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Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Loncastuximab tesirine (Lonca), an antibody conjugate targeting CD19, has demonstrated significant clinical benefit in R/R DLBCL in a global phase 2 LOTIS-2 study. In the China bridging pivotal phase 2 OL-ADCT-402-001 study, eligible patients aged ≥18 years with R/R DLBCL who had failed ≥ 2 lines of systemic therapies were enrolled and treated with Lonca every 3 week with 150 µg/kg for 2 cycles; then 75 µg/kg for subsequent cycles (up to 1 year). The primary endpoint was overall response rate (ORR) assessed by independent review committee. Primary analyses for efficacy and safety were performed on the patients who received at least one treatment and had at least 6 months of follow-up following an initial documented response. As of data-cutoff, 64 patients received Lonca (median: 4.0 cycles [range: 1 to 17]). The median number of prior lines of therapies was 3.0 (range: 2 to 12). The ORR was 51.6% (95% CI: 38.7% to 64.2%), and the complete response rate was 23.4%. Hematological events accounted for the majority of the most common (≥15%) Grade ≥3 treatment-emergent adverse events (TEAEs), in which increased gamma glutamyltransferase (25.0%), and hypokalaemia (18.8%) also were reported. Serious TEAEs were reported in 35 of 64 patients with 4 fatal TEAEs. In conclusion, Lonca monotherapy demonstrated clinically meaningful efficacy and was well-tolerated in heavily pretreated Chinese patients with R/R DLBCL, which was consistent with the results of the LOTIS-2 study in Caucasian patients.

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Some 'watch and wait' (W&W) FL patients suffer from rapid progression in a short term. Herein, we sought to identify these patients and also develop a risk score to screen them at diagnosis. Between 2008 and 2022, a total of 411 FL patients managed by the W&W strategy from 16 cancer centres were retrospectively enrolled in this study, and their time to lymphoma treatment (TLT) and progression-free survival (PFS) were evaluated. Thirty-five percent of W&W FL patients experienced TLT within 24 months (TLT24) after diagnosis. Their 5-year PFS rate was significantly lower than those without treatment at 24 months (62.3% vs. 89.5%). In multivariable analysis, five factors were identified as independent predictors of TLT24: stages III-IV, ß2 microglobulin ≥3 mg/L, lymphocyte-to-monocyte ratio <3.8, bone marrow involvement and spleen enlargement (above umbilical line). Their AUCs for TLT24 were 0.76 (95% CI, 0.70-0.82) in the training cohort and 0.76 (95% CI, 0.67-0.85) in the validation cohort respectively. Risk groups were also associated with PFS (p < 0.001). In FL patients initially managed by W&W, TLT24 was associated with poor outcomes. This multivariable model helps screening for predicting TLT24, which may be useful to identify candidates for early interventional treatment.

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Multidrug-resistant Klebsiella pneumoniae (MDR-KP) poses a significant challenge in global healthcare, underscoring the urgency for innovative therapeutic approaches. Phage therapy emerges as a promising strategy amidst rising antibiotic resistance, emphasizing the crucial need to identify and characterize effective phage resources for clinical use. In this study, we introduce a novel lytic phage, RCIP0100, distinguished by its classification into the Chaoyangvirus genus and Fjlabviridae family based on International Committee on Taxonomy of Viruses (ICTV) criteria due to low genetic similarity to known phage families. Our findings demonstrate that RCIP0100 exhibits broad lytic activity against 15 out of 27 tested MDR-KP strains, including diverse profiles such as carbapenem-resistant K. pneumoniae (CR-KP). This positions phage RCIP0100 as a promising candidate for phage therapy. Strains resistant to RCIP0100 also showed increased susceptibility to various antibiotics, implying the potential for synergistic use of RCIP0100 and antibiotics as a strategic countermeasure against MDR-KP.

