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1.
Anticancer Res ; 43(5): 2343-2349, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37097676

RESUMEN

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) improve long-term survival in advanced non-small cell lung cancer (NSCLC) and require robust predictive biomarkers for the selection of responders. This study investigated the optimal implementation of DNA damage repair (DDR) gene mutations to predict response to ICIs in real-world NSCLC patients. PATIENTS AND METHODS: We retrospectively reviewed 55 advanced NSCLC patients who had undergone targeted high-throughput sequencing and received ICIs. Patients with two or more DDR gene mutations were defined as DDR2 positive. RESULTS: The patients' median age was 68 (range=44-82) years, and 48 (87.3%) were men. Seventeen patients (30.9%) showed ≥50% high programmed death-ligand 1 (PD-L1) expression. Ten patients (18.2%) received an ICI-chemotherapy combination as first-line therapy, and 38 (69.1%) received ICI monotherapy as more than second-line therapy. Fourteen patients (25.5%) were DDR2-positive. The objective response rate of patients with DDR2-positive or PD-L1 ≥50% was 45.5%, and that of patients with DDR2-negative and PD-L1 <50% was 11.1% (p=0.007). In the PD-L1 low expression subgroup (<50%), patients with DDR2-positive had improved progression-free survival (PFS) and overall survival (OS) after ICIs compared to those with DDR2-negative (PFS: 5.8 vs. 1.9 months, p=0.026, OS: 14.4 vs. 7.2 months, p=0.078). DDR2-positive patients or those with PD-L1 ≥50% (24, 43.6%) had statistically significant improvement in PFS and OS after ICIs compared to DDR2-negative and those with PD-L1 <50% (PFS: 4.4 vs. 1.9 months, p=0.006, OS: 11.6 vs. 7.2 months, p=0.037). CONCLUSION: A dual biomarker combining DDR gene mutations and PD-L1 expression improves the prediction of response to ICIs in advanced NSCLC.


Asunto(s)
Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Masculino , Humanos , Anciano , Femenino , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Antígeno B7-H1/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Estudios Retrospectivos , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/genética , Mutación , Daño del ADN
2.
Oncology ; 101(1): 41-48, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36257294

RESUMEN

INTRODUCTION: Current standard chemotherapy for biliary tract cancer (BTC) has limited survival benefits, and the need for targeted therapies is increasing. This study investigated the genetic profiles and clinical implications of BRCA mutations in patients with advanced BTC. METHODS: Targeted high-throughput sequencing was performed on samples obtained from 25 patients with advanced BTC who had received palliative first-line platinum-based chemotherapy. RESULTS: Of the 25 patients, 16 (64.0%) were younger than 65 years of age and 16 (64.0%) were male. The BTC cases consisted of intrahepatic cholangiocarcinoma (9, 36.0%), extrahepatic cholangiocarcinoma (5, 20.0%), and gallbladder cancer (11, 44.0%). The median overall survival (OS) and progression-free survival (PFS) of all patients were 11.9 months (95% confidence interval [CI]: 9.2-14.6) and 5.6 months (95% CI: 3.8-7.3), respectively. Genomic alterations in TP53 (52.0%), BRCA (36.0%), ATM (32.0%), ERBB2 (24.0%), NOTCH1 (20.0%), and FGFR3 (20.0%) were frequently reported. TP53 and ATM mutations were associated with OS (TP53: hazard ratio [HR] 2.719, 95% CI: 1.074-6.881, p = 0.035; ATM: HR 2.780, 95% CI: 1.091-7.082, p = 0.032). Patients with BRCA mutations had a slightly improved PFS compared to those with intact BRCA (6.7 months [range, 2.7-10.7 months] vs. 5.3 months [range, 3.6-7.0 months], p = 0.090). However, there was no significant difference in OS between groups (BRCA mutant vs. intact: 10.6 months [range, 3.6-17.6 months] vs. 11.9 months [range, 7.5-16.3 months], p = 0.252). BRCA mutations were significantly associated with PFS in the multivariate analysis (HR 0.150, 95% CI: 0.034-0.655, p = 0.012). CONCLUSION: This study demonstrated that BRCA mutations might have a role as predictive biomarkers for palliative first-line platinum-based chemotherapy in patients with advanced BTC.


