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1.
Artigo em Inglês | MEDLINE | ID: mdl-34510272

RESUMO

PURPOSE: Homologous recombination deficiency (HRD) is related to tumorigenesis. Currently, the possibility of HRD as a prognostic biomarker to immune checkpoint inhibitors is unknown. We aimed to investigate whether HRD has potential as a biomarker for immunotherapy. METHODS: The status of homologous recombination deficiency (HRD) was assessed with the next-generation sequencing (NGS) TruSight™ Oncology 500 assay in 501 patients with advanced solid tumor including gastrointestinal (GI), genitourinary (GU), or rare cancer. RESULTS: among the 501 patients, HRD was observed as follows: 74.7% (347/501) patients; GU cancer (92.0%, 23 of 25), colorectal cancer (CRC) (86.1%, 130 of 151), hepatocellular carcinoma (HCC) (83.3%, 10 of 12), pancreatic cancer (PC) (76.2%, 32 of 42), biliary tract cancer (BTC) (75.0%, 36 of 48), sarcoma (65.0%, 39 of 60), melanoma (52.4%, 11 of 21), other GI cancers (50.0%, 11 of 22), and rare cancer (50.0%, 2 of 4). Sixty-five of the 501 patients had received immune checkpoint inhibitors (ICIs) during the course of the disease. Tumor types of 65 patients treated with ICIs are as follows: melanoma (95.2%, 20 of 21), HCC (33.3%, 4 of 12), rare cancer (25.0%, 1 of 4), GC (12.2%, 14 of 116), BTC (10.4%, 5 of 48), and sarcoma (5.0%, 3 of 60). The most frequently reported mutations were BRCA2 (n = 90), ARID1A (n = 77), ATM (n = 71), BARD1 (n = 67). Patients without HRD exhibited an objective response rate (ORR) of 33.3% (4 of 12), and patients with HRD exhibited an ORR of 34.0% (18 of 53). There was no significant difference in ORR between patients with and without HRD (P = 0.967). Progression-free survival (PFS) was 6.5 months (95% CI 0.000-16.175) in patients without HRD and 4.1 months (95% CI 2.062-6.138) in patients with HRD, revealing no statistical significance (P = 0.441). CONCLUSION: Herein, we reported the status of HRD using a cancer-panel for various solid tumor patients in routine clinical practice and demonstrated that HRD as a single biomarker was not sufficient to predict efficacy of ICIs in solid tumor patients.

2.
Cancer Med ; 10(20): 7253-7262, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34542244

RESUMO

BACKGROUND: Diffuse-type gastric cancer (GC) is known to be more aggressive and relatively resistant to conventional chemotherapy. Hence, more optimized treatment strategy is urgently needed in diffuse-type GC. METHODS: Using a panel of 10 GC cell lines and 3 GC patient-derived cells (PDCs), we identified cell lines with high EMTness which is a distinct feature for diffuse-type GC. We treated GC cells with high EMTness with ramucirumab alone, TGF-ß receptor kinase inhibitor (TEW-7197) alone, or in combination to investigate the drug's effects on invasiveness, spheroid formation, EMT marker expression, and tumor-induced angiogenesis using a spheroid-on-a-chip model. RESULTS: Both TEW-7197 and ramucirumab treatments profoundly decreased invasiveness of EMT-high cell lines and PDCs. With a 3D tumor spheroid-on-a-chip, we identified versatile influence of co-treatment on cancer cell-induced blood vessel formation as well as on EMT progression in tumor spheroids. The 3D tumor spheroid-on-a-chip demonstrated that TEW-7197 + ramucirumab combination significantly decreased PDC-induced vessel formation. CONCLUSIONS: In this study, we showed TEW-7197 and ramucirumab considerably decreased invasiveness, thus EMTness in a panel of diffuse-type GC cell lines including GC PDCs. Taken together, we confirmed that combination of TEW-7197 and ramucirumab reduced tumor spheroid and GC PDC-induced blood vessel formation concomitantly in the spheroid-on-a-chip model.