Assuntos

Antibacterianos , Bacteriófagos , Farmacorresistência Bacteriana Múltipla , Klebsiella pneumoniae , Terapia por Fagos , Klebsiella pneumoniae/virologia , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/genética , Bacteriófagos/genética , Bacteriófagos/fisiologia , Antibacterianos/farmacologia , Infecções por Klebsiella/microbiologia , Genoma Viral , Humanos , Testes de Sensibilidade Microbiana

RESUMO

Background: The western region of China has a dense population, relatively underdeveloped economy, and a significant number of left-behind children. Currently, the prevalence of adolescent psychological abuse, neglect, and the factors associated with these issues in the region remain unclear. This study aims to evaluate the current status of adolescent psychological abuse and neglect and its associated factors in this region.Methods: Data were collected from 50 schools in western China through cluster sampling to target adolescents aged 12 to 18. A comprehensive survey form was used to collect socio-demographic characteristics of adolescents. The Child Psychological Abuse and Neglect Scale was employed to assess the current psychological abuse and neglect of adolescents. Independent samples t-tests were used for inter-group comparisons. A Directed Acyclic Graph was constructed for controlling confounding variables. Subsequently, binary logistic regression analysis was performed, and a nomogram risk factors model was developed using R Studio.Results: This study included 12,743 teenagers, with an average age of 15.53(±1.39) years. Among them, 4,965 individuals, accounting for 39.0%, reported experiences of psychological abuse, while 4,167 individuals, accounting for 32.7%, reported experiences of neglect. The rates of psychological abuse and neglect in adolescents are influenced by gender, grade, left-behind experience, parental marital status, and living on campus (P < .05).Conclusion: Adolescents in western China exhibit higher rates of psychological abuse and neglect compared to those in the eastern and northern regions of China. Gender, grade, left-behind experience, and family factors significantly influence the psychological abuse and neglect of adolescents.

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This study is the first large-scale, multi-centre, cross-sectional analysis of psychological abuse and neglect among youth in Western China, a region with relatively underdeveloped economic and social conditions.This article fills in the gap in the region's research on psychological abuse and neglect by addressing the issues of small sample size, limited coverage, and a lack of variables included.This provides a crucial theoretical foundation for enhancing the mental well-being of youth in this region and preventing psychological and mental illnesses among youth.

Assuntos

Maus-Tratos Infantis , Humanos , Adolescente , China/epidemiologia , Masculino , Feminino , Estudos Transversais , Prevalência , Fatores de Risco , Maus-Tratos Infantis/estatística & dados numéricos , Maus-Tratos Infantis/psicologia , Inquéritos e Questionários , Criança , Abuso Emocional/estatística & dados numéricos , Abuso Emocional/psicologia , Instituições Acadêmicas

RESUMO

A drug-drug interaction (DDI) trial of cytochrome P450 3A (CYP3A) is a necessary part of early-phase trials of drugs mainly metabolized by this enzyme, but CYP3A DDI clinical trials do not have a standard design, especially for Chinese people. We aimed to offer specific recommendations for CYP3A DDI clinical trial design. This was an open, three-cycle, self-controlled study. Healthy subjects were given different administration strategies of CYP3A4 perpetrators. In each cycle, blood samples were collected before and within 24 h after the administration of midazolam, the CYP3A indicator substrate. The plasma concentrations of midazolam and 1-hydroxymidazolam was obtained using liquid chromatography tandem mass spectrometry assay. For CYP3A inhibition, itraconazole exposure with a loading dose could increase the exposure of midazolam by 3.21-fold based on maximum plasma concentration (Cmax), 8.37-fold based on area under the curve Pharmacology Research & Perspectives for review only from zero to the time point (AUC0-t), and 11.22-fold based on area under the curve from zero to infinity (AUC0-∞). The data were similar for itraconazole pretreatment without a loading dose. For CYP3A induction, the exposure of rifampin for 7 days decreased the plasma concentration of midazolam ~0.27-fold based on Cmax, ~0.18-fold based on AUC0-t, and ~0.18-fold based on AUC0-∞. Midazolam exposure did not significantly change when the pretreatment of rifampin increased to 14 days. This study showed that itraconazole pretreatment for 3 days without a loading dose was enough for CYP3A inhibition, and pretreatment with rifampin for 7 days could induce near-maximal CYP3A levels.

