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1.
Curr Probl Cancer ; 53: 101149, 2024 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-39312854

RESUMO

INTRODUCTION: This study aimed to assess the survival outcomes of four versus six cycles of first-line platinum-based chemotherapy (PBCT) in the era of immune checkpoint inhibitor (ICI) for patients with advanced urothelial carcinoma (UC). PATIENTS AND METHODS: Patients with histologically confirmed advanced UC were allocated to either the 4-cycle PBCT (C4) or 6-cycle PBCT (C6) groups and retrospectively analyzed. After the planned cycles, active surveillance was conducted every 6-8 weeks, followed by second-line treatments, including ICIs, upon progression. The primary endpoint was overall survival (OS). RESULTS: Of the 161 patients initiated with PBCT between September 2016 and February 2023, 27 were deemed ineligible, leaving 134 patients for analysis (C4, n = 58; C6, n = 77). Baseline characteristics, including cisplatin eligibility, were similar between the groups. With a median follow-up of 23.7 months (95 % confidence interval (CI), 20.3-27.1), no significant difference was observed in OS between the C6 and C4 groups (18.7 months vs. 17.0 months; hazard ratio (HR) 1.27, P = 0.343). In multivariate analysis adjusted for sex, initial presentation, metastatic lesion, and ECOG PS, no significant difference was observed between the C6 and C4 groups (HR 1.29, 95 % CI, 0.78-2.14, P = 0.315). CONCLUSIONS: This study showed that four cycles of PBCT do not differ from six cycles regarding OS.

2.
Clin Cancer Res ; 30(20): 4635-4643, 2024 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-39150517

RESUMO

PURPOSE: Recently, anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD1/L1) immunotherapy has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TIL) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD1. EXPERIMENTAL DESIGN: Pretreatment hematoxylin and eosin (H&E)-stained whole-slide images from 339 patients with advanced BTC who received anti-PD1 as second-line treatment or beyond, were employed for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD1. Next, data and images of the BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IP in BTC. RESULTS: Overall, AI-IP were classified as inflamed [high intratumoral TIL (iTIL)] in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 patients (49.3%), and immune-desert (low TIL overall) in 132 patients (38.9%). The inflamed IP group showed a substantially higher overall response rate compared with the noninflamed IP groups (27.5% vs. 7.7%, P < 0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the noninflamed IP group (OS, 12.6 vs. 5.1 months; P = 0.002; PFS, 4.5 vs. 1.9 months; P < 0.001). In the TCGA cohort analysis, the inflamed IP showed increased cytolytic activity scores and IFNγ signature compared with the noninflamed IP. CONCLUSIONS: AI-IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD1 therapy. Further validation is necessary in the context of anti-PD1/L1 plus gemcitabine-cisplatin.


Assuntos
Inteligência Artificial , Neoplasias do Sistema Biliar , Biomarcadores Tumorais , Inibidores de Checkpoint Imunológico , Linfócitos do Interstício Tumoral , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/imunologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Prognóstico
3.
J Pathol Transl Med ; 58(4): 147-164, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-39026440

RESUMO

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

4.
Eur J Cancer ; 208: 114194, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38968872

RESUMO

INTRODUCTION: This multicenter phase I/IIa study aimed to determine the recommended phase II dose (RP2D) and evaluate the safety and preliminary efficacy of liposomal irinotecan (nal-IRI), oxaliplatin, and S-1 (NASOX) as first-line treatment for advanced pancreatic adenocarcinoma. METHODS: Patients with locally advanced or metastatic pancreatic adenocarcinoma without prior systemic treatment for advanced disease, aged ≥ 19 years, with measurable disease, and Eastern Cooperative Oncology Group performance status of 0-1 were eligible. The primary endpoints were to determine the dose-limiting toxicity (DLT) in the phase I cohort and overall response rate (ORR) in the phase IIa cohort. The intention-to-treat (ITT) analysis included patients who received the RP2D. RESULTS: In phase I, seven patients were screened, and six were assessed for DLT. None experienced DLT during the first cycle. The RP2D was determined as nal-IRI 50 mg/m2 and oxaliplatin 60 mg/m2 on day 1, S-1 40 mg/m2 twice daily on days 1-7 every 14 days. For the ITT (N = 41; 7, and 34 from phases I and IIa, respectively), the most common grade 3-4 treatment-emergent adverse events were neutropenia (31.7 %), enterocolitis (9.8 %), anorexia (7.3 %), and diarrhea (2.4 %). The ORR was 58.5 % (1 complete, and 23 partial responses). Two underwent conversion surgery; both achieved R0 resection. With median follow-up of 17.5 months, median progression-free survival was 6.5 months (95 % confidence interval [CI], 5.0-8.1) and median overall survival was 11.4 months (95 % CI, 9.8-15.5). CONCLUSION: NASOX exhibited a manageable safety profile and encouraging efficacy outcomes consistent with NALIRIFOX, showing potential to replace infusional 5-fluorouracil with oral S-1 in the triplet regimen.


