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Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.
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BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/epidemiologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/complicações , Feminino , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Difosfonatos/uso terapêutico , Fatores de Risco , Bases de Dados Factuais , República da Coreia/epidemiologia , Conservadores da Densidade Óssea/uso terapêutico , Razão de Chances , Fraturas Espontâneas/etiologia , Fraturas Espontâneas/epidemiologia , Compressão da Medula Espinal/etiologia , Adulto , Modelos LogísticosAssuntos
Anemia Aplástica , Soro Antilinfocitário , Triazóis , Humanos , Soro Antilinfocitário/uso terapêutico , Anemia Aplástica/tratamento farmacológico , Triazóis/uso terapêutico , Masculino , Feminino , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/complicações , Adulto , Pessoa de Meia-Idade , Antifúngicos/uso terapêutico , IdosoRESUMO
INTRODUCTION: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis. METHODS: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations. RESULTS: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected. CONCLUSION: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis.
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Sequenciamento de Nucleotídeos em Larga Escala , Janus Quinase 2 , Mutação , Policitemia , Humanos , Policitemia/genética , Policitemia/diagnóstico , Janus Quinase 2/genética , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Mutação em Linhagem Germinativa , Centros de Atenção Terciária , Adulto Jovem , Idoso de 80 Anos ou mais , Adolescente , Predisposição Genética para DoençaAssuntos
Pirazóis , Piridonas , Trombose Venosa , Humanos , Projetos Piloto , Pirazóis/uso terapêutico , Trombose Venosa/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Piridonas/uso terapêutico , Inibidores do Fator Xa/uso terapêutico , Idoso , Adulto , Circulação Esplâncnica/efeitos dos fármacos , Doença AgudaRESUMO
Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.
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Aspergilose , Humanos , Aspergilose/tratamento farmacológico , Mananas , Galactose , Glucose/uso terapêutico , Soluções de Nutrição Parenteral , Sensibilidade e Especificidade , Antígenos de FungosRESUMO
PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.
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Talidomida , Macroglobulinemia de Waldenstrom , Humanos , Bortezomib/efeitos adversos , Talidomida/efeitos adversos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/etiologia , Dexametasona/uso terapêutico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Previous studies have reported that collagen tripeptide (CTP) derived from collagen hydrolysate has various beneficial effects on health by protecting against skin aging and improving bone formation and cartilage regeneration. Collagen-Tripep20TM (CTP20), which is a low-molecular-weight CTP derived from fish skin, contains a bioactive CTP, Gly-Pro-Hyp >3.2% with a tripeptide content >20%. Herein, we investigated the osteogenic effects and mechanisms of CTP20 (<500 Da) on MG-63 osteoblast-like cells and SW1353 chondrocytes. And we measured promoting ratio of the longitudinal bone growth in childhood rats. First, CTP20 at 100 µg/mL elevated the proliferation (15.0% and 28.2%), alkaline phosphatase activity (29.3% and 32.0%), collagen synthesis (1.25- and 1.14-fold), and calcium deposition (1.18- and 1.15-fold) in MG-63 cells and SW1353, respectively. In addition, we found that CTP20 could promote the longitudinal growth and height of the growth plate of the tibia in childhood rats. CTP20 enhanced the protein expression of insulin-like growth factor-1 (IGF-1) in MG-63 and SW1353 cells, and in the growth plate of childhood rats, along with Janus Kinase 2, and signal transducer and activator of transcription 5 activation in MG-63 and SW1353 cells. CTP20 also elevated the expression levels of bone morphogenetic proteins (BMPs) in MG-63 and SW1353 cells and in the growth plates of childhood rats. These results indicate that CTP20 may promote the endochondral ossification and longitudinal bone growth, through enhancing of IGF-1 and BMPs. (Clinical Trial Registration number: smecae 19-09-01).
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Desenvolvimento Ósseo , Fator de Crescimento Insulin-Like I , Humanos , Ratos , Animais , Fator de Crescimento Insulin-Like I/metabolismo , Fator de Crescimento Insulin-Like I/farmacologia , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas Morfogenéticas Ósseas/farmacologia , Osteogênese , Colágeno/farmacologiaRESUMO
INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.