Asunto(s)
Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , Humanos , Masculino , Adolescente , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/patología , Colangiocarcinoma/tratamiento farmacológico , Mutación , Platino (Metal)/uso terapéutico , Conductos Biliares Intrahepáticos/patología
3.
Oncology ; 100(6): 313-319, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35390786

RESUMEN

BACKGROUND: Elderly patients with extensive-disease small-cell lung cancer (ED-SCLC) have a high risk of chemotherapy toxicity due to multiple comorbidities and poor performance status. Although dose modification is often used to avoid toxicity in elderly patients with ED-SCLC, there is little data on the effect of initial dose-reduced chemotherapy on survival outcomes. METHODS AND PATIENTS: We retrospectively reviewed 100 elderly patients (≥70 years) with ED-SCLC who received first-line etoposide plus platinum chemotherapy between January 2006 and December 2020. RESULTS: The median age was 74 years. Eighty-nine patients (89%) had a history of smoking, and 38 (38%) had chronic lung disease. Thirty-four patients (34%) received dose-reduced etoposide plus platinum in the first cycle. The dose-reduced group had significantly higher age, lower body mass index, and poor Eastern Cooperative Oncology Group Performance Score. There were no significant differences in survival outcomes between the dose-reduced and full-dose chemotherapy (median overall survival [OS], 4.9 vs. 6.5 months, p = 0.440; median progression-free survival [PFS], 3.7 vs. 4.6 months, p = 0.272). In multivariate analyses, DR in the first cycle (hazard ratio 0.519, 95% CI: 0.269-1.000, p = 0.050) was significantly associated with OS. Following a subgroup analysis of 59 patients who received minimum four cycles, no significant differences in survival outcomes between the two groups (median OS, 10.9 vs. 9.4 months, p = 0.817; median PFS, 6.3 vs. 6.5 months, p = 0.902) were noted. CONCLUSIONS: The dose-reduced chemotherapy with first-line etoposide plus platinum had non-inferior survival outcomes compared to the full-dose chemotherapy in elderly patients with ED-SCLC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Etopósido , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Relación Dosis-Respuesta a Droga , Etopósido/administración & dosificación , Etopósido/efectos adversos , Etopósido/uso terapéutico , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Compuestos de Platino/administración & dosificación , Compuestos de Platino/efectos adversos , Compuestos de Platino/uso terapéutico , Estudios Retrospectivos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/mortalidad
4.
Oncology ; 99(6): 365-372, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33730723

RESUMEN

BACKGROUND: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. PATIENTS AND METHODS: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. RESULTS: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. CONCLUSION: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígeno B7-H1/metabolismo , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Biomarcadores de Tumor/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Platino (Metal)/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de los Conductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Femenino , Neoplasias de la Vesícula Biliar/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Cuidados Paliativos , Platino (Metal)/uso terapéutico , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Gemcitabina
5.
In Vivo ; 35(1): 499-505, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33402502

RESUMEN

BACKGROUND/AIM: Biliary tract cancer (BTC) has a poor prognosis due to its highly invasive and metastatic potential. Ataxia-telangiectasia mutated (ATM) is a key regulator of DNA damage response and an emerging therapeutic target; however, the association between the expression of ATM and the prognosis in advanced BTC is unknown. We aimed to identify the relationship between ATM expression, clinicopathological characteristics, and survival outcomes in patients with advanced BTC. PATIENTS AND METHODS: We analyzed 113 patients with advanced BTC who received first-line gemcitabine and platinum. RESULTS: The tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 43 patients, extrahepatic cholangiocarcinoma (EH-CCC) in 49, and gallbladder (GB) cancer in 21 patients. Fifty-four patients (47.8%) exhibited loss of ATM protein expression. The overall response rate (ORR) of ATM loss and intact ATM was 13.3% and 19.6%, respectively. In a subgroup analysis, EH-CCC patients with ATM loss tended to have improved PFS after platinum-based chemotherapy compared to those with intact ATM (7.9 vs. 6.2 months, respectively; p=0.050). CONCLUSION: We demonstrated that ATM loss could be a prognostic marker after platinum-based chemotherapy in patients with advanced EH-CCC.


