unstable thermal stratifications. We find that both skewness and kurtosis generally obey Monin–Obukhov similarity theory and tend to be constant values(1.5 and 5.3, respectively) when the stability parameter z/L <-2. Quantitative formulas of the similarity functions are proposed. The temperature probability density function(PDF) is close to Gaussian in near neutral stratification and non-Gaussian in unstable stratification. The influence of coherent motions on the PDF behavior is analyzed using the quadrant analysis technique. It shows that PDF behaviors are controlled by ejections and sweeps. The results also indicate that the PDF type of the ejections always follows a Gaussian distribution, while the PDF of the sweeps changes with stability.
文摘The application of new materials is an important direction for automotive lightweighting.On the basis of ensuring the comprehensive performance of components,the optimization of new material structures through topology optimization methods can further improve the level of lightweight components.This paper takes the automobile frame as the research object,based on the magnesium alloy,studies the frame topology with the objective function of mass and strength under multiple working conditions,and realizes the lightweight of the automobile frame structure through the multi-objective topology optimization method.According to the topological optimization method of penalty function for solid isotropic materials,the objective function of the quality topology optimization and the objective function of intensity topology optimization under multi-operating conditions are defined by the compromised programming approach.This method avoids the disadvantage that single-target topology optimization cannot consider other factors and is suitable for multi-objective topology optimization of continuum structures.
基金supported by grants from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-12M-C&T-B-081 and 2022-I2M-1-022)the National Nature Science Foundation of China(82170193,82370197,82200215)+1 种基金the Tianjin Health Science and Technology Project(TJWJ2022XK021)the Tianjin Health Research Project(TJSQNYXXR-D2-152).
文摘Large granular lymphocytic leukemia(LGLL)is characterized by the clonal proliferation of cytotoxic T lymphocytes or NK cells.Standard first-line immunosuppressive treatments have limitations,achieving complete remission(CR)rates of up to 50%.Immune system dysregulation is implicated in LGLL.Promising results for thalidomide,an immunomodulatory drug,combined with prednisone and methotrexate(TPM),were observed in our pilot study.This multicenter study evaluated the effcacy and safety of a thalidomide,prednisone,and methotrexate(TPM)regimen in 52 symptomatic,methotrexate-and thalidomide-naive LGLL patients from June 2020 to August 2022.Thalidomide(100 mg daily for up to 24 months),prednisone(0.5-1.0 mg/kg every other day,tapered after 3 months),and methotrexate(10 mg/m^(2) weekly for up to 12 months)were administered.The primary objective was to determine the CR rate.The median follow-up duration was 29.0 months(range:4.0-42.0).Forty-seven patients(90.4%)achieved hematological and symptomatic responses.Thirty-nine patients(75.0%)achieved CR.The median time to response was 3.0 months(range:3.0-9.0).The median progression-free survival was 40.0 months(95%confidence interval(Cl):38.0-42.0),and the median duration of response was 39.0 months(95%Cl:36.1-41.9).The most common adverse event was peripheral neuropathy(24.1%),most of which(84.6%)were grades 1-2.Four patients experienced grade≥3 adverse events.In conclusion,the TPM regimen was an effective and safe treatment for symptomatic LGLL patients,with a particularly high CR rate.This trial was registered at www.clinicaltrials.gov(#NCT04453345).
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81370632, 81200395）, the National Science and Technology Supporting Program （No. 2014BAI09B 12）, the Fundamental Application and Advanced Technology Research Program of Tianjin （No. 15JCYBJC27900）, and the National Public Health Grand Research Foundation （No. 201202017）.
文摘Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together, To predict the time to first treatment （TTFT） in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index （CLL-PI）. Methods： Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region （1GI：tV） in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results： The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages （P 〈 0.001） or with 11q- （P = 0.002）, 17p- （P 〈 0.001）, unmutated IGHV （P 〈 0.001）, negative 13q- （P = 0.007） and elevated lactate dehydrogenase levels （P = 0.001 ） tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified： advanced clinical stage （P = 0.002）, 17p- （P = 0.050） and unmutated 1GHV （P = 0.049）. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize tbur different risk groups （low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]） with significantly different TTFT （median TTFT of not reached （NR）, 65.0 months, 36.0 months and 19.0 months, respectively, P 〈 0.001 ）. Conclusions： This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.