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Neoplasias Colorretais , Tromboembolia Venosa , Trombose Venosa , Humanos , Cetuximab/efeitos adversos , Irinotecano/uso terapêutico , Oxaliplatina/efeitos adversos , Tromboembolia Venosa/induzido quimicamente , Tromboembolia Venosa/epidemiologia , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Trombose Venosa/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.
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Aminoacil-tRNA Sintetases , Humanos , Aminoacil-tRNA Sintetases/química , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Fibrose , Prolina/genética , Prolina/metabolismo , Biossíntese de ProteínasRESUMO
AIM: In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72-h REM sleep-deprived (SD) rats, a mania model. Additionally, the expression levels of miR-325-3p, miR-326-3p, and miR-330-5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA-325-3p, miR-326-3p, and miR-330-5p modulate TH and manic-like behaviors in SD rats. METHODS: Manic-like behaviors were assessed using the open field test (OFT) and elevated plus-maze (EPM) test. The direct binding activity of miRNAs to the 3'-untranslated region (3'-UTR) of the Th gene was measured in HEK-293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR-330-5p agomir to SD rats, along with manic-like behaviors. RESULTS: We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA-325-3p, miR-326-3p, and miR-330-5p expressions in the prefrontal cortex of SD rats, together with increased manic-like behaviors. The luciferase reporter assay showed that miR-330-5p could repress TH expression through direct binding to its target site in the 3'-UTR of Th, whereas miR-326-3p and miR-330-5p could not. In addition, ICV injection of miR-330-5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic-like behaviors. CONCLUSIONS: TH expression regulation through miR-330-5p may be implicated in the pathophysiology of mania in SD rats.
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MicroRNAs , Tirosina 3-Mono-Oxigenase , Animais , Humanos , Ratos , Regulação para Baixo , Células HEK293 , Mania , MicroRNAs/metabolismo , Projetos Piloto , RNA Mensageiro , Sono REM , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
BACKGROUND: Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. METHODS: Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression-free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune-related adverse events (irAEs). RESULTS: Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second-line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all-grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). CONCLUSIONS: Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Inibidores da Dipeptidil Peptidase IV , Neoplasias Pulmonares , Metformina , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Metformina/farmacologia , Metformina/uso terapêutico , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
Dasatinib, a tyrosine kinase inhibitor, is usually prescribed for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, some patients may develop an intolerance to this drug over the years. Among various toxicities related to dasatinib, dasatinib-associated interstitial pneumonitis is not reported frequently in the literature yet. Moreover, published studies have reported only few cases of dasatinib-associated pneumonitis, almost exclusively in chronic myeloid leukemia. In this study, we describe three cases of dasatinib-associated interstitial pneumonitis in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia (a 56-year-old man, a 34-year-old man, and a 46-year-old woman) at our institution. In all three patients, the time from the initiation of dasatinib therapy to the onset of interstitial pneumonitis varied greatly. Among them, one patient underwent a surgical lung biopsy, which revealed chronic granulomatous inflammation without any causative pathogen. In all patients, dasatinib was discontinued after the diagnosis of interstitial pneumonitis, and two patients were treated with systemic steroids. Although infrequent, dasatinib-induced pneumonitis should be considered a possible diagnosis in dasatinib-treated patients with fever and respiratory symptoms. In addition, hematologists and pulmonologists should be aware of this rare but critical toxicity.