Assuntos

Povo Asiático , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Itraconazol , Midazolam , Humanos , Midazolam/farmacocinética , Midazolam/administração & dosagem , Midazolam/sangue , Midazolam/análogos & derivados , Itraconazol/farmacologia , Itraconazol/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Masculino , Adulto , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Adulto Jovem , Rifampina/farmacologia , Rifampina/administração & dosagem , Voluntários Saudáveis , Feminino , Indutores do Citocromo P-450 CYP3A/farmacologia , Área Sob a Curva , Projetos de Pesquisa , Ensaios Clínicos como Assunto , População do Leste Asiático

RESUMO

Aim: Glioma accounts for 81% of all cancers of the nervous system cancers and presents one of the most drug-resistant malignancies, resulting in a relatively high mortality rate. Despite extensive efforts, the complete treatment options for glioma remain elusive. The effect of isocucurbitacin B (isocuB), a natural compound extracted from melon pedicels, on glioma has not been investigated. This study aims to investigate the inhibitory effect of isocuB on glioma and elucidate its underlying mechanisms, with the objective of developing it as a potential therapeutic agent for glioma. Methods: We used network pharmacology and bioinformatics analysis to predict potential targets and associated pathways of isocuB in glioma. Subsequently, the inhibitory effect of isocuB on glioma and its related mechanisms were assessed through Counting Kit-8 (CCK-8), wound healing, transwell, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments, alongside tumor formation experiments in nude mice. Results: Based on this investigation, it suggested that isocuB might inhibit the growth of gliomas through the PI3K-AKT and MAPK pathways. Additionally, we proposed that isocuB may enhance glioma drug sensitivity to temozolomide (TMZ) via modulation of hsa-mir-1286a. The CCK-8 assay revealed that isocuB exhibited inhibitory effects on U251 and U87 proliferation and outperformed TMZ. Wound healing and transwell experiments showed that isocuB inhibited the invasion and migration of U251 cells by suppressing the activity of MMP-2/9, N-cadherin, and Vimentin. The TdT-mediated dUTP-biotin nick end labeling (TUNEL) and flow cytometry (FCM) assays revealed that isocuB induced cell apoptosis through inhibition of BCL-2. Subsequently, we conducted RT-qPCR and WB experiments, which revealed that PI3K/AKT and MAPK pathways might be involved in the mechanism of the inhibition isocuB on glioma. Additionally, isocuB promoted the sensitivity of glioma U251 to TMZ by inhibiting hsa-mir-1286a. Furthermore, we constructed TMZ-resistant U251 strains and demonstrated effective inhibition by isocuB against these resistant strains. Finally, we confirmed that isocuB can inhibit tumor growth in vivo through experiments on tumors in nude mice. Conclusion: IsocuB may protect against glioma by acting on the PI3K/AKT and MAPK pathways and promote the sensitivity of glioma U251 to TMZ by inhibiting hsa-mir-1286a.

RESUMO

Insertion sequences (ISs) promote the transmission of antimicrobial resistance genes (ARGs) across bacterial populations. However, their contributions and dynamics during the transmission of resistance remain unclear. In this study, we selected IS26 as a representative transposable element to decipher the relationship between ISs and ARGs and to investigate their transfer features and transmission trends. We retrieved 2656  translocatable  IS 26 -bounded  units with  ARGs (tIS26-bUs-ARGs) in complete bacterial genomes from the NCBI RefSeq database. In total, 124 ARGs spanning 12 classes of antibiotics were detected, and the average contribution rate of IS26 to these genes was 41.2%. We found that  IS 26 -bounded  units (IS26-bUs) mediated extensive ARG dissemination within the bacteria of the Gammaproteobacteria class, showing strong transfer potential between strains, species, and even phyla. The IS26-bUs expanded in bacterial populations over time, and their temporal expansion trend was significantly correlated with antibiotic usage. This wide dissemination could be due to the nonspecific target site preference of IS26. Finally, we experimentally confirmed that the introduction of a single copy of IS26 could lead to the formation of a composite transposon mediating the transmission of "passenger" genes. These observations extend our knowledge of the IS26 and provide new insights into the mediating role of ISs in the dissemination of antibiotic resistance.