3.
N Engl J Med ; 385(8): 683-694, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34407342

RESUMO

BACKGROUND: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence. METHODS: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point. RESULTS: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred. CONCLUSIONS: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nefrectomia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Renais/mortalidade , Neoplasias Renais/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida
4.
J Nanosci Nanotechnol ; 21(12): 5881-5889, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34229782

RESUMO

Recently, flexible electronic device technology has evolved beyond curved devices with the development of flexible/stretchable devices that can be crumpled or stretched. Both elasticity and durability are essential for these devices, which should have high-conductivity for antennas and repeatability for sensors. In addition, electronic-skins, which can have a direct impact on the human-body, should be harmless to the human-body and should not be deformed by contact with sweat or organic matter. In this study, PDMS substrates were used to satisfy the above conditions. PDMS is used to fabricate human-friendly, flexible/stretchable substrates, and it has excellent repeat durability characteristics. To improve the adhesion of these PDMS films and electrodes, conductive paste was produced based on PDMS resins of the same properties. In addition, two types of Ag particles were selected as conductive fillers because the electrode characteristics of the antenna application requires excellent conductivity, and conductive paste were produced using flake Ag, which could affect conductivity, and Ag nanoparticles that affect stretchability and repeatability. The paste was applied using a high-efficiency printing technique. The printed electrodes were cured in a thermal oven. For higher conductivity, photonic-sintering was carried out during post-processing. As a result, 1.1117×106 (S/m) had excellent conductivity, performed well in repeated tensile-durability experiments of 30% to 100 times, and produced a bow-tie antenna for the above electrodes. As a result of tensing up to 35% through a Network-Analyzer, there was no performance change in the resonance-frequency or return-loss values, and excellent electrodes were developed that would achieve excellent performance even if they are applied in the sub-frequency area of 5G-antennas in the future.


Assuntos
Nanopartículas Metálicas , Dispositivos Eletrônicos Vestíveis , Eletrodos , Eletrônica , Humanos , Prata
5.
N Engl J Med ; 384(22): 2102-2114, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34077643

RESUMO

BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Nivolumabe/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Nivolumabe/efeitos adversos , Placebos/uso terapêutico , Qualidade de Vida , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
6.
Clin Cancer Res ; 27(17): 4700-4709, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33975862

RESUMO

PURPOSE: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. PATIENTS AND METHODS: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. RESULTS: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9). CONCLUSIONS: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment.See related commentary by Ashworth, p. 4667.

7.
J Nanosci Nanotechnol ; 21(10): 5222-5228, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-33875110

RESUMO

In industry, recent research developments include flexible films and foldable films. The next step is the development of stretchable films, and studies are being intensively carried out. Research on the development of stretchable and transparent materials is also increasing greatly. Currently, polydimethylsiloxane (PDMS) is the most commonly used film in the industry. However, PDMS surfaces are hydrophobic, so their use is limited to making materials and compounds with hydrophilic properties. In this study, we developed a transparent polyurethane film that can be used for multiple purposes. A transparency comparison between the transparent polyurethane film and the general polyurethane film was used to verify their future application. The conventional polyurethane films showed a transmittance rate of 2.2 percent, but the transparent polyurethane films achieved a high transmittance rate of 85 percent. To determine whether the film can be realized, we produced a conductive paste using resin for the transparent polyurethane film. In addition, a conductive paste was made based on the material used in the transparent polyurethane film to verify the hardness and reliability of the adhesion of electrodes, and we confirmed this with thermogravimetric analysis (TGA). The transparent polyurethane based paste was made with stretchable electrodes through a screen printing method. The manufactured stretchable electrodes were demonstrated by mechanical and adhesion tests. Finally, a permittivity test was conducted to determine the suitability of the film for application to printed electrodes for antennas in the future. The genetic rate of transparent polyurethane films was better than that of conventional polyurethane films. Moreover, the adhesion of the transparent polyurethane film and stretchable electrodes was as good as that of conventional polyurethane film and stretchable electrodes, and observation by optical microscopy confirmed that the printing performance was also excellent. In addition, the conductive paste made based on the transparent polyurethane film material was cured for 1 hour at 120 °C, and TGA analysis confirmed that both the binders and curing agent responded well in the test for curing the developed stretchable electrodes and transparent polyurethane.


Assuntos
Poliuretanos , Condutividade Elétrica , Eletrodos , Reprodutibilidade dos Testes
8.
Oncology ; 99(6): 365-372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730723

RESUMO

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.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Platina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Platina/uso terapêutico , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
9.
Korean J Intern Med ; 36(3): 491-514, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33561334