Asunto(s)
Ataxia Telangiectasia , Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/uso terapéutico , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/genética , Desoxicitidina/análogos & derivados , Humanos , Platino (Metal) , Pronóstico , Gemcitabina
6.
Investig Clin Urol ; 61(6): 588-593, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32985144

RESUMEN

PURPOSE: To assess the efficacy and safety of docetaxel rechallenge in the salvage setting in metastatic castration-resistant prostate cancer (mCRPC) patients. MATERIALS AND METHODS: Clinicopathologic data from patients treated with docetaxel rechallenge were collected from a single-center cancer registry. Among 227 patients who received first-line docetaxel for mCRPC between January 2011 and June 2019, 23 undergo rechallenge docetaxel after failure to androgen receptor targeting agents and/or cabazitaxel treatment. Endpoints included radiologic progression-free survival (PFS), treatment duration, and prostate-specific antigen (PSA) response and safety. RESULTS: Overall, 30%, 44%, 13%, and 13% of patients received docetaxel rechallenge as either the third, fourth, fifth, or sixth-line therapy, respectively, at a median of 23.6 months after stopping first-line docetaxel. With first-line docetaxel and rechallenge, median treatment duration was 6.4 and 3.3 months, respectively. With docetaxel rechallenge, PSA response was 35% (95% confidence interval [CI], 15% to 54%) and median PFS was 4.5 months (95% CI, 1.9 to 7.1 months). The median OS was 24.3 months (95% CI, 4.6 to 44.0 months). There were 7 severe adverse events (grade 3 or more) including anemia (8.7%), neutropenia, thrombocytopenia, leukopenia, diarrhea, and nausea (4.3% each). CONCLUSIONS: Docetaxel rechallenge showed meaningful anti-tumor activity with acceptable toxicity in heavily pretreated patients with mCRPC.


Asunto(s)
Antineoplásicos/uso terapéutico , Docetaxel/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Antineoplásicos/efectos adversos , Docetaxel/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
7.
BMC Cancer ; 20(1): 727, 2020 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-32758163

RESUMEN

BACKGROUND: Anti-PD1 inhibitors have been approved for the treatment of recurrent or metastatic head and neck cancer (HNC), as a result of Global Phase III trials. However, the clinical outcomes of immune checkpoint inhibitors in patients who are not eligible for clinical trials or have various medical conditions have not been fully elucidated. METHODS: We retrospectively reviewed 46 patients with recurrent or metastatic HNC who received pembrolizumab or nivolumab between June 2016 and June 2019. RESULTS: Thirty-five patients had head and neck squamous cell carcinoma (HNSCC) affecting the oropharynx, oral cavity, hypopharynx, larynx, nasal cavity, or paranasal sinuses, and eleven patients had nasopharyngeal cancer (NPC). The median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.8 months, respectively, for patients with HNSCC, and 4.3 months and 11.8 months, respectively, for patients with NPC. The objective response rate (ORR) in all patients was 21%. Of 30 patients with HNSCC, 5 patients achieved complete response and 2 achieved partial response (ORR 23%); 1 of 8 NPC patients achieved partial response (13%). Patients who previously underwent radiotherapy had better OS than those who did not (median OS, 7.6 months vs. 2.3 months, p = 0.006). OS was longer in patients treated with pembrolizumab than in those treated with nivolumab (median OS, 11.8 months vs. 6.8 months, p = 0.017). CONCLUSION: Consistent with previous reports, immune checkpoint inhibitors showed promising efficacy in patients with previously treated recurrent or metastatic HNC in a real-world setting.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nivolumab/uso terapéutico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/radioterapia , Recurrencia Local de Neoplasia/mortalidad , Supervivencia sin Progresión , República de Corea , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Resultado del Tratamiento , Adulto Joven
8.
BMC Gastroenterol ; 20(1): 207, 2020 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-32615928

RESUMEN

An amendment to this paper has been published and can be accessed via the original article.

9.
Blood ; 136(22): 2548-2556, 2020 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-32584959

RESUMEN

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.