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Leucemia Mielogênica Crônica BCR-ABL Positiva , Doenças Pulmonares Intersticiais , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Adulto , Dasatinibe/efeitos adversos , Cromossomo Filadélfia , Pirimidinas/efeitos adversos , Tiazóis/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Inibidores de Proteínas Quinases/uso terapêutico , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnósticoRESUMO
BACKGROUND/AIM: Sleep loss is proposed as a trigger for manic episodes in bipolar disorder in humans. It has been shown that sleep and wakefulness can affect changes in mitochondrial gene expression, oxidative phosphorylation (OXPHOS) activity, and morphology in the brain. In this study, we investigated alterations in mitochondrial bioenergetic function in the brain of rats after 72-h rapid eye movement sleep deprivation (REM-SD). MATERIALS AND METHODS: Alterations in the mitochondrial DNA (mtDNA) copy number were detected in the prefrontal cortex and hippocampus through amplification of mitochondrially encoded NADH dehydrogenase 1 (mt-Nd1) gene using quantitative real-time polymerase chain reaction. The expression levels of mitochondrial biogenesis-related proteins such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), cytochrome c oxidase subunit 4I1 (COX4I1) and sirtuin 3 (SIRT3) were assessed using western blot analysis and immunohistochemistry. RESULTS: We found that REM-SD significantly increased the mtDNA copy number in the hippocampus but not in the prefrontal cortex. In addition, REM-SD increased the protein expression of COX4I1 in the hippocampus. Furthermore, we observed manic-like behaviors in rats exposed to 72-h REM-SD. REM-SD increased locomotion in the open-field test and the time spent in open arms in the elevated plus-maze test. CONCLUSION: REM-SD may induce mitochondrial dysfunction in the brain, which may be involved in the induction of mania.
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Biogênese de Organelas , Privação do Sono , Animais , Encéfalo , DNA Mitocondrial/genética , Hipocampo/metabolismo , Ratos , Privação do Sono/metabolismoRESUMO
Systemic mastocytosis with associated hematological neoplasm (SM-AHN) poses diagnostic challenges because of the coexistence of atypical mast cell proliferation and hematological neoplasms. We assessed the presence of SM-AHN in patients with acute myeloid leukemia (AML) with RUNX1::RUNX1T1 from 2014 to 2020. Bone marrow (BM) samples were evaluated for mast cell aggregates using CD117 and CD25 immunohistochemical (IHC) staining. The KIT D816V variant burden at diagnosis and post induction was assessed using droplet digital PCR. Among 23 patients diagnosed as having AML with RUNX1::RUNX1T1, four (17.4%) were also diagnosed as having SM-AHN. No significant differences in clinical characteristics or overall survival (P=0.565) were observed between patients with or without SM-AHN, except for the presence of KIT variants (P=0.040). After induction therapy, IHC staining revealed the presence of mast cell aggregates in the BM, and the KIT D816V variant burden decreased with decreasing blast count and was similar in BM aspirates, smear slides, and sections. Concomitant SM-AHN was not infrequent in AML patients with RUNX1::RUNX1T1. This study showed the importance of CD117 and CD25 IHC staining after induction chemotherapy for SM-AHN screening, especially in patients with KIT variants.
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Subunidade alfa 2 de Fator de Ligação ao Core , Neoplasias Hematológicas , Leucemia Mieloide Aguda , Mastocitose Sistêmica , Proteínas de Fusão Oncogênica , Proteína 1 Parceira de Translocação de RUNX1 , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Imuno-Histoquímica , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Mastocitose Sistêmica/metabolismo , Mastocitose Sistêmica/patologia , Proteínas de Fusão Oncogênica/metabolismo , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteína 1 Parceira de Translocação de RUNX1/metabolismo , Coloração e RotulagemRESUMO
OBJECTIVES: This study investigated the treatment pattern and the rate of bleeding complications in real-world practice in cancer-associated venous thromboembolism (CT) patients. METHODS: We used the Korean Health Insurance Review and Assessment Service database (2014-2018). Among patients with venous thromboembolism, patients with concomitant malignancy diagnostic codes were categorized as CT, while all others were categorized as non-CT. Treatments were categorized as direct oral anticoagulant (DOAC), parenteral anticoagulant (PAC), warfarin, and mixed anticoagulants. RESULTS: We identified 27,205 CT and 57,711 non-CT patients. DOACs were the most frequently used anticoagulants. The proportion of patients treated with PAC was higher in CT than in non-CT patients (35.7 vs. 19.5%; p < 0.01). In CT, the cumulative incidence of any/major bleeding was higher with DOAC (8.1%/3.9%) than with PAC (7.5%/3.2%; p = 0.04 and 0.01, respectively). However, there was no difference in major bleeding when compared with warfarin (p = 0.11) or mixed anticoagulants (p = 0.94). Overall, gastrointestinal (GI) cancer patients showed higher risks of bleeding. The cumulative incidence of major GI bleeding was higher with DOAC than with PAC (4.9 vs. 3.0%; p < 0.01), while there was no difference compared with warfarin (p = 0.59) or mixed anticoagulants (p = 0.80). Major bleeding with each DOAC showed no difference among entire CT (p = 0.94), GI cancer (p = 0.27), and genitourinary cancer (p = 0.88) patients. CONCLUSION: Five years after their introduction into clinical practice, DOACs have become the most prescribed anticoagulant in Korea. In our patient population, bleeding complications occurred more frequently in CT than in non-CT, especially in patients treated with DOACs.