RESUMO

Klebsiella pneumoniae, a major clinical pathogen known for causing severe infections, is attracting heightened attention due to its escalating antibiotic resistance. Phages are emerging as a promising alternative to antibiotics; however, their specificity to particular hosts often restricts their use. In this study, a collection of 114 phages is obtained and subjected to analysis against 238 clinical K. pneumoniae strains, revealing a spectrum of lytic behaviors. A correlation between putative tail protein clusters and lysis patterns leads to the discovery of six receptor-binding protein (RBP) clusters that determine host capsule tropism. Significantly, RBPs with cross-capsular lysis capabilities are identified. The newly-identified RBPs provide a toolbox for customizing phages to target diverse capsular types. Building on the toolbox, the engineered phages with altered RBPs successfully shifted and broadened their host capsule tropism, setting the stage for tunable phage that offer a precise and flexible solution to combat K. pneumoniae infections.

Assuntos

Cápsulas Bacterianas , Bacteriófagos , Klebsiella pneumoniae , Klebsiella pneumoniae/virologia , Klebsiella pneumoniae/genética , Bacteriófagos/genética , Bacteriófagos/fisiologia , Cápsulas Bacterianas/metabolismo , Cápsulas Bacterianas/genética , Infecções por Klebsiella/microbiologia , Humanos

RESUMO

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group ( P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244 .

Assuntos

Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/tratamento farmacológico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Aminopiridinas/uso terapêutico , Benzamidas/uso terapêutico , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , China/epidemiologia , Transplante Autólogo , Idoso , Taxa de Sobrevida , Adulto Jovem , Quimioterapia de Manutenção , Autoenxertos , Indução de Remissão , Adolescente

RESUMO

Relapsed or refractory diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) patients still faced with poor survival, representing an unmet clinical need. In-depth research into the disease's pathogenesis and the development of targeted treatment strategies are urgently needed. Here, we conducted a comprehensive bioinformatic analysis of gene mutation and expression using data from our center and public databases. Cell cycle-related genes especially for CDKN2A/B-CDK4/6/CCND1 machinery altered frequently in DLBCL and MCL. Clinically, high CDK4 and CDK6 expression were correlated with poor prognosis of DLBCL and MCL patients. Furthermore, we also validated the pharmacological efficacy of CDK4/6 inhibitor palbociclib and its synergy effect with PI3K inhibitor idelalisib utilizing in vitro cell lines and in vivo cell-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. Our results provided sufficient pre-clinical evidence to support the potential combination of palbociclib and idelalisib for DLBCL and MCL patients.

Assuntos

Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Sinergismo Farmacológico , Piperazinas , Purinas , Piridinas , Quinazolinonas , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Purinas/farmacologia , Animais , Piperazinas/farmacologia , Piridinas/farmacologia , Quinazolinonas/farmacologia , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/metabolismo , Camundongos , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas/genética , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/genética , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/genética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Feminino , Inibidores de Proteínas Quinases/farmacologia

RESUMO

Acalabrutinib studies have limited Asian participation. This phase 1/2 study (NCT03932331) assessed acalabrutinib in Chinese patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL). Primary endpoint was blinded independent central review (BICR)-assessed overall response rate (ORR). Overall, 34 patients were enrolled. Most patients were men (88%); median age was 63 years and 59% had ≥3 prior treatments. Median treatment duration was 14 months (range, 1-24). Any-grade adverse events (AEs) and grade ≥3 AEs occurred in 85.3% and 44.1% of patients, respectively. AEs causing treatment discontinuation were aplastic anemia, thrombocytopenia, and gastrointestinal infection (n = 1 each). Fatal AEs occurred in 2 patients (aplastic anemia and multiple organ dysfunction syndrome [n = 1 each]). BICR-assessed ORR was 82.4% (95% confidence interval [CI]: 65.5, 93.2); 12 (35.3%) patients achieved complete response. Estimated 12-month OS was 84.5% (95% CI: 66.6, 93.3). Acalabrutinib yielded tolerable safety and high response rates in Chinese patients with R/R MCL.