Assuntos
Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Combinação de Medicamentos , Irinotecano , Oxaliplatina , Ácido Oxônico , Neoplasias Pancreáticas , Tegafur , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Masculino , Irinotecano/uso terapêutico , Irinotecano/administração & dosagem , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Oxaliplatina/efeitos adversos , Feminino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Ácido Oxônico/efeitos adversos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/secundário , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Tegafur/efeitos adversos , Lipossomos , Adulto , Intervalo Livre de Progressão
5.
Clin Genitourin Cancer ; 22(3): 102069, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38580522

RESUMO

PURPOSE: The study aimed to investigate the impact of adjuvant chemotherapy on time to recurrence (TTR) and overall survival (OS) in patients with histologic variants of upper tract urothelial carcinoma (VUTUC) following radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective review of 131 VUTUC patients' medical records, from a pool of 368 non-metastatic localized or locally advanced UTUC cases, treated at a single tertiary referral center between January 2011 and January 2021. The intervention was adjuvant chemotherapy administration post-RNU. TTR and OS were evaluated using Kaplan-Meier and Cox proportional hazard regression, covariates adjusted for age, postoperative GFR, history of neoadjuvant chemotherapy, T and N stage with stabilized inverse probability of treatment weighting (sIPTW). RESULTS: The application of adjuvant chemotherapy showed a significant extension in TTR (P = .01), but no substantial impact on OS (P = .19) after sIPTW adjustment for covariates. Multivariate analysis revealed adjuvant chemotherapy, tumor size, and lymphovascular invasion as significant prognostic factors for TTR. In contrast, only tumor size and perineural invasion were significant for OS. Adjuvant chemotherapy reduced the progression risk in certain VUTUC subtypes (squamous or glandular/micropapillary), but not in sarcomatoid variants. CONCLUSIONS: Adjuvant chemotherapy appears to improve TTR, albeit without a significant effect on OS, in nonmetastatic localized and locally advanced VUTUC patients post-RNU. While beneficial to some VUTUC subtypes, it did not yield significant advantages for sarcomatoid variants. Despite adjustments for known confounders, the study's findings may be subject to potential selection bias and unmeasured confounding factors.


Assuntos
Quimiorradioterapia Adjuvante , Nefroureterectomia , Neoplasias Ureterais , Neoplasias Urológicas , Quimiorradioterapia Adjuvante/métodos , Taxa de Sobrevida , Neoplasias Ureterais/mortalidade , Neoplasias Ureterais/patologia , Neoplasias Ureterais/cirurgia , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Neoplasias Urológicas/cirurgia , Neoplasias Urológicas/terapia , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Humanos , Masculino , Feminino , Idoso , Estimativa de Kaplan-Meier , Carcinoma de Células de Transição/mortalidade , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Antibióticos Antineoplásicos
6.
Int J Surg ; 110(7): 4074-4082, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38537071