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Neoplasias , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/complicações , Varfarina/efeitos adversos , Administração Oral , Anticoagulantes/efeitos adversos , Hemorragia Gastrointestinal/etiologia , Hemorragia Gastrointestinal/induzido quimicamente , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: The incidence of venous thromboembolism (VTE) has gradually increased in the Korean population. This study aimed to evaluate the annual age- and sex-adjusted incidence rates (ASR) of VTE and anticoagulation trends between 2014 and 2018. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified VTE patients between 2014 and 2018 using both diagnostic and medication anticoagulant codes assigned within 6 months of the initial index event. Anticoagulant patterns were classified as follows: direct oral anticoagulants (DOAC), parenteral anticoagulants, warfarin, and mixed anticoagulation regimens. RESULTS: We identified 95,205 patients with VTE (female, 56.8%). The ASR for VTE per 100,000 person-years increased from 32.8 in 2014 to 53.7 cases in 2018 (relative risk of 1.63; 95% confidence interval, 1.6-1.67). The VTE incidence rates were 25 times higher in the ≥ 80 group than in the 30s group. VTE occurred 1.29 times more often in women than in men. The proportion of DOAC prescriptions increased from 40.5% to 72.8%, whereas warfarin prescriptions decreased from 27% to 5.6% in 2014 and 2018. CONCLUSION: In Korea, the ASRs of VTE continued to increase since 2014, but the rate of increase slowed in 2018. The VTE occurred more often in the elderly and in women. Five years after the introduction of DOACs in 2013, they accounted for 73% of all anticoagulants used to treat VTE.
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Tromboembolia Venosa , Idoso , Anticoagulantes/uso terapêutico , Feminino , Humanos , Incidência , Masculino , Estudos Retrospectivos , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/tratamento farmacológico , Tromboembolia Venosa/epidemiologia , Varfarina/uso terapêuticoRESUMO
INTRODUCTION: Thrombopoietin receptor agonists (TPO-RAs) are a reliable second-line immune thrombocytopenia (ITP) treatment. Despite an increase in use of TPO-RAs, the treatment pattern among adults with ITP is not well understood. MATERIALS AND METHODS: From January 2015 to December 2018, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database. RESULTS: Of the total 3885 adult patients with ITP, 1745 (44.9%) required treatment, with a median follow-up duration of 31.4 months (range, 0.1-59.8 months). Of these, 46.5% and 36.6% continued treatment for more than 6 months and more than 12 months, respectively. Corticosteroids were the most common first-line therapy. Of the treated patients, 83 (4.8%) received TPO-RAs (eltrombopag, 86.7%; romiplostim, 13.3%). The median age of the group treated with TPO-RAs was 62 years, 62.6% were female, and the median time from first diagnosis to initial TPO-RA treatment was 12.5 months (range, 0.4-48.0 months). A total of 52 (62.7%) patients received TPO-RAs as a second-line treatment for ITP. Splenectomy was performed in 19 patients (22.9%) before initiation of TPO-RAs. When clinical efficacy was analyzed before and during TPO-RA use, there was a significant decrease in platelet transfusion and a tendency toward reduced bleeding events. CONCLUSIONS: This population-based study is the first to describe the treatment pattern of TPO-RAs for ITP among patients in Korea.
