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Frontiers in Pediatrics 2021To investigate the clinical characteristics, treatment, and prognosis of children with systemic juvenile xanthogranuloma (JXG). Clinical data of children with JXG who...
To investigate the clinical characteristics, treatment, and prognosis of children with systemic juvenile xanthogranuloma (JXG). Clinical data of children with JXG who were hospitalized in Beijing Children's Hospital, Capital Medical University, from January 2012 to December 2019 were retrospectively analyzed, including clinical manifestations, laboratory determinations, treatment, and prognosis of the children. Patients were treated with vindesine + prednisone as the first-line treatment and cytarabine + vindesine + dexamethasone ± cladribine as the second-line treatment. Ten patients, including 8 males and 2 females, with a median of onset age of 1.95 (0.80-7.30) years, exhibited multi-system dysfunction. The median age of diagnosis was 2.45 (1.30-12.10) years. The most common location of extracutaneous lesions was the central nervous system (6 cases), followed by the lung (5 cases) and bone (4 cases). Nine patients underwent first-line chemotherapy, and 6 patients underwent second-line chemotherapy, including 5 patients with poorly controlled disease after first-line treatment. The median observation time was 29 (3-115) months. Nine patients survived, whereas one patient died of respiratory failure caused by pulmonary infection. At the end of follow-up, 7 patients were in active disease (AD)/regression state (AD-better), and 2 patients were in an AD/stable state (AD-stable). Three patients had permanent sequelae, mainly central diabetes insipidus. The rates of response to the first-line treatment and the second-line treatment were 40.0 and 66.7% respectively. The chemotherapy protocol for Langerhans cell histiocytosis (LCH) may be effective for patients with systemic JXG. Central nervous system involvement may not impact overall survival, but serious permanent sequelae may occur.
PubMed: 34178890
DOI: 10.3389/fped.2021.672547 -
British Journal of Haematology Nov 2021Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different... (Comparative Study)
Comparative Study
Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.
Topics: Adult; Aged; Aged, 80 and over; Allografts; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; CD28 Antigens; Carboplatin; Cyclophosphamide; DNA Copy Number Variations; Doxorubicin; Etoposide; Female; Genes, p53; Hematopoietic Stem Cell Transplantation; Humans; INDEL Mutation; Kaplan-Meier Estimate; Lenalidomide; Leukemia-Lymphoma, Adult T-Cell; Male; Middle Aged; Mutation; Nitrosourea Compounds; Polymorphism, Single Nucleotide; Prednisolone; Prednisone; Prognosis; Receptors, CCR4; Vincristine; Vindesine
PubMed: 34405395
DOI: 10.1111/bjh.17749 -
European Journal of Medical Research Mar 2023An immune-related gene signature (IGS) was established for discriminating prognosis, predicting benefit of immunotherapy, and exploring therapeutic options in...
BACKGROUND
An immune-related gene signature (IGS) was established for discriminating prognosis, predicting benefit of immunotherapy, and exploring therapeutic options in hepatocellular carcinoma (HCC).
METHODS
Based on Immune-related hub genes and The Cancer Genome Atlas (TCGA) LIHC dataset (n = 363), an immune-related gene signature (IGS) was established by least absolute shrinkage and selection operator (LASSO) analysis. The prognostic significance and clinical implications of IGS were verified in International Cancer Genome Consortium (ICGC) and Chinese HCC (CHCC) cohorts. The molecular and immune characteristics and the benefit of immune checkpoint inhibitor (ICI) therapy in IGS-defined subgroups were analyzed. In addition, by leveraging the Cancer Therapeutics Response Portal (CTRP) and PRISM Repurposing datasets, we determined the potential therapeutic agents for high IGS-risk patients.
RESULTS
The IGS was constructed based on 8 immune-related hub genes with individual coefficients. The IGS risk model could robustly predict the survival of HCC patients in TCGA, ICGC, and CHCC cohorts. Compared with 4 previous established immune genes-based signatures, IGS exhibited superior performance in survival prediction. Additionally, for immunological characteristics and enriched pathways, a low-IGS score was correlated with IL-6/JAK/STAT3 signaling, inflammatory response and interferon α/γ response pathways, low TP53 mutation rate, high infiltration level, and more benefit from ICI therapy. In contrast, high IGS score manifested an immunosuppressive microenvironment and activated aggressive pathways. Finally, by in silico screening potential compounds, vindesine, ispinesib and dasatinib were identified as potential therapeutic agents for high-IGS risk patients.