RESUMO

BACKGROUND: There is no standardized assessment for evaluating response although neoadjuvant chemotherapy (NAT) is widely accepted for borderline resectable or locally advanced pancreatic cancer (BRPC or LAPC). This study was aimed to evaluate NAT response using positron emission tomography (PET) with 2-deoxy-2-[fluorine-18]fluoro-D-glucose ( 18 F-FDG-PET/CT) parameters alongside carbohydrate antigen (CA) 19-9 levels. METHODS: Patients who underwent surgery after NAT for BRPC and LAPC between 2017 and 2021 were identified. The study assessed the prognostic value of PET-derived parameters after NAT, determining cutoff values using the K-adaptive partitioning method. It created four groups based on the elevation or normalization of PET parameters and CA19-9 levels, comparing survival between these groups. RESULTS: Of 200 eligible patients, FOLFIRINOX and gemcitabine-based NAT was administered in 166 and 34 patients, respectively (mean NAT cycles, 8.3). In a multivariate analysis, metabolic tumor volume (MTV) demonstrated the most robust performance in assessing response [hazard ratio (HR) 3.11, 95% confidence interval (CI) 1.73-5.58, P <0.001] based on cutoff value of 2.4. Patients with decreased MTV had significantly better survival than those with elevated MTV among individuals with CA19-9 levels less than 37 IU/l (median survival; 35.5 vs. 20.9 months, P <0.001) and CA19-9 levels at least 37 IU/l (median survival; 34.3 vs. 17.8 months, P =0.03). In patients suspected to be Lewis antigen negative, the predictive performance of MTV was found to be limited ( P =0.84). CONCLUSION: Elevated MTV is an influential prognostic factor for worse survival, regardless of post-NAT CA19-9 levels. These results could be helpful in identifying patients with a poor prognosis despite normalization of CA19-9 levels after NAT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Terapia Neoadjuvante , Neoplasias Pancreáticas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Carga Tumoral , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Prognóstico , Carga Tumoral/efeitos dos fármacos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fluordesoxiglucose F18 , Antígeno CA-19-9/sangue , Antígeno CA-19-9/metabolismo , Fluoruracila/administração & dosagem , Adulto , Oxaliplatina/administração & dosagem , Oxaliplatina/uso terapêutico , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Irinotecano
7.
Curr Oncol Rep ; 26(4): 307-317, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38381366

RESUMO

PURPOSE OF REVIEW: To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. RECENT FINDINGS: Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC.


Assuntos
Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Humanos , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Fator A de Crescimento do Endotélio Vascular , Imunoterapia , Terapia Combinada , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética
8.
Pancreatology ; 24(3): 424-430, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38395676

RESUMO

BACKGROUND: Modified FOLFIRINOX (mFOLFIRINOX) is one of the standard first-line therapies in borderline resectable pancreatic cancer (BRPC) and locally advanced unresectable pancreatic cancer (LAPC). However, there is no globally accepted second-line therapy following progression on mFOLFIRINOX. METHODS: Patients with BRPC and LAPC (n = 647) treated with first-line mFOLFIRINOX between January 2017 and December 2020 were included in this retrospective analysis. The details of the treatment outcomes and patterns of subsequent therapy after mFOLFIRINOX were reviewed. RESULTS: With a median follow-up duration of 44.2 months (95% confidence interval [CI], 42.3-47.6), 322 patients exhibited disease progression on mFOLFIRINOX-locoregional progression only in 177 patients (55.0%) and distant metastasis in 145 patients (45.0%). The locoregional progression group demonstrated significantly longer post-progression survival (PPS) than that of the distant metastasis group (10.1 vs. 7.3 months, p = 0.002). In the locoregional progression group, survival outcomes did not differ between second-line chemoradiation/radiotherapy and systemic chemotherapy (progression-free survival with second-line therapy [PFS-2], 3.2 vs. 4.3 months; p = 0.649; PPS, 10.7 vs. 10.2 months; p = 0.791). In patients who received second-line systemic chemotherapy following progression on mFOLFIRINOX (n = 211), gemcitabine plus nab-paclitaxel was associated with better disease control rates (69.2% vs. 42.3%, p = 0.005) and PFS-2 (3.8 vs. 1.7 months, p = 0.035) than gemcitabine monotherapy. CONCLUSIONS: The current study showed the real-world practice pattern of subsequent therapy and clinical outcomes following progression on first-line mFOLFIRINOX in BRPC and LAPC. Further investigation is necessary to establish the optimal therapy after failure of mFOLFIRINOX.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gencitabina , Estudos Retrospectivos , Adenocarcinoma/patologia , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Terapia Neoadjuvante , Progressão da Doença , Irinotecano , Oxaliplatina
9.
Clin Genitourin Cancer ; 22(2): 413-419, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38228412