基金National Nature Science Foundation of China(Nos.81900203,81970187,82170193,and 81920108006)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(Nos.2022-12M-1-022,2021-I2M-C&T-B-081)
文摘To the Editor:As a rare indolent B cell non-Hodgkin lymphoma,lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia(LPL/WM)has unique clinical and biological characteristics.[1]However,due to the difficulties in obtaining tumor metaphase for karyotyping and slow cell proliferation,only very few studies have detected the cytogenetic aberration of LPL/WM.[2,3]In addition,6q deletion is the most common cytogenetic aberration in WM,with an incidence rate of about 50%.[2]Nevertheless,other cytogenetic aberrations remain largely unclear,and the prognostic role of cytogenetic aberrations needs to be further explored.In the present study,we systematically analyzed 305 LPL/WM cases in China,focusing on the characteristics and cytogenetic aberrations in Chinese patients.
基金CAMS Innovation Fund for Medical Sciences(Nos.CIFMS 2022-I2M-1-022 and 2020-I2M-C&T-B-085)
文摘To the Editor:Diffuse large B-cell lymphoma(DLBCL)exhibits clinical significance and biological diversity.Over the last two decades,rituximab with cyclophosphamide,doxorubicin,vincristine,and prednisone(R-CHOP)has substantially improved outcomes for DLBCL patients.However,approximately one-third of DLBCL cases continue to experience disease progression,resulting in long-term survival ranging from 50%to 60%.[1]Efforts to improve DLBCL patient outcomes by modifying R-CHOP dosing schedules have yielded limited success,and the addition of new drugs has benefited only specific patient subgroups.Nevertheless,intensive immunochemotherapy(IIC)has demonstrated promise and cost-effectiveness in recent years.The regimen of dose-adjusted etoposide.
基金supported by grants from the National Nature Science Foundation of China(81970187,82170193,81920108006,and 81900203)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2022-I2M-1-022,2021-I2M-C,and T-B-081).
文摘Waldenstrom macroglobulinemia(WM)is a type of incurable,indolent B-cell lymphoma that is prone to relapse.Over time,treatment strategies have progressed from cytotoxic drugs to rituximab(R)-or bortezomib(V)-based regimens,and have now entered into an era of Bruton tyrosine kinase inhibitor(BTKi)-based regimens.However,the optimal treatment for the relapsed patients is still unclear.Herein,we analyzed the outcomes of the first-and second-line therapies in 377 patients with WM to illustrate the optimal choices for second-line therapy.After a median follow-up of 45.4 months,89 patients received second-line therapy,and 53 patients were evaluated for response.The major response rates(MRR)of first-and second-line treatment were 65.1%and 67.9%(P=0.678).The median progression-free survival(PFS)for the second-line therapy(PFS2)was shorter than that for the first-line therapy(PFS1)(56.3 vs 40.7 months,P=0.03).However,PFS2 in targeted drugs group(R-/V-/BTKi-based regimens)was comparable to PFS1(60.7 months vs 44.7 months,respectively,P=0.21).Regarding second-line therapy,patients who underwent sequential treatment escalation—such as transitioning from cytotoxic drugs to R-/V-/BTKi-based regimens or from R-/V-based to BTKi-based regimens(escalation group)—had higher MRR(80.6%vs 47.1%,respectively,P=0.023)and longer PFS2(50.4 vs 23.5 months,respectively,P<0.001)compared to the non-escalation group.Patients in the escalation group also had longer post-relapse overall survival compared with the non-escalation group(median,not reached vs 50.7 months,respectively,P=0.039).Our findings indicate that sequential treatment escalation may improve the survival of patients with WM.