CONCLUSIONS
This study developed a robust IGS model for survival prediction of HCC patients, providing new insights into integrating tailored risk stratification with precise immunotherapy and screening potentially targeted agents.
Topics: Humans; Carcinoma, Hepatocellular; Immunotherapy; Interferon-gamma; Liver Neoplasms; Prognosis; Tumor Microenvironment
PubMed: 36918943
DOI: 10.1186/s40001-023-01091-w -
Blood Advances Aug 2023Most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and... (Clinical Trial)
Clinical Trial
Most patients with diffuse large B-cell lymphoma (DLBCL) can be cured with immunochemotherapy such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Patients with progression or relapse in the central nervous system (CNS) face dismal outcomes. The impact of more aggressive regimens used in frontline therapy has not been systematically investigated in this context. To this end, we analyzed a large cohort of 2203 younger patients with DLBCL treated on 10 German (German Lymphoma Alliance [GLA]/The German High Grade Non-Hodgkin's Lymphoma Study Group [DSHNHL]) and French (The Lymphoma Study Association [LYSA]) prospective phase 2 and 3 trials after first-line therapy with R-CHOP, R-CHOEP (R-CHOP + etoposide), dose-escalated R-CHOEP followed by repetitive stem cell transplantation (R-MegaCHOEP), or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycine, and prednisone) followed by consolidation including multiple drugs crossing the blood-brain barrier (BBB). Patients with DLBCL with an age-adjusted International Prognostic Index (aaIPI) of 0 to 1 showed very low cumulative incidence rates of CNS relapse regardless of first-line therapy and CNS prophylaxis (3-year cumulative incidences 0%-1%). Younger high-risk patients with aaIPI of 2 to 3 had 3-year cumulative incidence rates of 1.6% and 4% after R-ACVBP plus consolidation or R-(Mega)CHO(E)P, respectively (hazard ratio 2.4; 95% confidence interval: 0.8-7.4; P = .118). Thus, for younger high-risk patients, frontline regimens incorporating agents crossing the BBB may reduce often fatal CNS relapse.
Topics: Humans; Rituximab; Prednisone; Prospective Studies; Antibodies, Monoclonal, Murine-Derived; Neoplasm Recurrence, Local; Lymphoma, Large B-Cell, Diffuse; Vincristine; Chronic Disease; Central Nervous System; Cyclophosphamide; Doxorubicin; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36716220
DOI: 10.1182/bloodadvances.2022008888 -
Anti-cancer Drugs Apr 2023Although Philadelphia chromosome-positive acute leukemia (Ph + -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are...
Although Philadelphia chromosome-positive acute leukemia (Ph + -ALL) has been revolutionized with tyrosine kinase inhibitors (TKIs), resistance and mutation are universal events during treatment with first-generation and second-generation TKIs. The present third-generation TKI has a dose-dependent, increased risk of serious cardiovascular events and the sensitivity is poor for patients with ≥2 mutations accompanied by the T315I mutation. Thus, novel and well-tolerated TKIs should be explored. This study analyzes the efficacy and advert effects of olverembatinib, a novel third TKI, in the treatment of newly diagnosed adult Ph + -ALL in induction therapy. Four adult patients with newly diagnosed Ph + -ALL were treated with olverembatinib as the first-line treatment. For induction therapy, these patients received 40 mg of oral olverembatinib quaque omni die for 28 days, 1 mg/kg/d of prednisone for 14 days, then tapered and stopped at 28 days and vindesine 4 mg/d at days 1, 8 and 15. After induction therapy, these patients received median or high-dose of cytarabine and methotrexate combined with oral olverembatinib as consolidation therapy. Then the allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed. All patients reached complete remission with a complete cytogenetic response after induction therapy. Two patients reached major molecular remission and one with complete molecular remission. Before allo-HSCT, all the patients achieved complete molecular remission. All the patients have survived disease-free for 3-6 months. No severe advert effects were observed. It is well-tolerated and effective for olverembatinib in the treatment of newly diagnosed adult patients with Ph + -ALL. A prospective study should be performed to further testify the role.
