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1.
Rev Med Suisse ; 15(673): 2190-2194, 2019 Nov 27.
Artigo em Francês | MEDLINE | ID: mdl-31778047

RESUMO

For more than 30 years, cisplatin-based neoadjuvant chemotherapy (NAC) has been administered to patients with muscle-invasive bladder cancer (MIBC). However, the benefit is modest. With the advent of modern immunotherapies, new therapeutic strategies are also opening up to bladder cancer. Unfortunately, the initial results in the neoadjuvant context show a response rate of only 20-35 %. Other therapeutic strategies, such as Pan-FGFR inhibitors, do not show better response. Due to the high genetic variability of bladder cancer, a «â€…one drug fits all ¼ concept is not an ideal solution. Patient selection based on the probability of response appears to be a promising strategy to improve this modest benefit of each treatment. In this context, the NAC will also continue to play an important role.


Assuntos
Cisplatino/uso terapêutico , Imunoterapia/tendências , Terapia Neoadjuvante/tendências , Invasividade Neoplásica , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Quimioterapia Adjuvante , Humanos , Seleção de Pacientes
2.
Cancer Immunol Immunother ; 68(12): 1909-1920, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31641796

RESUMO

Tumour-associated macrophages (TAMs) are the key components in the tumour microenvironment. TAMs have two major subtypes, M1 and M2. M1 macrophages are tumour inhibitory, while M2 macrophages are tumour promotive. Repolarising TAMs from M2 to M1 is a promising strategy in cancer treatment. M1 and M2 macrophages were generated from murine bone marrow-derived macrophages (BMDMs). We found that chloroquine (CQ), an autophagy inhibitor, was able to repolarise M2 macrophages to the anti-tumour M1 phenotype. The repolarised macrophages demonstrated higher phagocytotic activity towards Hep-2 laryngeal tumour cells and re-sensitised Hep-2 cells to cisplatin (CDDP) treatment in vitro. While CQ did not demonstrate cytotoxicity to Hep-2 cells in vitro, CQ treatment reduced Hep-2 laryngeal tumour growth in vivo and improved CDDP treatment outcomes. It seems that CQ-induced M2-to-M1 macrophage repolarisation played an important role in tumour growth inhibition, and the CQ/CDDP combined therapy might have clinical potential in laryngeal cancer treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Laríngeas/imunologia , Macrófagos/fisiologia , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células , Transdiferenciação Celular , Cloroquina/farmacologia , Citocinas/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias Laríngeas/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Th1/imunologia , Células Th2/imunologia
3.
DNA Cell Biol ; 38(11): 1366-1373, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31633393

RESUMO

The long noncoding RNA cancer susceptibility candidate 2 (CASC2) has been shown to play a crucial role in cancer cell chemoresistance. However, its function and underlying molecular mechanism in hepatocellular carcinoma (HCC) chemoresistance remain unknown. In this study, we used cisplatin (DDP)-resistant HCC cells to investigate CASC2 function and its underlying mechanism. The results demonstrated that CASC2 expression was significantly reduced in HCC tissues and cells, especially in DDP-resistant HCC tissues and cells. Lower CASC2 expression was strongly correlated with shorter survival times in patients with HCC. Functionally, CASC2 overexpression sensitized DDP-resistant Huh7/DDP and SMMC-7721/DDP cells to DDP. Mechanically, CASC2 improved the sensitivity of HCC cells to DDP through sponging miR-222. Taken together, these findings suggested that overexpression of CASC2 overcame DDP resistance in HCC by regulating miR-222 expression, thereby providing a potential therapeutic strategy for overcoming HCC cell chemoresistance.


Assuntos
Carcinoma Hepatocelular , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Hepáticas , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética
4.
Medicine (Baltimore) ; 98(42): e17335, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626089