RESUMO

INTRODUCTION: Metastatic disease affects approximately 15% to 17% of patients with pheochromocytomas and paragangliomas (PPGLs). Unfortunately, treatment options for metastatic PPGLs are limited and rely on small, nonrandomized clinical trials. The impact of germline mutation status on systemic treatment outcomes remains unclear. To address these gaps, we retrospectively evaluated treatment outcomes in patients with PPGL. PATIENTS AND METHODS: Between December 2004 and December 2021, 33 patients were diagnosed with metastatic PPGLs and received systemic treatment at the Department of Oncology, Asan Medical Center, Seoul, South Korea. RESULTS: The median age of the patients was 49. Germline mutations were revealed in nine patients (39.1%) out of 23 who underwent germline testing, with SDHB mutation being the most frequent in 5 patients. Cyclophosphamide, vincristine, and dacarbazine (CVD) chemotherapy was administered to 18 patients, with an objective response rate (ORR) of 22% and a disease control rate (DCR) of 67%. The median progression-free survival (PFS) was 7.9 and the median overall survival (OS) was 36.2 months. Sunitinib was given to 6 patients, which had an ORR of 33%, a DCR of 83%, and a median PFS of 14.6 months. Notably, patients with SDHB/SDHD mutation (4 patients and one patient, respectively) who received CVD treatment had a significantly better OS than those without (median OS 94.0 months vs. 13.7 months, P = .01). CONCLUSION: Our study reveals that CVD and sunitinib are effective treatments for metastatic PPGLs. The results are consistent with previous studies and patients with SDHB and SDHD mutations may benefit most from CVD treatment.


Assuntos
Neoplasias das Glândulas Suprarrenais , Doenças Cardiovasculares , Paraganglioma , Feocromocitoma , Humanos , Feocromocitoma/tratamento farmacológico , Feocromocitoma/genética , Feocromocitoma/diagnóstico , Mutação em Linhagem Germinativa , Estudos Retrospectivos , Sunitinibe/uso terapêutico , Succinato Desidrogenase/genética , Paraganglioma/tratamento farmacológico , Paraganglioma/genética , Dacarbazina/uso terapêutico , Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/diagnóstico , Ciclofosfamida/uso terapêutico
10.
Cancer Res Treat ; 56(2): 624-633, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38037320

RESUMO

PURPOSE: Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype. MATERIALS AND METHODS: Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population. RESULTS: A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1-expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02). CONCLUSION: Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.


Assuntos
Carcinoma de Células Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Humanos , Masculino , Idoso , Feminino , Carcinoma de Células Pequenas/terapia , Carcinoma de Células Pequenas/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/patologia , Etoposídeo , Neoplasias Pulmonares/patologia , Microambiente Tumoral
11.
Cancer Res Treat ; 2023 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-38037319

RESUMO

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

12.
PLoS One ; 18(6): e0287146, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37310967

RESUMO

Macrophage inhibitory cytokine 1 (MIC-1), which is overproduced in various human cancers and associated with cachexia, acts on the hypothalamus to suppress appetite and reduce body weight. We investigated the mechanisms through which MIC-1 affects bile acid metabolism and gallstone formation, which are poorly understood. Over 6 weeks, male C57BL/6 mice fed either standard chow or a lithogenic diet were intraperitoneally injected with phosphate-buffered saline (PBS) or MIC-1 (200 µg/kg/week). Among lithogenic diet-fed mice, MIC-1 treatment resulted in increased gallstone formation compared with PBS treatment. Compared with PBS treatment, MIC-1 treatment decreased hepatic cholesterol and bile acid levels and reduced expression of HMG-CoA reductase (HMGCR), the master cholesterol metabolism regulator sterol regulatory element-binding protein 2, cholesterol 7α-hydroxylase (CYP7A1), mitochondrial sterol 27-hydroxylase, and oxysterol 7α-hydroxylase. Compared with PBS treatment, MIC-1 treatment had no effect on small heterodimer partner, farnesoid X receptor, or pregnane X receptor expression, and extracellular signal-related kinase and c-Jun N-terminal kinase phosphorylation decreased, suggesting that these factors do not contribute to the MIC-1-induced reduction in CYP7A1 expression. Compared with PBS treatment, MIC-1 treatment increased AMP-activated protein kinase (AMPK) phosphorylation. Treatment with the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) reduced CYP7A1 and HMGCR expression, whereas the AMPK inhibitor Compound C reversed MIC-1-induced reductions in CYP7A1 and HMGCR expression. Furthermore, in MIC-1-treated mice, total biliary cholesterol levels increased together with increased ATP-binding cassette subfamily G (ABCG)5 and ABCG8 expression. Compared with PBS treatment, MIC-1 treatment did not affect expression of liver X receptors α and ß, liver receptor homolog 1, hepatocyte nuclear factor 4α, or NR1I3 (also known as constitutive androstane receptor), which are upstream of ABCG5/8; however, MIC-1 treatment increased ABCG5/8 expression and promoter activities. Our study indicates that MIC-1 influences gallstone formation by increasing AMPK phosphorylation, reducing CYP7A1 and HMGCR expression, and increasing ABCG5 and ABCG8 expression.