Asunto(s)
Neoplasias del Sistema Nervioso Central/prevención & control , Linfoma Extranodal de Células NK-T/prevención & control , Metotrexato/administración & dosificación , Modelos Biológicos , Anciano , Neoplasias del Sistema Nervioso Central/metabolismo , Neoplasias del Sistema Nervioso Central/patología , Femenino , Humanos , Células Asesinas Naturales/metabolismo , Células Asesinas Naturales/patología , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Masculino , Persona de Mediana Edad , Factores de Riesgo
10.
Target Oncol ; 15(2): 203-209, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32314267

RESUMEN

BACKGROUND: A taxane plus ramucirumab as second-line therapy followed by a checkpoint inhibitor (CPI) in third line has become a standard treatment strategy for advanced gastric cancer. OBJECTIVE: Herein, we investigated the impact of prior ramucirumab use on the efficacy of third-line immunotherapy and performed an exploratory analysis to identify potential biomarkers for the success of immunotherapy. PATIENTS AND METHODS: We retrospectively analyzed patients receiving CPI as a third-line treatment for advanced gastric cancer between January 2015 and March 2019. Clinicopathologic data, including patient characteristics, histopathologic reports, and treatment types and outcomes, were reviewed. RESULTS: Of the 74 patients included in this study, 45 (61%) received nivolumab and 29 (39%) received pembrolizumab as a third-line CPI. For second-line therapy, 41 patients (55%) were treated with ramucirumab plus a taxane, and 33 (45%) received a chemotherapy regimen without ramucirumab. The disease control rates of CPIs were not statistically different according to prior use of ramucirumab. The overall survival (OS) with CPI was higher in patients receiving second-line therapy without ramucirumab compared with those receiving ramucirumab and taxane (5.6 vs 4.8 months, HR 0.56, 95% confidence interval [CI] 0.33-0.96; p = 0.03); however, this was not significant in a multivariate analysis. Patients achieving a response to second-line ramucirumab and a taxane showed greater benefit from subsequent CPI treatment compared with those not achieving a response (median OS 9.9 vs 2.3 months, HR 0.20, 95% CI 0.07-0.54; p < 0.001) as found in an exploratory analysis. Multivariate analysis also showed that prior response to ramucirumab and a taxane was an independent prognostic factor of OS with third-line CPI. CONCLUSIONS: Response to ramucirumab and a taxane as a second-line treatment is an important prognostic marker for OS with subsequent third-line CPI. This data might provide useful information when applying CPIs as third-line therapies in advanced gastric cancer patients.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Ramucirumab
11.
Diagnostics (Basel) ; 10(4)2020 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-32340330

RESUMEN

We investigated the size-based isolation and enumeration of circulating tumor cells (CTCs) using a centrifugal microfluidic device equipped with a fluid-assisted separation technology (FAST) disc. We further assessed the correlations among CTCs, cancer antigen-125 (CA125) levels, and clinical course of the disease in a prospective analysis of 47 serial blood samples collected at multiple time-points from 13 ovarian cancer patients. CTCs were isolated from whole blood using the FAST disc and were classified as epithelial cell adhesion molecule (EpCAM)/cytokeratin+, CD45-, and 4',6-diamidino-2-phenylindole (DAPI)+. Mean CTC count at baseline was 20.2; 84.62% of patients had more than one CTC at baseline and had decreased CTCs counts after surgery and chemotherapy. The CTC counts in eight patients with complete responses were <3. CTC counts were correlated with CA125 levels in three patients without recurrence; they were elevated in three patients with recurrence and normal CA125 concentrations. CTC counts and CA125 levels showed high concordance with directional changes (increasing 71.4%; non-increasing 75.0%). CTC counts showed higher associations with clinical status, sensitivity (100.0% vs. 60.0%), positive predictive value (55.6% vs. 42.9%), and negative predictive value (100.0% vs. 87.5%) than CA125 levels. CTC counts were better associated with treatment response and recurrence than CA125 levels.