Assuntos

Benzamidas , Linfoma de Célula do Manto , Pirazinas , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Pirazinas/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/patologia , Idoso , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Adulto , Resultado do Tratamento , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Resistencia a Medicamentos Antineoplásicos , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Antineoplásicos/efeitos adversos , China/epidemiologia , População do Leste Asiático

RESUMO

The growth and development of apricot flower organs are severely impacted by spring frosts. To better understand this process, apricot flowers were exposed to temperatures ranging from 0 °C to -8 °C, including a control at 18 °C, in artificial incubators to mimic diverse low-temperature environments. We aimed to examine their physiological reactions to cold stress, with an emphasis on changes in phenotype, membrane stability, osmotic substance levels, and antioxidant enzyme performance. Results reveal that cold stress induces significant browning and cellular damage, with a sharp increase in browning rate and membrane permeability below -5 °C. Soluble sugars and proteins initially rise as osmoprotectants, but their content decreases at lower temperatures. Proline content consistently increases, suggesting a protective role. Antioxidant enzyme activities, including catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), exhibit a complex pattern, with initial increases followed by declines at more severe cold conditions. Correlation and principal component analyses highlight the interplay between these responses, indicating a multifaceted adaptation strategy. The findings contribute to the understanding of apricot cold tolerance and inform breeding efforts for improved crop resilience.

RESUMO

The incorporation of real-world data (RWD) into medical product development and evaluation has exhibited consistent growth. However, there is no universally adopted method of how much information to borrow from external data. This paper proposes a study design methodology called Tree-based Monte Carlo (TMC) that dynamically integrates patients from various RWD sources to calculate the treatment effect based on the similarity between clinical trial and RWD. Initially, a propensity score is developed to gauge the resemblance between clinical trial data and each real-world dataset. Utilizing this similarity metric, we construct a hierarchical clustering tree that delineates varying degrees of similarity between each RWD source and the clinical trial data. Ultimately, a Gaussian process methodology is employed across this hierarchical clustering framework to synthesize the projected treatment effects of the external group. Simulation result shows that our clustering tree could successfully identify similarity. Data sources exhibiting greater similarity with clinical trial are accorded higher weights in treatment estimation process, while less congruent sources receive comparatively lower emphasis. Compared with another Bayesian method, meta-analytic predictive prior (MAP), our proposed method's estimator is closer to the true value and has smaller bias.

RESUMO

The genetic predisposition to lymphoma is not fully understood. We identified 13 lymphoma-cancer families (2011-2021), in which 27 individuals developed lymphomas and 26 individuals had cancers. Notably, male is the predominant gender in lymphoma patients, whereas female is the predominant gender in cancer patients (p = .019; OR = 4.72, 95% CI, 1.30-14.33). We collected samples from 18 lymphoma patients, and detected germline variants through exome sequencing. We found that germline protein truncating variants (PTVs) were enriched in DNA repair and immune genes. Totally, we identified 31 heterozygous germline mutations (including 12 PTVs) of 25 DNA repair genes and 19 heterozygous germline variants (including 7 PTVs) of 14 immune genes. PTVs of ATM and PNKP were found in two families, respectively. We performed whole genome sequencing of diffuse large B cell lymphomas (DLBCLs), translocations at IGH locus and activation of oncogenes (BCL6 and MYC) were verified, and homologous recombination deficiency was detected. In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.

Assuntos

Reparo do DNA , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Linfoma Difuso de Grandes Células B , Humanos , Masculino , Feminino , Reparo do DNA/genética , Pessoa de Meia-Idade , Adulto , Linfoma Difuso de Grandes Células B/genética , Idoso , Linfoma/genética , Sequenciamento do Exoma , Adulto Jovem , Linhagem , Proteínas Mutadas de Ataxia Telangiectasia/genética , Adolescente

RESUMO

ABSTRACT: Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Assuntos

Aminopterina , Linfoma de Células T Periférico , Humanos , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Adulto , Idoso de 80 Anos ou mais , Resultado do Tratamento , Recidiva , Adulto Jovem