RESUMO

BACKGROUND: Previous studies have shown that microRNA-32 (miRNA-32) is an exosome microRNA that affects the proliferation and metastasis of non-small cell lung cancer (NSCLC) cells. In this study, our goal was to assess the expression of plasma microRNA-32 and its potential as a biomarker to predict the tumor response and survival of patients with NSCLC undergoing platinum-based chemotherapy. METHODS: Plasma microRNA-32 levels before and after 1 cycle of platinum-based chemotherapy in 43 patients with NSCLC were measured using a quantitative real-time polymerase chain reaction assay (qPCR). In addition, the demographic and survival data of the patients were collected for analysis. RESULTS: A significant correlation was observed between the changes in microRNA-32 levels before and after 1 chemotherapy cycle and the treatment response (P = .035). In addition, Kaplan-Meier analysis showed that the level of microRNA-32 after 1 chemotherapy cycle was significantly correlated with the prognosis of patients. The median progression-free survival (P = .025) and overall survival (P = .015) of patients with high microRNA-32 levels (≥7.73) after 1 chemotherapy cycle was 9 and 21 months, respectively. In contrast, the median survival of patients with low microRNA-32 levels (<7.73) was 5 and 10 months, respectively. CONCLUSIONS: The plasma levels of microRNA-32 correlated with the efficacy of platinum-based chemotherapy and survival, indicating that microRNA-32 may be useful for predicting the effectiveness of platinum-based chemotherapy and prognosis in NSCLC.


Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/genética , MicroRNAs/genética , Carcinoma de Pequenas Células do Pulmão/genética , Idoso , Biomarcadores Tumorais/genética , Estudos Controlados Antes e Depois , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Terapia Neoadjuvante , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Carcinoma de Pequenas Células do Pulmão/sangue , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/mortalidade , Resultado do Tratamento
5.
Orv Hetil ; 160(42): 1647-1654, 2019 Oct.
Artigo em Húngaro | MEDLINE | ID: mdl-31608691

RESUMO

Current advances in molecular techniques and bioinformatics allowed the analysis of complex molecular patterns in various cancers including muscle-invasive bladder cancer. As a consequence, in the last few years numerous gene- and protein expression-based molecular classifications have been recommended. Recently a comprehensive consensus classification for muscle-invasive urothelial bladder cancer has been published, distinguishing 6 subgroups with a potential impact on clinical decision-making. At the same time, the therapeutic landscape of muscle-invasive bladder cancer becomes increasingly differentiated as novel checkpoint inhibitors have been available for cisplatin-ineligible and/or resistant patients. Furthermore, promising results have been obtained with FGFR targeting agents. Therefore, molecular subtyping will probably have a crucial role in individualized therapeutic decision-making in bladder cancer. In the present work, we summarize the evolution, recent advances and potential therapeutic relevance of molecular subclassifications in bladder cancer. Orv Hetil. 2019; 160(42): 1647-1654.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/terapia , Cisplatino/uso terapêutico , Imunoterapia , Neoplasias da Bexiga Urinária/terapia , Urotélio/patologia , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma de Células de Transição/patologia , Terapia Combinada , Humanos , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia
6.
Med Oncol ; 36(11): 93, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595355

RESUMO

In patients with locally advanced human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC), cisplatin and radiation therapy (CisRT) resulted in a local-regional recurrence (LRR) rate of 35%, progression-free survival (PFS) of 49%, and overall survival (OS) of 60%. We, and others, showed that nab-paclitaxel is an active agent in metastatic and locally advanced HNSCC. The aim of this report was to assess the efficacy of nab-paclitaxel-based induction chemotherapy and CisRT in HPV-unrelated HNSCC. We performed a retrospective single-institution analysis of patients treated with nab-paclitaxel-based chemotherapy and CisRT. Key inclusion criteria included stage III-IV HPV-unrelated HNSCC. Induction chemotherapy included nab-paclitaxel and cisplatin (AP), AP + 5-fluorouracil (APF), or APF + Cetuximab (APF-C). Endpoints included LRR, overall relapse, PFS, and OS. Thirty-eight patients were the subject of this analysis. Patient characteristics included median age 59 years (IQR: 54-64) and smoking history in 36 patients (95%). Primary tumor sites included larynx/hypopharynx (27), p16 negative oropharynx (10), and oral cavity (1). Most patients had bulky disease: 82% T3-4 (n = 31) and 74% N2b-3 (n = 28). Median follow-up was 44 months (IQR: 23-59). The three-year LRR rate was 16% (95% confidence interval [CI] 7-34) and the overall relapse rate was 22% (95% CI 11-41). The three-year PFS was 64% (95% CI 46-77) and OS was 72% (95% CI 54-84). Among patients with HPV-unrelated HNSCC, nab-paclitaxel-based induction chemotherapy and CisRT resulted in a lower-than-expected rate of LRR and more favorable PFS and OS compared to historical results with CisRT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Albuminas/administração & dosagem , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
7.
Medicine (Baltimore) ; 98(37): e17114, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517847