RESUMO

In 2017, Korean Society of Medical Oncology (KSMO) published the Korean management guideline of metastatic prostate cancer. This paper is the 2nd edition of the Korean management guideline of metastatic prostate cancer. We updated recent many changes of management in metastatic prostate cancer in this 2nd edition guideline. The present guideline consists of the three categories: management of metastatic hormone sensitive prostate cancer; management of metastatic castration resistant prostate cancer; and clinical consideration for treating patients with metastatic prostate cancer. In category 1 and 2, levels of evidence (LEs) have been mentioned according to the general principles of evidence-based medicine. And grades of recommendation (GR) was taken into account the quality of evidence, the balance between desirable and undesirable effects, the values and preferences, and the use of resources and GR were divided into strong recommendations (SR) and weak recommendations (WR). A total of 16 key questions are selected. And we proposed recommendations and described key evidence for each recommendation. The treatment landscape of metastatic prostate cancer is changing very rapid and many trials are ongoing. To verify the results of the future trials is necessary and should be applied to the treatment for metastatic prostate cancer patients in the clinical practice. Especially, many prostate cancer patients are old age, have multiple underlying medical comorbidities, clinicians should be aware of the significance of medical management as well as clinical efficacy of systemic treatment.


Assuntos
Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/terapia , República da Coreia
10.
BMB Rep ; 54(4): 209-214, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33407995

RESUMO

Invariant natural killer T (iNKT) cells are involved in various autoimmune diseases. Although iNKT cells are arthritogenic, transforming growth factor beta (TGFß)-treated tolerogenic peritoneal macrophages (Tol-pMφ) from wild-type (WT) mice are more tolerogenic than those from CD1d knock-out iNKT cell-deficient mice in a collagen-induced arthritis (CIA) model. The underlying mechanism by which pMφ can act as tolerogenic antigen presenting cells (APCs) is currently unclear. To determine cellular mechanisms underlying CD1d-dependent tolerogenicity of pMφ, in vitro and in vivo characteristics of pMφ were investigated. Unlike dendritic cells or splenic Mφ, pMφ from CD1d+/- mice showed lower expression levels of costimulatory molecule CD86 and produced lower amounts of inflammatory cytokines upon lipopolysaccharide (LPS) stimulation compared to pMφ from CD1d-deficient mice. In a CIA model of CD1d-deficient mice, adoptively transferred pMφ from WT mice reduced the severity of arthritis. However, pMφ from CD1d-deficient mice were unable to reduce the severity of arthritis. Hence, the tolerogenicity of pMφ is a cell-intrinsic property that is probably conferred by iNKT cells during pMφ development rather than by interactions of pMφ with iNKT cells during antigen presentation to cognate T cells. [BMB Reports 2021; 54(4): 209-214].

11.
Cancer Sci ; 112(1): 305-313, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33047430

RESUMO

Tislelizumab, an anti-programmed death protein-1 (PD-1) monoclonal antibody, was engineered to minimize binding to the FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. This single-arm phase 2 trial (NCT04004221/CTR20170071) assessed the safety, tolerability, and efficacy of tislelizumab in patients with PD-L1-positive urothelial carcinoma who progressed during/following platinum-containing therapy and had no prior PD-(L)1 inhibitor treatment. Patients were considered PD-L1 positive if ≥ 25% of tumor/immune cells expressed PD-L1 when using the VENTANA™ PD-L1 (SP263) assay. The primary endpoint was objective response rate by independent review committee. As of September 16, 2019, 113 patients had a median study follow-up time of 9.4 mo. Most patients (76%) had visceral metastases, including 24% with liver and 23% with bone metastases. Among 104 efficacy-evaluable patients, confirmed objective response rate was 24% (95% confidence interval, 16, 33), including 10 complete and 15 partial responses. Median duration of response was not reached. Among 25 responders, 17/25 (68%) had ongoing responses. Median progression-free survival and overall survival times were 2.1 and 9.8 mo, respectively. The most common treatment-related adverse events were anemia (27%) and pyrexia (19%). Anemia (7%) and hyponatremia (5%) were the only grade 3-4 treatment-related adverse events and occurred in ≥ 5% of patients. Three investigator-assessed deaths were considered to be possibly related to study treatment (hepatic failure, n = 2; respiratory arrest, n = 1). Tislelizumab demonstrated meaningful clinical benefits in patients with previously treated locally advanced or metastatic PD-L1-positive urothelial carcinoma and had a manageable safety profile.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático , Carcinoma de Células de Transição/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Intervalo Livre de Progressão , Neoplasias Urológicas/mortalidade
12.
Cancer Res Treat ; 2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-33285049