Assuntos
Cálculos Biliares , Humanos , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Fator 15 de Diferenciação de Crescimento , Proteínas Quinases Ativadas por AMP , Dieta , Macrófagos , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Lipoproteínas
14.
Yonsei Med J ; 64(2): 86-93, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36719015

RESUMO

PURPOSE: Evidence in favor of adding docetaxel in treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has led to docetaxel in conjunction with androgen deprivation therapy (ADT) as standard therapy. The aim of this study was to examine the effectiveness of docetaxel with ADT for Korean patients with mHSPC in real-world practice. MATERIALS AND METHODS: A retrospective cohort study was performed at six Korean hospitals for patients with mHSPC treated with docetaxel plus ADT. Patients were treated every 3 weeks for up to six cycles with 75 mg/m² of docetaxel. The primary endpoint was time to castration resistant prostate cancer (CRPC). RESULTS: This study included 46 eligible patients from June 2016 to February 2021. Median age was 68.5 years (range, 52-84) and all patients present with de novo M1 with high-volume disease. The median prostate-specific antigen (PSA) level at ADT initiation was 205.4 (7.7-1933) ng/mL, and time from ADT to docetaxel was 2.4 months (0-5.3). All six planned cycles of docetaxel were delivered in 36 patients (78%), 7 patients (15%) discontinued treatment due to adverse events, and 3 patients (7%) discontinued due to progression. At the time of the analysis, CRPC had developed in 34 patients (74%), and the median time to CRPC was 18.0 (95% confidence interval, 14.1-21.9) months. PSA <0.2 ng/mL was achieved in 11 patients (24%) after 6 months of ADT and in 10 patients (22%) after 12 months. At last follow-up, 35 patients (76%) were alive; the median overall survival was not reached. CONCLUSION: The effect of docetaxel combined with ADT for Korean patients with mHSPC is comparable with prior results in Western studies.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Neoplasias da Próstata , Idoso , Humanos , Masculino , Antagonistas de Androgênios/uso terapêutico , Androgênios , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Docetaxel/uso terapêutico , Docetaxel/efeitos adversos , Antígeno Prostático Específico , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , República da Coreia , Estudos Retrospectivos , Resultado do Tratamento , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais
15.
J Cancer Res Clin Oncol ; 149(3): 1131-1143, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35344080

RESUMO

PURPOSE: To evaluate the safety and effectiveness of aflibercept in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) in Korean patients with metastatic colorectal cancer (mCRC) who progressed with oxaliplatin-containing regimen. METHODS: This was a prospective observational study conducted at 22 sites across Korea between February 2018 and September 2019. Patients aged > 19 years with a diagnosis of mCRC who were prescribed aflibercept plus FOLFIRI, after progression with an oxaliplatin-containing regimen were included. Disease assessment was performed every 6 weeks. RESULTS: A total of 185 patients were included (males, 58.9%; right-sided tumors, 23.8%; and ECOG performance factor ≥ 1, 68.6%). A total of 514 adverse events (AEs) occurred in 134 patients, of which 206 (49.2%; 95% CI 42.0%, 56.4%) events were considered as adverse drug reactions (ADRs), 172 unexpected AEs (49.7%; 95% CI 42.5%, 56.9%), and 53 serious AEs (22.2%; 95% CI16.2%, 28.2%). The most common serious ADR was pneumonia (n = 2, 1.6%). The most common all grade hematological AE and non-hematological AE were neutropenia (21.6%) and nausea (16.2%), respectively. Over a median follow-up of 5.6 months, a total of five grade 5 (1.0%) AEs were reported. Median OS was 9.4 months, and median progression-free survival (PFS) was 7.3 months. The overall response rate was 14.6%. Right-sided tumor location and prior bevacizumab treatment were independent factors of poor PFS in multivariate analysis. CONCLUSION: Aflibercept in combination with FOLFIRI was effective and showed an acceptable safety profile in Korean patients with mCRC in daily clinical practice.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Neoplasias Retais , Masculino , Humanos , Oxaliplatina/uso terapêutico , Neoplasias Colorretais/patologia , Camptotecina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Bevacizumab/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Fluoruracila/uso terapêutico , Leucovorina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , República da Coreia
16.
Eur J Cancer ; 174: 81-89, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35985251