12.
Int J Mol Sci ; 21(8)2020 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-32325639

RESUMEN

Despite comprehensive genomic analyses, no targeted therapies are approved for bladder cancer. Here, we investigate whether a single and combination therapy with targeted agents exert antitumor effects on bladder cancer cells through genomic alterations using a three-dimensional (3D) high-throughput screening (HTS) platform. Seven human bladder cancer cell lines were used to screen 24 targeted agents. The effects of 24 targeted agents were dramatically different according to the genomic alterations of bladder cancer cells. BEZ235 (dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor) showed antitumor effects against most cell lines, while AZD2014 (mTOR inhibitor) had an IC50 value lower than 2 µM in 5637, J82, and RT4 cell lines. AZD5363 (protein kinase B (AKT) inhibitor) exerted antitumor effects on 5637, J82, and 253J-BV cells. J82 cells (PI3KCA and mTOR mutations) were sensitive to AZD5363, AZD2014, and BEZ235 alone or in AZD5363/AZD2014 and AZD5363/BEZ235 combinations. Although all single drugs suppressed cell proliferation, the combination of drugs exhibited synergistic effects on cell viability and colony formation. The synergistic effects of the combination therapy on the PI3K/Akt/mTOR pathway, apoptosis, and EMT were evident in Western blotting. Thus, the 3D culture-based HTS platform could serve as a useful preclinical tool to evaluate various drug combinations.


Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Proliferación Celular/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Morfolinas/farmacología , Mutación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/farmacología , Pirroles/farmacología , Quinolinas/farmacología , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Vejiga Urinaria/enzimología , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/metabolismo
13.
BMC Gastroenterol ; 20(1): 20, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992208

RESUMEN

BACKGROUND: Biliary tract cancers (BTC) have a poor prognosis even after curative resection because of frequent local and distant recurrences. Therefore, the importance of adjuvant therapy in BTC has been advocated to improve outcomes. However, the choice of adjuvant therapy is still controversial. The aim of this study was to compare the effects of adjuvant concurrent chemoradiotherapy (CCRT) and chemotherapy on resected BTC. METHODS: We analyzed 92 patients who had curatively resected BTC and had received adjuvant CCRT or chemotherapy from January 2000 to December 2017 at Keimyung University Dongsan Medical Center. RESULTS: Of the patients, 46 received adjuvant CCRT and 46 received adjuvant chemotherapy. The median recurrence-free survival (RFS) for the adjuvant CCRT and chemotherapy groups were 13.8 and 11.2 months (p = 0.014), respectively. The median overall survival (OS) for the adjuvant CCRT and chemotherapy groups were 30.1 and 26.0 months (p = 0.222), respectively. Adjuvant CCRT had significantly better RFS and numerically higher OS than did chemotherapy. For subgroups with no lymph node (LN) involvement (RFS p = 0.006, OS p = 0.420) or negative resection margins (RFS p = 0.042, OS p = 0.098), adjuvant CCRT led to significantly longer RFS and numerically higher OS than did chemotherapy. For multivariate analysis, the pattern of adjuvant treatment (chemotherapy vs. CCRT, p = 0.004, HR 2.351), histologic grade (poor vs. well, p = 0.023, HR 4.793), and LN involvement (p = 0.028, HR 1.912) were the significant prognostic factors for RFS. CONCLUSIONS: Our study demonstrated the superiority of adjuvant CCRT over chemotherapy for improving RFS in curatively resected BTC.


Asunto(s)
Neoplasias del Sistema Biliar/terapia , Quimioradioterapia Adyuvante , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/cirugía , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/prevención & control , Pronóstico
14.
Korean J Intern Med ; 34(6): 1324-1332, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30360020

RESUMEN

BACKGROUND/AIMS: The occurrence of brain metastasis (BM) has increased due to improved overall survival (OS) in uterine cervical cancer. However, research about prognostic factors and therapeutic guidelines for BM in uterine cervical cancer remains scarce due to the rarity of BM in this type of cancer. The present study evaluated the clinical characteristics and prognostic factors influencing OS in patients with BM from uterine cervical cancer. METHODS: A total of 19 BM patients of uterine cervical cancer were analyzed retrospectively from January 1995 to December 2016. RESULTS: The median and mean OS of all patients was 9.6 and 15.4 months. Treatment (vs. palliative care, p < 0.001), fewer than three regimens of chemotherapy before BM (vs. ≥ 3, p < 0.013), and chemotherapy after BM (vs. absence, p < 0.001) significantly increased the OS time. The Karnofsky performance status ≥ 70 (vs. < 70, p = 0.213), single BM (vs. multiple BM, p = 0.157), and small cell carcinoma (vs. others, p = 0.351) had numerically higher OS than others. Dual therapy (vs. single therapy, p = 0.182; vs. no therapy, p = 0.076) were associated with a longer OS time, but the difference did not reach statistical significance. In addition, the graded prognostic assessment (GPA) appeared to be a better prognostic tool than the recursive partitioning analysis. CONCLUSION: The results of the present study suggest active multimodal treatment including neurosurgery, radiotherapy, and chemotherapy for BM of uterine cervical cancer with single BM, good performance status, histology of small cell carcinoma, and a better GPA.