RESUMO

BACKGROUND: We will investigate the efficacy and safety of weekly cisplatin (WC) for treatment of patients with breast cancer (BC) systematically. METHODS: This study will describe and critically appraise shared decision approaches used in randomized controlled trials of WC for treatment of patients with BC. We will comprehensively search the following databases: PubMed, EMBASE, Web of Science, Cochrane Library, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Wanfang, and Chinese Biomedical Literature Database from inception through July 1, 2019. We will utilize RevMan V.5.3 software (London, UK) for statistical analysis. RESULTS: This study will systematically explore the efficacy and safety of WC for the treatment of patients with BC through evaluating primary outcomes of overall survival, pathological complete response; and secondary outcomes of cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide latest evidence of WC for the treatment of patients with BC. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019145358.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Cisplatino/normas , Adulto , Cisplatino/uso terapêutico , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Resultado do Tratamento
9.
J Cancer Res Clin Oncol ; 145(12): 3067-3073, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563974

RESUMO

BACKGROUND: The combination of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) is an established salvage regimen for lymphoma patients. We hypothesized that a modified administration schedule for cisplatin and cytarabine results in lower toxicity and improved efficacy. METHODS: We retrospectively analysed 119 patients with relapsed or refractory, aggressive, or indolent B-cell lymphomas, mantle-cell lymphomas, peripheral T-cell lymphomas, or Hodgkin's lymphomas who were treated with the modified DHAP (mDHAP) regimen (dexamethasone 40 mg 15 min-i.v. infusion, days 1-4; cytarabine 2 × 0.5 g/m2 1 h-i.v. infusion, days 1-4; cisplatin 25 mg/m2 24 h-i.v. infusion, days 1-4). Responding and eligible patients underwent stem-cell transplantation. RESULTS: In total, 185 treatment cycles were evaluable. Severe myelosuppression was the main toxicity occurring in 90% of the cycles. Febrile neutropenia or documented infection was found in less than 40%. Two patients died related to treatment (TRM, 1.7%). Nephrotoxicity did not exceed CTC grade 3, which occurred in four cycles only (2.2%). Complete (CR) or partial (PR) responses after mDHAP were documented in 16% and 39% (overall response rate 55%). Harvest of autologous stem cells was successful in 94 (79%) patients and 85 patients (71%) proceeded to stem-cell transplantation. The median overall and progression-free survival was 50.8 and 25.8 months. CONCLUSIONS: An improvement in efficacy could not be observed after modified DHAP regimen; however, manageable toxicity and reduced renal complications suggest further investigation. The study, however, also underlines the need for new concepts in the management of advanced and high-risk lymphomas.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Adulto , Idoso , Cisplatino/uso terapêutico , Citarabina/uso terapêutico , Dexametasona/uso terapêutico , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Terapia de Salvação/métodos , Adulto Jovem
10.
Bull Cancer ; 106(10): 896-902, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31466695

RESUMO

Metastatic testicular germ cell tumors are rare entities with a high cure rate owing to their major chemosensitivity. Current guidelines should be strictly followed to ensure maximal cure rate. Germ cell tumor treatment requires multidisciplinary skills and is based on cisplatin-based chemotherapy. The current challenge for these patients with favorable prognosis is to limit over- or under-treatment. Centralization of care for patients with these rare cancers is a key point to achieve the best chance of cure.


Assuntos
Neoplasias Embrionárias de Células Germinativas/secundário , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Testiculares/secundário , Neoplasias Testiculares/terapia , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Terapia Combinada/métodos , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/patologia , Orquiectomia , Prognóstico , Neoplasias Testiculares/classificação , Neoplasias Testiculares/patologia
11.
Medicine (Baltimore) ; 98(31): e16673, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374045