RESUMO

PURPOSE: To analyse the incidence of pneumonitis related to enfortumab vedotin (EV) in patients with metastatic urothelial cell carcinoma (mUC). METHODS: Patients with mUC who participated in two EV clinical trials in South Korea were analysed for the incidence and clinical course of EV-related pneumonitis through retrospective, independent review. The clinical characteristics and radiologic attributes of potential pneumonitis were identified and reviewed by the participating investigators and pulmonologists. RESULTS: Between October 2018 and January 2020, 64 patients were enrolled in the EV-201 and EV-301 trials across eight institutions in South Korea and were treated with EV. Among them, 18 (28.1%) developed all-grade EV-related pneumonitis, from which 2 (11.1%) patients died. The median time between the last dosing of immunotherapy and the start of EV was 5.6 weeks (range, 0.71-143.1). The median time from the start of EV treatment to the onset of pneumonitis was 13 weeks (range, 2.7-51.0). Of the patients who developed pneumonitis, 7 (38.9%) were clinically asymptomatic. The most common radiologic finding was organising pneumonia (66.7%). CONCLUSIONS: Although we could not rule out the relationship with prior immunotherapy administration, EV-related pneumonitis occurred in approximately 25% of the patients who had received EV in two prospective clinical trials, from which two died. Clinicians should closely monitor patients who have experienced immunotherapy treatment failure for the development of pneumonitis. A delay between initiating EV after termination of immunotherapy should be considered with caution.


Assuntos
Carcinoma de Células de Transição , Pneumonia , Insuficiência Respiratória , Neoplasias da Bexiga Urinária , Anticorpos Monoclonais , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Pneumonia/induzido quimicamente , Pneumonia/tratamento farmacológico , Pneumonia/epidemiologia , Estudos Prospectivos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/epidemiologia , Estudos Retrospectivos
17.
Clin Orthop Surg ; 14(2): 220-226, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35685966

RESUMO

Background: Most epidemiologic studies of anterior cruciate ligament reconstruction (ACLR) to date have been conducted in Western populations, whereas no studies have been conducted in Asian populations. In this study, the incidence and trend of ACLR in Korea were investigated through an epidemiological big data analysis. Methods: The data were collected by the Health Insurance Review and Assessment Service from 2008 to 2016 in Korea. Patient records with the coding of cruciate ligament reconstruction were allocated, and ACLR patients were further refined by medical diagnosis coding. The total number and incidence of ACLR procedures per 100,000 person-years were investigated and more detailed analysis was conducted according to sex and age. Furthermore, concomitant surgical procedures performed during ACLR were investigated. Results: The total number and incidence of ACLR procedures rose from 10,248 and 21.8 to 14,500 and 29.1 between 2008 and 2016, respectively. The incidence of ACLR procedures increased by 33.5% over this 9-year period. Over this period, the total number and incidence increased from 8,543 and 36.4 to 11,534 and 46.4, respectively, in males and from 1,705 and 7.2 to 2,966 and 11.9, respectively, in females. ACLR was performed more frequently in males than in females; however, the increase rate was higher in females than males. ACLR was performed most frequently in patients in their 20s, followed by patients in their 30s, 40s, and 10s. The most frequent concomitant procedures performed during ACLR were meniscectomy (13.6% in 2008 and 9.8% in 2016) and meniscal repair (5.8% in 2008 and 8.8% in 2016). Conclusions: The incidence of ACLR consistently rose between 2008 and 2016 in Korea. The current study will enhance our understanding of the epidemiology of ACLR, which is needed to devise cost-effective preventive measures.