Topics: Adult; Humans; Tyrosine Kinase Inhibitors; Philadelphia Chromosome; Prospective Studies; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation
PubMed: 36730312
DOI: 10.1097/CAD.0000000000001455 -
Theranostics 2018Vinca alkaloids, the well-known tubulin-binding agents, are widely used for the clinical treatment of malignant tumors. However, little attention has been paid to their...
Vinca alkaloids, the well-known tubulin-binding agents, are widely used for the clinical treatment of malignant tumors. However, little attention has been paid to their vascular disrupting effects, and the underlying mechanisms remain largely unknown. This study aims to investigate the vascular disrupting effect and the underlying mechanisms of vinca alkaloids. The capillary disruption assay and aortic ring assay were performed to evaluate the vascular disrupting effect of desacetylvinblastine monohydrazide (DAVLBH), a derivate of vinblastine, and the vascular disrupting effect was assessed on HepG2 xenograft model using magnetic resonance imaging, hematoxylin and eosin staining and immunohistochemistry. Tubulin polymerization, endothelial cell monolayer permeability, western blotting and immunofluorescence assays were performed to explore the underlying mechanisms of DAVLBH-mediated tumor vascular disruption. DAVLBH has potent vascular disrupting activity both and . DAVLBH disrupts tumor vessels in a different manner than classical tubulin-targeting VDAs; it inhibits microtubule polymerization, promotes the internalization of vascular endothelial cadherin (VE-cadherin) and inhibits the recycling of internalized VE-cadherin to the cell membrane, thus increasing endothelial cell permeability and ultimately resulting in vascular disruption. DAVLBH-mediated promotion of VE-cadherin internalization and inhibition of internalized VE-cadherin recycling back to the cell membrane are partly dependent on inhibition of microtubule polymerization, and Src activation is involved in DAVLBH-induced VE-cadherin internalization. This study sheds light on the tumor vascular disrupting effect and underlying mechanisms of vinca alkaloids and provides new insight into the molecular mechanism of tubulin-targeting VDAs.
Topics: Animals; Antigens, CD; Cadherins; Capillary Permeability; Cell Line, Tumor; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Hep G2 Cells; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Rats; Rats, Sprague-Dawley; Vindesine
PubMed: 29290815
DOI: 10.7150/thno.22222 -
Journal of Medicinal Chemistry Apr 2018The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry...
The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ∼17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC values under 10 μM, including several sub-micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 μM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well-characterized anti-EBOV inhibitors reported to date.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Drug Discovery; Drug Evaluation, Preclinical; Ebolavirus; HeLa Cells; Humans; Molecular Structure; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Virus Internalization
PubMed: 29624387
DOI: 10.1021/acs.jmedchem.8b00035 -
The Oncologist May 2024Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the...
BACKGROUND
Pegylated liposomal doxorubicin (PLD) is a liposome-encapsulated form of doxorubicin with equivalent efficacy and less cardiotoxicity. This phase 2 study evaluated the efficacy and safety of the PLD-containing CHOP regimen in newly diagnosed patients with aggressive peripheral T-cell lymphomas (PTCL).
METHODS
Patients received PLD, cyclophosphamide, vincristine/vindesine, plus prednisone every 3 weeks for up to 6 cycles. The primary endpoint was the objective response rate at the end of treatment (EOT).
RESULTS
From September 2015 to January 2017, 40 patients were treated. At the EOT, objective response was achieved by 82.5% of patients, with 62.5% complete response. As of the cutoff date (September 26, 2023), median progression-free survival (mPFS) and overall survival (mOS) were not reached (NR). The 2-year, 5-year, and 8-year PFS rates were 55.1%, 52.0%, and 52.0%. OS rate was 80.0% at 2 years, 62.5% at 5 years, and 54.3% at 8 years. Patients with progression of disease within 24 months (POD24) had worse prognosis than those without POD24, regarding mOS (41.2 months vs NR), 5-year OS (33.3% vs 94.4%), and 8-year OS (13.3% vs 94.4%). Common grade 3-4 adverse events were neutropenia (87.5%), leukopenia (80.0%), anemia (17.5%), and pneumonitis (17.5%).