RESUMO

The aim of this study was to analyze dose-volume histogram (DVH) of the remnant liver for postoperative cholangiocarcinoma (CCA) patients, to find toxicity rates, and to confirm efficacy of postoperative radiation therapy (RT).Thirty-two postoperative CCA patients received partial liver resection and postoperative RT with curative intent. The "liver reduction rate" was calculated by contouring liver volume at computed tomography (CT) just before the surgery and at CT for planning the RT. To evaluate late toxicity, the radiation-induced hepatic toxicity (RIHT) was determined by the common terminology criteria for adverse events toxicity grade of bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, and albumin, and was defined from 3 months after RT until liver metastasis was revealed. The radiation-induced liver disease (RILD) was also evaluated.Tumor stages were distributed as follows: I: 1, II: 8, IIIA: 1, IIIB: 6, IIIC: 14, IVA: 2. Median prescribed total dose was 50 Gy. Median follow-up time was 27 months. Two-year overall survival (OS): 72.4%, disease-free survival: 47.7%, local control: 65.3%, and the median survival time was 40 months. The median "liver reduction rate" was 21%. The OS had statistically significant difference in nodal status (P = .032) and "liver reduction rate" >30% (P = .016). In the association between the ≥grade 2 RIHT and DVH, there were significantly differences in V30 and V40 (P = .041, P = .034), respectively. The grade ≥2 RIHT rates differ also significantly by sex (P = .008). Two patients (6.2%) were suspected of RILD.We suggest that RT for remnant liver should be considered the liver V30, V40 to prevent radiation-induced liver dysfunction.


Assuntos
Colangiocarcinoma/radioterapia , Hepatopatias/prevenção & controle , Neoplasias Hepáticas/radioterapia , Lesões por Radiação/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Cisplatino/uso terapêutico , Terapia Combinada , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Combinação de Medicamentos , Hepatectomia , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ácido Oxônico/uso terapêutico , Piridinas/uso terapêutico , Radiossensibilizantes/uso terapêutico , Dosagem Radioterapêutica , Radioterapia Adjuvante , Tegafur/uso terapêutico , Tomografia Computadorizada por Raios X
12.
Medicine (Baltimore) ; 98(35): e16593, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31464894

RESUMO

RATIONALE: Limbic encephalitis is one of the most common paraneoplastic neurological disorders (PND). The role of brain Fluorine-18-fluorodeoxyglucose position emission tomography/computed tomography (CT) in paraneoplastic limbic encephalitis (PLE) and of the whole body 18F-FDG PET/CT in this setting, remains still not well defined. PATIENT CONCERNS: We report a case of a patient with chronic inflammatory rheumatism, psoriasis and Hashimoto thyroiditis and subsequent appearance of static and dynamic ataxia and episodic memory deficit who was diagnosed as PLE combined with small cell lung cancer (SCLC). DIAGNOSES: The diagnosis of SCLC was made with EBUS-TBNA of a mediastinal lymph node. INTERVENTIONS: Whole-body 18F-FDG PET/CT was performed for the initial staging of SCLC, in the planning of radiotherapy treatment, to evaluate therapeutic response and in the follow-up. A dedicated brain scan was included to the same PET session. Whole-body contrast enhanced computed tomography (CT) and contrast enhanced whole-brain MRI were also performed. OUTCOMES: She was administered neoadjuvant chemioterapy with Cisplatin and Etoposide with concomitant radiotherapy treatment. Whole body 18F-FDG PET/CT showed a complete metabolic response already after 3 cycles of chemioterapy. Brain functional study showed a metabolic pattern characterized by the migration of hypermetabolism in the bilateral hippocampal areas during the therapeutic treatment, which correlated with the persistence of clinical symptoms. LESSONS: In the era of personalized medicine and targeted therapy, this case highlights the importance of the 18F-FDG PET/CT study as an accurate tool to identify PLE and to guide the diagnostic work-up of the underlying tumor. Considering that most of these are 18F-FDG avid tumors and that the 18F-FDG PET/CT scan is often added to the diagnostic work-up when screening patients for malignancy, this functional imaging can play a decisive role.


Assuntos
Fluordesoxiglucose F18/administração & dosagem , Encefalite Límbica/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Encéfalo/diagnóstico por imagem , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Encefalite Límbica/tratamento farmacológico , Encefalite Límbica/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento , Imagem Corporal Total
13.
Anticancer Res ; 39(7): 3931-3936, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262923