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Púrpura Trombocitopênica Idiopática , Trombocitopenia , Adulto , Benzoatos/efeitos adversos , Pré-Escolar , Feminino , Humanos , Hidrazinas/efeitos adversos , Lactente , Recém-Nascido , Masculino , Púrpura Trombocitopênica Idiopática/diagnóstico , Receptores Fc/uso terapêutico , Receptores de Trombopoetina , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos Retrospectivos , Esplenectomia , Trombocitopenia/induzido quimicamente , Trombopoetina/uso terapêuticoRESUMO
PURPOSE: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the counter effect of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancers (CRCs). METHODS: Plasma HGF levels were analyzed with clinical outcomes of patients with metastatic CRC (mCRC) receiving palliative first-line chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition by capmatinib. RESULTS: A total of 80 patients were included: cetuximab + FOLFIRI (n = 35) and bevacizumab + FOLFIRI (n = 45). Both progression-free survival (PFS) and overall survival (OS) were significantly lesser in the high vs low HGF group: median 11.8 vs. 24.7 months, respectively, for PFS (p = 0.009), and median 21.1 months vs. not reached, respectively, for OS (p = 0.018). The difference was significantly evident in the cetuximab group. In five RAS/RAF wild-type CRC cells, the addition of HGF activated ERK1/2 and AKT via MET phosphorylation, resulting in cetuximab resistance in vitro. In cetuximab-sensitive Caco-2 and SNU-C4 cells, capmatinib overcame cetuximab resistance in the presence of HGF by attenuating HGF-induced MET signaling activation. CONCLUSION: Patients with mCRC receiving cetuximab + FOLFIRI who presented with high plasma HGF levels had significantly worse PFS and OS. Cetuximab resistance induced by HGF was mediated by AKT and ERK activation and overcome by MET inhibition in vitro.
Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Bevacizumab/uso terapêutico , Células CACO-2 , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/genética , GTP Fosfo-Hidrolases , Fator de Crescimento de Hepatócito/uso terapêutico , Humanos , Imidazóis , Proteínas de Membrana , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt , Proteínas Proto-Oncogênicas p21(ras)/genética , TriazinasRESUMO
Although the clinical outcome of newly diagnosed multiple myeloma has improved with maintenance therapy, maintenance with novel agents is not always available depending on medical expenses or drug accessibility. We intended to investigate the efficacy and toxicity of thalidomide/dexamethasone maintenance in Korean patients. In this multicenter phase 2 study, patients with newly diagnosed myeloma who underwent induction chemotherapy followed by autologous stem cell transplantation (ASCT) were enrolled to receive maintenance treatment of 100mg thalidomide daily for 28 days and 40mg dexamethasone daily for 4 days each cycle. Maintenance was given up to 12 cycles. The primary endpoint was a 1-year event free survival (EFS) rate. It was assumed that EFS at 1-year would be 91% with thalidomide and 1-year EFS below 82% would be of no effect. A total of 43 patients were consecutively enrolled (median age, 58 years [range, 34 - 65]; male, n = 31). With a median follow-up duration of 17.3 months (range, 1.1 - 32.2), EFS at 1 year was 65.1% (95% confidence interval [CI], 48.9 - 77.3). PFS and OS at 1 year was 85.6% (95% CI, 70.7 - 93.3) and 90.4 (95% CI, 76.3 - 96.3), respectively. In terms of side effects, 39 patients (90.7%) experienced adverse events (AEs) of any grade, and 14 patients (32.6%) experienced grade 3 or 4 adverse events. 15 patients (34.9%) failed to complete 12 cycles of maintenance, and the most common reason for premature termination was AEs (n = 6). In Korean patients the benefits of thalidomide maintenance does not seem to outweigh the toxicity of thalidomide, especially in high-risk MM. Considering the long clinical course of MM, preservation of quality of life and finances might be more beneficial for subsequent MM treatment.