CONCLUSION
This combination had long-term benefits and manageable tolerability, particularly with less cardiotoxicity, for aggressive PTCL, which might provide a favorable benefit-risk balance.
CLINICALTRIALS.GOV IDENTIFIER
Chinese Clinical Trial Registry, ChiCTR2100054588; IRB Approved: Ethics committee of Fudan University Shanghai Cancer Center (Date 2015.8.31/No. 1508151-13.
PubMed: 38821519
DOI: 10.1093/oncolo/oyae108 -
Turkish Journal of Haematology :... Aug 2023
Acute and Persistent Remission of Aggressive Natural Killer Cell Leukemia in an Older Patient Induced by Chidamide Combined with Cyclophosphamide, Vindesine, Prednisone, and Etoposide Therapy.
Topics: Humans; Prednisone; Etoposide; Vindesine; Leukemia, Large Granular Lymphocytic; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Vincristine
PubMed: 37464744
DOI: 10.4274/tjh.galenos.2023.2023.0227 -
JAMA Oncology Jun 2021Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Second-generation vs Third-generation Chemotherapy Regimens With Thoracic Radiotherapy on Unresectable Stage III Non-Small-Cell Lung Cancer: 10-Year Follow-up of a WJTOG0105 Phase 3 Randomized Clinical Trial.
IMPORTANCE
Insufficient data are available regarding the long-term outcomes and cumulative incidences of toxic effects that are associated with chemoradiotherapy (CRT) for patients with stage III non-small-cell lung cancer.
OBJECTIVE
To evaluate survival and late toxic effects 10 years after patients were treated with curative CRT.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, phase 3 West Japan Thoracic Oncology Group (WJTOG) 0105 randomized clinical trial was conducted between September 2001 and September 2005 in Japan. Patients with histologically or cytologically confirmed non-small-cell lung cancer with unresectable stage III disease were assessed for eligibility. Additional data were analyzed from January 2018 to December 2019.
INTERVENTIONS
A total of 440 eligible patients were randomly assigned to groups as follows: A (control), 4 cycles of mitomycin/vindesine/cisplatin plus thoracic radiotherapy (TRT) of 60 Gy; B, weekly irinotecan/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of irinotecan/carboplatin consolidation; or C, weekly paclitaxel/carboplatin for 6 weeks plus TRT of 60 Gy followed by 2 courses of paclitaxel/carboplatin consolidation.
MAIN OUTCOMES AND MEASURES
The primary outcome was 10-year survival probability after CRT. The secondary outcome was late toxic effects that occurred more than 90 days after initiating CRT.
RESULTS
From September 2001 to September 2005, 440 patients (group A, n = 146 [33.2%; median (range) age, 63 (31-74) years; 18 women (12.3%)]; group B, n = 147 [33.4%; median (range) age, 63 (30-75) years; 22 women (15.0%)]; group C, n = 147 [33.4%; median (range) age, 63 (38-74) years; 19 women (12.9%)]) were enrolled. The median (range) follow-up was 11.9 (7.6-13.3) years. In groups A, B, and C, median (range) overall survival times were 20.5 (17.5-26.0), 19.8 (16.7-23.5), and 22.0 (18.7-26.2) months, respectively, and 10-year survival probabilities were 13.6%, 7.5%, and 15.2%, respectively. There were no significant differences in overall survival among treatment groups. The 10-year progression-free survival probabilities were 8.5%, 6.5%, and 11.1% in groups A, B, and C, respectively. Grade 3 or 4 late toxic effect rates were 3.4% (heart, 0.7%; lung, 2.7%) in group A, and those only affecting the lung represented 3.4% and 4.1% in groups B and C, respectively. No other cases of late toxic effects (grades 3/4) were observed since the initial report.
CONCLUSION AND RELEVANCE
In this 10-year follow-up of a phase 3 randomized clinical trial, group C achieved similar efficacy and toxic effect profiles as group A 10 years after initiating treatment. These results serve as a historical control for the long-term comparisons of outcomes of future clinical trials of CRT.
TRIAL REGISTRATION
UMIN Clinical Trial Registry: UMIN000030811.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Lung Neoplasms; Neoplasm Staging; Paclitaxel
PubMed: 33734289
DOI: 10.1001/jamaoncol.2021.0113