RESUMO

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a highly curable disease, while novel therapy is needed for refractory or relapsed (R/R) patients. This phase II trial aimed to evaluate the role of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) in R/R cHL patients. METHODS: Transplant-eligible patients with R/R cHL were enrolled and received two 14-day cycles of camrelizumab 200 mg intravenously (IV) and two 28-day cycles of camrelizumab 200 mg IV, gemcitabine 1000 mg/m2 IV, and oxaliplatin 100 mg/m2 IV on days 1 and 15. Patients with partial response (PR) or stable disease received an additional cycle of combination therapy. Those who achieved complete response (CR) or PR proceeded to autologous stem cell transplantation (ASCT). The primary endpoint was the CR rate at the end of protocol therapy before ASCT. RESULTS: Forty-two patients were enrolled. At the end of protocol therapy, the objective response rate and CR rate were 94.9% (37/39) and 69.2% (27/39) in the evaluable set, and 88.1% (37/42) and 64.3% (27/42) in the full analysis set, respectively. Twenty-nine patients (69.0%) proceeded to ASCT, and 4 of 5 patients with PR achieved CR after ASCT. After a median follow-up of 20.7 months, the 12-month progression-free survival rate was 96.6% and the 12-month overall survival rate was 100%. Grade 3 or higher treatment emergent adverse events occurred in 28.6% of patients (12/42), mainly hematological toxicity. CONCLUSIONS: Camrelizumab combined with GEMOX constitutes an effective salvage therapy for R/R cHL, proving to be relatively well-tolerated and facilitating ASCT in most patients, thus promoting sustained remission. TRIAL REGISTRATION: ClinicalTrials.gov NCT04239170. Registered on January 1, 2020.

Assuntos

Anticorpos Monoclonais Humanizados , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/etiologia , Doença de Hodgkin/patologia , Gencitabina , Oxaliplatina/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento

RESUMO

Introduction: Suicidal ideation is a critical early stage in the progression towards suicidal be havior. Prior research has established links between sleep quality, impulsivity, and suicidal tendencies, yet the interaction among these factors has been less explored. This study aims to explore the mediating role of impulsivity in the relationship between sleep quality and suicidal ideation in adolescents. Methods: Employing a cross-sectional study design, 6,974 questionnaires were distributed,including the Socio-demographic Characteristics Questionnaire, Barratt Impulsiveness Scale, the Positive and Negative Suicide Ideation Inventory,and the Pittsburgh Sleep Quality Index Scale. The participants were high school and middle school students from 33 schools in northeastern Sichuan, China, selected through random cluster sampling. Results: Of these 6,786 questionnaires were analyzed. The participant distribution included 47.2% male and 52.8% female students, with 68.3% from junior schools and 31.7% from senior schools. The prevalence of suicidal ideation was found to be 13.6%. The analysis, which involved correlation analysis and the construction of a structural equation model, revealed that sleep quality had a significant positive effect on impulsivity (ß:0.289,p < 0.05), and impulsivity, in turn, had a positive impact on suicidal ideation (ß:0.355,p < 0.05).Moreover, sleep quality was directly linked to suicidal ideation (ß:0.208,p < 0.05). Thus, sleep quality affects suicidal ideation both directly and indirectly through impulsivity. Discussion: The results of this study suggest that both sleep quality and impulsivity are significant direct influencers of suicidal ideation among adolescents in the region studied, with impulsivity also playing an indirect role in the relationship between sleep quality and suicidal ideation.

RESUMO

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Assuntos

Linfoma de Células B , Inibidores de Proteínas Quinases , Quinase Syk , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Quinase Syk/antagonistas & inibidores , Idoso , Adulto , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/efeitos adversos , Adulto Jovem , Idoso de 80 Anos ou mais , Resultado do Tratamento , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Dose Máxima Tolerável , Pirazinas/administração & dosagem , Pirazinas/uso terapêutico , Pirazinas/farmacocinética , Pirazinas/efeitos adversos , Recidiva , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Indazóis , Morfolinas