RESUMO

Purpose: The objective of this study was to describe and analyze the clinicopathological features of primary choriocarcinoma (PCC) observed in male patients treated at the Samsung Medical Center between 1996 and 2020. Materials and Methods: We reviewed the clinical records of 14 male patients with PCC retrospectively to assess their demographic, histological, and clinical characteristics at the time of diagnosis as well as identify the treatment outcomes. Results: The median age of the patients was 33 years. The primary tumor site was the testicles in seven cases (50%), the mediastinum in six cases (43%), and the brain in one case (7%). The most common metastatic site was the lungs (79%), followed by the brain (43%). All patients with PCC received cytotoxic chemotherapy. Twelve patients had records of their response to cytotoxic chemotherapy; of these 12 patients, 8 (8/12, 67%) achieved an objective response, and 4 (4/12, 33%) achieved stable disease response as the best response during chemotherapy. Conclusion: It is known that most male PCC patients eventually develop resistance to cytotoxic chemotherapy and die. Factors such as poor response to chemotherapy, high disease burden, brain metastasis, and hemoptysis at the time of diagnosis are associated with shorter survival time in male PCC patients. Programmed death-1/programmed death-ligand 1 blockade therapy can be a salvage treatment for chemotherapy-resistant male PCC patients.

13.
Ther Adv Med Oncol ; 12: 1758835920965842, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224274

RESUMO

Regorafenib (Stivarga, BAY 73-4506; Bayer Pharma AG, Berlin, Germany) is a novel oral multikinase inhibitor that blocks the activity of several protein kinases. However, few guidelines exist for novel biomarkers to select patients who will likely benefit from regorafenib treatment. Metastatic colorectal cancer (mCRC) patients treated with regorafenib were evaluated in this study. Tumor tissues of these patients were subjected to next-generation sequencing-based cancer panel tests. The relationship between molecular profiling and efficacy of regorafenib was analyzed. Among the 76 mCRC patients, the median age was 58 years (range 22-79 years), and 73.7% received regorafenib as a third-line therapy. The primary tumor locations were the right side (n = 15, 19.8%) and the left side (n = 61, 80.2%). Most patients (97.4%) had received prior anti-angiogenetic agents, and a prior anti-Epidermal Growth Factor Receptor (EGFR) agent had been administered to 32.9%. Of these 76 patients, 65 were evaluated to determine the efficacy of treatment. We observed zero complete responses, seven confirmed partial responses (PR 9.2%), 26 stable disease states (34.2%), and 32 disease progressions (42.1%). The overall confirmed response rate and the disease control rate were 9.2% and 43.4%, respectively. Genomic analysis revealed that APC mutations were significant in patients who demonstrated a tumor response to regorafenib (p < 0.05). Interestingly, FGFR1 amplification was detected in only three of 76 patients (3.9%), and these three patients achieved a PR to regorafenib. The median progression-free survival time was 2.8 months (95% Confidence Interval [CI] 1.6-4.0). Patients with BRAF mutation and/or SMAD4 mutation had significantly worse progression-free survival (PFS) than those without such a mutation. On pathway analysis, Tumor Growth Factor (TGF)-beta pathways were significantly associated with worse PFS. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and TGF-beta pathway were associated with worse PFS after regorafenib. We found that efficacy of regorafenib might be correlated with specific genetic aberrations, such as APC mutation and FGFR1 amplification. In addition, SMAD4 mutation and the TGF-beta pathway were associated with worse PFS after regorafenib.

14.
J Cancer ; 11(24): 7202-7208, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193883

RESUMO

Purpose: To investigate the effect of bone metastasis (BM) on survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line tyrosine kinase inhibitors (TKI) by performing propensity-score matching (PSM) analysis. Materials & Methods: We retrospectively reviewed 1,151 patients with mRCC who were treated with first-line TKI from December 2006 to September 2016. After excluding 135 patients, 1,016 patients with mRCC were finally analyzed. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. After 1:1 PSM analysis, survival outcomes were compared between patients with BM (n=237) and without BM (n=237). Multivariate Cox regression analysis was used to determine predictors of survival. Results: Among 1,016 total patients, 27.5% (n=279) had BM. Before PSM, patients with BM had worse OS outcomes than those without BM. Even after PSM, OS was significantly poorer in patients with BM compared to those without BM. Of note, the presence of BM was identified as an independent predictor of OS (HR=1.36), in addition to prior nephrectomy, sarcomatoid differentiation, and IMDC risk group. However, there were no differences in PFS according to the presence of BM after PSM. In the subgroup analysis, only intermediate IMDC risk group showed significant differences in OS according to the presence of BM. Conclusion: Based on PSM analysis, the presence of BM negatively affected OS outcomes in patients with mRCC treated with first-line TKI, particularly in the IMDC intermediate risk group.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33051982