Assuntos
Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Lesões do Menisco Tibial , Lesões do Ligamento Cruzado Anterior/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Meniscectomia , Lesões do Menisco Tibial/cirurgia
18.
Front Immunol ; 13: 875872, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35514996

RESUMO

Treatment strategies combining immune checkpoint blockade (ICB) with other agents have emerged as a promising approach in the treatment of cancers. AHCC®, a standardized extract of cultured Lentinula edodes mycelia, has been reported to inhibit tumor growth and enhance immune cell function. Here we investigated whether AHCC® promotes the therapeutic effect of immunotherapy in cancers. A combination of oral AHCC® and dual immune checkpoint blockade (DICB), including PD-1/CTLA-4 blockade, had reduced tumor growth and increased granzyme B and Ki-67 expression by tumor-infiltrating CD8+ T cells in MC38 colon cancer bearing mice compared to a combination of water and DICB. In the same tumor bearing mice, AHCC® and DICB treatment also altered the composition of the gut microbiome with the increased abundance of the species of Ruminococcaceae family which is associated with increased therapeutic efficacy of immunotherapy. The anti-tumor effect of AHCC® and DICB was not found in MC38 tumor-bearing mice treated with antibiotics. These data suggest that AHCC® increases the anti-tumor effect of DICB by enhancing T cell function and affecting the gut microbiome.


Assuntos
Neoplasias do Colo , Cogumelos Shiitake , Animais , Linfócitos T CD8-Positivos , Neoplasias do Colo/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Camundongos , Extratos Vegetais
19.
Curr Probl Cancer ; 46(3): 100848, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35344842

RESUMO

Immune checkpoint inhibitors (ICIs) have become a standard treatment for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy. However, the prognostic factors for patients with mUC receiving ICIs are not well established. We retrospectively collected clinical and laboratory data and reviewed the survival outcomes of patients with mUC who were treated with ICIs after platinum-based chemotherapy. We used univariate and multivariable Cox proportional hazard models to identify independent prognostic factors, and the concordance index (C-index) to evaluate the performance of the new prognostic model. In addition, bootstrap analysis was employed for internal validation of the prognostic model. A total of 224 patients were included in the study. With a median follow-up of 10.5 months (interquartile range, 5.1-17.4 months), median overall survival (OS) was 13.6 months (95% confidence interval [CI], 9.7-17.3 months). In multivariable analysis, independent prognostic factors predicting adverse OS were the presence of liver metastasis (LM), hypoalbuminemia, and neutrophil-lymphocyte ratio (NLR) >5. When patients were categorized into 3 risk groups, median OS was not reached (NR) (95% CI, 17.3-NR), 9.5 months (6.8-NR), and 2.9 months (2.3-4.4) for patients with a score of 0, 1, and 2+, respectively. The C-index for the new model was 0.763 (95% CI, 0.739-0.787). A novel prognostic model, including LM, hypoalbuminemia, and NLR, was developed and validated to estimate OS in patients with platinum-refractory disease on second- or subsequent-line ICI therapy. Further investigations, including prospective validation, are needed.


Assuntos
Carcinoma de Células de Transição , Hipoalbuminemia , Neoplasias da Bexiga Urinária , Carcinoma de Células de Transição/tratamento farmacológico , Humanos , Hipoalbuminemia/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Platina/uso terapêutico , Prognóstico , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/tratamento farmacológico
20.
Am J Clin Oncol ; 45(2): 61-65, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34991106

RESUMO

OBJECTIVES: Treatment with trastuzumab and chemotherapy significantly improves the outcome in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC). CT-P6 (trastuzumab-pkrb; Herzuma) is a trastuzumab biosimilar approved for the treatment of HER2-positive gastric cancer. In this study, we aimed to compare the efficacy and safety of CT-P6 and reference trastuzumab as first-line treatment for HER2-positive AGC. MATERIALS AND METHODS: The medical records of 102 patients with HER2-positive AGC treated with first-line trastuzumab-based chemotherapy were retrospectively reviewed. These patients were treated with either reference trastuzumab (n=72) or a biosimilar (n=30). Treatment outcomes, such as objective response rate, progression-free survival (PFS), and overall survival (OS), were compared between the reference and biosimilar groups. RESULTS: The objective response rate of both groups (52.8% and 56.8% in the reference and biosimilar groups, respectively) were comparable (P=0.72). No statistically significant difference was observed with the reference versus biosimilar trastuzumab for PFS (median PFS, 6.9 vs. 5.4 mo; P=0.98) or OS (median OS, 12.3 mo vs. not reached; P=0.42). Safety profiles were similar between the 2 groups. CONCLUSIONS: Biosimilar trastuzumab showed equivalent outcome to reference trastuzumab, with similar adverse events. Biosimilar trastuzumab can suitably and safely replace trastuzumab as a reference for the treatment of HER2-positive AGC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Trastuzumab/efeitos adversos , Resultado do Tratamento
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