RESUMO

This study aimed to explore the distribution, characteristics and prognostic value of baseline peripheral blood lymphocyte subsets in patients with extranodal NK/T-cell lymphoma (NKTCL). We conducted this cross-sectional study of 205 newly-diagnosed NKTCL patients receiving first-line chemotherapy and radiation at our institute between 2010 and 2020. Baseline peripheral blood lymphocytes were detected using flow cytometry, and the clinical value was analyzed. Compared with healthy controls, patients with NKTCL presented with a distinct peripheral immunity with higher levels of cytotoxic CD8+ T cells (33.230 ± 12.090% vs. 27.060 ± 4.010%, p < 0.001) and NKT cells (7.697 ± 7.219% vs. 3.550 ± 2.088%, p < 0.001) but lower proportions of suppressive regulatory T cells (Treg, 2.999 ± 1.949% vs. 3.420 ± 1.051%, p = 0.003) and CD4+ helper T cells (Th, 33.084 ± 11.361% vs. 37.650 ± 3.153%, p < 0.001). Peripheral lymphocytes were differentially distributed according to age, stage, and primary site in patients with NKTCL. The proportion of Th cells/lymphocytes was associated with tumor burden reflected by stage (p = 0.037), serum lactate dehydrogenase (p = 0.0420), primary tumor invasion (p = 0.025), and prognostic index for NK/T-cell lymphoma (PINK) score (p = 0.041). Furthermore, elevated proportions of T cells (58.9% vs. 76.4%, p = 0.005), Th cells (56.3% vs. 68.8%, p = 0.047), or Treg cells (49.5% vs. 68.9%, p = 0.040) were associated with inferior 5-year progression-free survivals (PFS) via univariable survival analysis. Multivariate cox regression revealed elevated Th cells as an independent predictor for unfavorable PFS (HR = 2.333, 95% CI, 1.030-5.288, p = 0.042) in NKTCL. These results suggested the proportion of Th cells positively correlated with tumor burden and was a potential non-invasive biomarker for inferior survival for patients with NKTCL.

Assuntos

Linfoma Extranodal de Células T-NK , Humanos , Prognóstico , Citometria de Fluxo , Estudos Transversais , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfócitos T Auxiliares-Indutores , Linfócitos/patologia

RESUMO

Objective To evaluate the efficacy and prognostic factors of high-dose therapy/autologous stem cell transplantation (HDT/ASCT) in treating refractory and relapsed peripheral T-cell lymphoma (R/R PTCL). Methods We included medical records from 48 R/R PTCL patients treated with HDT/ASCT at the Beijing Cancer Hospital from January 2003 to December 2021, and these patients were followed up. Results We followed up with patients for a median of 71.0 months (interquartile range 48.8-124.4 months). The progression-free survival (PFS) at five years was 43.4%, and the five-year overall survival (OS) was 54.7. The five-year PFS and subgroups were as follows: 14 patients with anaplastic large-cell lymphoma (57.1%, 62.9%), 14 patients with NK/T-cell lymphoma (NKTCL) (28.6%, 28.6%), nine with angioimmunoblastic T-cell lymphoma (44.4%, 51.9%), and 11 with PTCL not otherwise specified (41.6%, 80.8%). Univariate analysis revealed that females had a better PFS than males (hazard ratio [HR] = 0.301, 95% confidence interval [CI] 0.091-0.996, P = 0.049); the NKTCL type had worse OS than the non-NKTCL type (HR = 0.292, 95% CI 0.122-0.698, P = 0.006); the patients with the relapsed disease did better than those with refractory disease (HR for PFS: 0.161, 95% CI 0.072-0.357, P < 0.001; HR for OS: 0.171, 95% CI 0.066-0.444, P < 0.001). The PIT score was significantly better for T-cell lymphoma with score = 0 than for score ≥ 1 group (HR for PFS: 0.261, 95% CI 0.109-0.625, P = 0.003; HR for OS: 0.305, 95% CI 0.111-0.842, P = 0.022). The pre-transplantation disease status also influences survival. Patients who achieved complete response (CR) did better (HR for PFS: 0.104, 95% CI 0.044-0.247, P < 0.001; HR for OS: 0.139, 95% CI 0.050-0.383, P < 0.001). Pre-transplantation status was an independent influencing factor associated with PFS and OS (better survival in those achieving CR) (HR for PFS: 0.126, 95% CI 0.030-0.530, P = 0.005; HR for OS: 0.154, 95% CI 0.040-0.603, P = 0.007); the pathological classification independently influenced OS (better in the those with non-NKTCL) (HR = 0.210, 95% CI 0.081-0.549, P = 0.001). CR, with a PIT score of 0 (n = 17), was associated with more prolonged PFS. None of the 48 patients experienced HDT/ASCT-related deaths. Conclusion HDT/ASCT as a salvage therapy for R/R PTCL patients can partially improve outcomes with a favorable safety profile. Prospective, randomized, and controlled studies are necessary to validate the value of HDT/ASCT for patients with diverse pathological subtypes and pre-transplantation states.