RESUMO

AIM: Radium-223, a targeted alpha therapy, is approved widely for the treatment of patients with metastatic castrate-resistant prostate cancer, based on a pivotal phase 3 study in predominantly white patients. We investigated the efficacy and safety of radium-223 in Asian patients with castrate-resistant prostate cancer and metastatic bone disease. METHODS: This multicenter, prospective, single-arm, open-label phase 3 trial evaluated the efficacy and safety of the standard radium-223 regimen (55 kBq/kg every 4 weeks for six cycles) in patients from Asian countries. The primary endpoints were the safety and overall survival. RESULTS: A total of 226 patients were enrolled and received at least one dose of radium-223. Median overall survival was 14.0 months (95% confidence interval [CI], 11.2-17.4). Median time to total alkaline phosphatase and prostate-specific antigen progression were 7.5 (95% CI, 6.8-7.7) and 3.6 (95% CI, 3.1-3.7) months, respectively. Median skeletal-related event-free survival was 26.0 months (95% CI, 12.6-not reached). Grade ≥3 treatment-emergent adverse events were reported in 103 (46%) of 226 patients, with anemia being the most common event (34 [15%] patients). Grade ≥3 drug-related treatment-emergent adverse events occurred in 39 (17%) of 226 patients. Serious treatment-emergent adverse events were reported in 65 (29%) of 226 patients. Seven (3%) patients had an adverse event leading to death; none were considered to be related to radium-223. CONCLUSION: The results of this study support the use of the standard radium-223 regimen for the treatment of Asian patients with castrate-resistant prostate cancer and symptomatic bone metastases.

16.
N Engl J Med ; 383(13): 1218-1230, 2020 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-32945632

RESUMO

BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Neoplasias Urológicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos , Carboplatina/administração & dosagem , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Análise de Sobrevida , Neoplasias Urológicas/mortalidade , Urotélio
17.
Lancet Oncol ; 21(12): 1574-1588, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32971005

RESUMO

BACKGROUND: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. METHODS: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. FINDINGS: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). INTERPRETATION: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. FUNDING: AstraZeneca.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Urológicas/tratamento farmacológico , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/secundário , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/patologia , Urotélio/efeitos dos fármacos , Urotélio/patologia
18.
Infect Chemother ; 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32869552

RESUMO

Cushing's syndrome is characterized by excessive cortisol and immuno-suppression. We experienced a case of Cushing's syndrome caused by adrenocortical carcinoma that was complicated by multiple opportunistic infections. A 37-year-old woman with adrenocortical carcinoma (ACC) presented with decreased mental ability and high fever one week after undergoing chemotherapy. Her initial blood culture revealed methicillin-resistant Staphylococcus aureus bacteremia accompanied by septic pneumonia. We admitted her to the intensive care unit and treated her for invasive pulmonary aspergillosis (IPA), Pneumocystis jirovecii pneumonia (PJP), candidemia, and Stenotrophomonas maltophilia pneumonia with broad-spectrum antibiotics and antifungal agents. Nevertheless, her clinical course worsened and she died. Herein, we report a case of Cushing's syndrome associated with cortisol-secreting ACC that presented with multiple opportunistic infections, including MRSA bacteremia, septic pneumonia, candidemia, PJP, and IPA, illuminating a relationship between hypercortisolemia and opportunistic infections.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32923890

RESUMO

PURPOSE: Some gastric cancers harbor MET gene amplifications that can be targeted by selective MET inhibitors to achieve tumor responses, but resistance eventually develops. Savolitinib, a selective MET inhibitor, is beneficial for treating patients with MET-driven gastric cancer. Understanding the resistance mechanisms is important for optimizing postfailure treatment options. PATIENTS AND METHODS: Here, we identified the mechanisms of acquired resistance to savolitinib in 3 patients with gastric cancer and MET-amplified tumors who showed a clinical response and then cancer progression. Longitudinal circulating tumor DNA (ctDNA) is useful for monitoring resistance during treatment and progression when rebiopsy cannot be performed. RESULTS: Using a next-generation sequencing 100-gene panel, we identified the target mechanisms of resistance MET D1228V/N/H and Y1230C mutations or high copy number MET gene amplifications that emerge when resistance to savolitinib develops in patients with MET-amplified gastric cancer. CONCLUSION: We demonstrated the utility of ctDNA in gastric cancer and confirmed this approach using baseline tumor tissue or rebiopsy.

20.
Investig Clin Urol ; 61(6): 588-593, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32985144

RESUMO

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.


Assuntos
Antineoplásicos/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Docetaxel/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
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