Asunto(s)
Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Carcinoma de Células Pequeñas/mortalidad , Carcinoma de Células Pequeñas/secundario , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/patología , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/terapia , Carcinoma de Células Pequeñas/terapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Femenino , Humanos , Incidencia , Estado de Ejecución de Karnofsky , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Neoplasias del Cuello Uterino/terapia
15.
Tuberc Respir Dis (Seoul) ; 78(3): 190-5, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26175771

RESUMEN

BACKGROUND: Although organizing pneumonia (OP) responds well to corticosteroid therapy, relapse is common during dose reduction or follow-up. Predictors of relapse in OP patients remain to be established. The aim of the present study was to identify factors related to relapse in OP patients. METHODS: This study was retrospectively performed in a tertiary referral center. Of 66 OP patients who were improved with or without treatment, 20 (30%) experienced relapse. The clinical and radiologic parameters in the relapse patient group (n=20) were compared to that in the non-relapse group (n=46). RESULTS: Multivariate analysis demonstrated that percent predicted forced vital capacity (FVC), PaO2/FiO2, and serum protein level were significant predictors of relapse in OP patients (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.70-0.97; p=0.018; OR, 1.02; 95% CI, 1.00-1.04; p=0.042; and OR, 0.06; 95% CI, 0.01-0.87; p=0.039, respectively). CONCLUSION: This study shows that FVC, PaO2/FiO2 and serum protein level at presentation can significantly predict relapse in OP patients.

16.
Tuberc Respir Dis (Seoul) ; 77(3): 124-31, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25309607

RESUMEN

BACKGROUND: Bronchial anthracofibrosis (BAF), which is associated with exposure to biomass smoke in inefficiently ventilated indoor areas, can take the form of obstructive lung disease. Patients with BAF can mimic or present with an exacerbation of chronic obstructive pulmonary disease (COPD). The purpose of the current study was to investigate the prevalence of BAF in Korean patients with COPD exacerbation as well as to examine the clinical features of these patients in order to determine its clinical relevance. METHODS: A total of 206 patients with COPD exacerbation were divided into BAF and non-BAF groups, according to computed tomography findings. We compared both clinical and radiologic variables between the two groups. RESULTS: Patients with BAF (51 [25%]) were older, with a preponderance of nonsmoking women; moreover, they showed a more frequent association with exposure to wood smoke compared to those without BAF. However, no differences in the severity of illness and clinical course between the two groups were observed. Patients in the BAF group had less severe airflow obstruction, but more common and severe pulmonary hypertension signs than those in the non-BAF group. CONCLUSION: Compared with non-BAF COPD, BAF may be associated with milder airflow limitation and more frequent signs of pulmonary hypertension with a more severe grade in patients presenting with COPD exacerbation.

17.
Tuberc Respir Dis (Seoul) ; 77(2): 81-4, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25237379

RESUMEN

A patient treated with venlafaxine for major depression developed an interstitial lung disease (ILD) with the characteristic clinical, radiological and pathological features of chronic hypersensitivity pneumonitis. A high resolution computed tomography scan demonstrated ground glass opacity, mosaic perfusion with air-trapping and traction bronchiectasis in both lungs. The pathological findings were consistent with a nonspecific interstitial pneumonia pattern. Clinical and radiological improvements were noted after the discontinuation of venlafaxine and the administration of a corticosteroid. This report provides further evidence that the anti-depressant venlafaxine can cause ILD.

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