RESUMO

BACKGROUND/AIM: Platinum plus 5-fluorouracil (FP) is a first-line regimen of palliative chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma (RM-ESCC). In this retrospective study, we evaluated the efficacy and safety of S-1 monotherapy as a salvage line treatment for RM-ESCC, focusing on the reasons for discontinuation of prior FP. MATERIALS AND METHODS: The subjects of this study had RM-ESCC and received S-1 after failure of FP. RESULTS: Eleven patients were enrolled. Nine patients were refractory and two were intolerant to prior FP. The median progression-free survival and overall survival time were 3.0 and 11.7 months, respectively. Overall response rate was 22.2% and disease control rate of the 11 patients was 36.4%. Median relative dose intensity of 5-FU was 100% (range=85-100%). CONCLUSION: S-1 efficacy in RM-ESCC when given after FP was modest. Favorable OS may be attributed to good local control rather than to the efficacy of S-1 monotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Ácido Oxônico/uso terapêutico , Tegafur/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Cisplatino/uso terapêutico , Combinação de Medicamentos , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Fluoruracila/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Terapia de Salvação , Falha de Tratamento
14.
Nat Med ; 25(7): 1073-1081, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270502

RESUMO

Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances1,2. Recent molecular characterization has defined new (epi)genetic drivers and potential targets for bladder cancer3,4. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients5-8. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (PtenloxP/loxP; Trp53loxP/loxP; Rb1loxP/loxP; Rbl1-/-) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.


Assuntos
Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Proteína Potenciadora do Homólogo 2 de Zeste/fisiologia , Feminino , Antígenos de Histocompatibilidade , Humanos , Camundongos , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
15.
Drugs ; 79(11): 1231-1239, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267481

RESUMO

For more than 20 years, the combination of a platinum agent and a taxane has served as the primary chemotherapy strategy for epithelial ovarian cancer. Alternative approaches employing these drugs (intraperitoneal drug delivery, neoadjuvant therapy) have favorably impacted outcomes in selected patient populations. Multiple single agent and combination therapy strategies have been delivered in the second-line (or later) setting with the goal to prolong survival and optimize quality-of-life. The anti-angiogenic agent bevacizumab has been shown to be clinically active when added to chemotherapy and delivered as a "maintenance" strategy in the front-line, platinum-sensitive recurrent and platinum-resistant settings. Several poly-(ADP-ribose) polymerase (PARP) inhibitors are currently utilized as single-agent "second-line" treatment options or in the maintenance setting. Recent clinical research efforts in ovarian cancer have focused on the potential role of checkpoint inhibitors used alone or in combination with PARP inhibitors or anti-angiogenic agents.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Carboplatina/uso terapêutico , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Terapia Neoadjuvante , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Taxoides/uso terapêutico
16.
Biol Res ; 52(1): 37, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31319879

RESUMO

BACKGROUND: Berberine (BBR), a compound extracted from a variety of medicinal herbs, has been shown multiple pharmacological effects against cancer cells of different origins. Cisplatin (DDP) is known as an effective chemotherapeutic agent against cancer by inducing DNA damage and cell apoptosis. However, the effect of the combined used of BBR and DDP on cell necroptosis in ovarian cancer has not been reported. METHODS: OVCAR3 and three patient-derived primary ovarian cancer cell lines (POCCLs) were chosen as the experimental objects. To determine the potential anti-cancer activity of BBR and DDP in combination, we firstly treated OVCAR3 and POCCLs cells with BBR and/or DDP. The cell viability of OVCAR3 and POCCLs with treatment of BBR or DDP for different hours was measured by CCK-8 assay. Flow cytometry was used to analyze cell cycle distribution and changes in apoptotic cells after treatment with BBR and/or DDP. The morphological changes of OVCAR3 cells were observed by using Transmission electron microscopy (TEM) analysis. Proliferation, apoptosis and necroptosis related markers of OVCAR3 and POCCLs with treatment of BBR or DDP were measured by RT-qPCR, western blotting and immunofluorescence assay. RESULTS: Our results demonstrated that BBR significantly inhibited the proliferation of OVCAR3 and primary ovarian cancer cells in a dose- and time-dependent manner. The combination treatment of BBR and DDP had a prominent inhibitory effect on cancer cell growth and induced G0/G1 cell cycle arrest. TEM revealed that the majority of cells after BBR or DDP treatment had an increasing tendency of typical apoptotic and necrotic cell death morphology. Besides, BBR and DDP inhibited the expression of PCNA and Ki67 and enhanced the expression and activation of Caspase-3, Caspase-8, RIPK3 and MLKL. CONCLUSION: This study proposed that the combination therapy of BBR and DDP markedly enhanced more ovarian cancer cell death by inducing apoptosis and necroptosis, which may improve the anticancer effect of chemotherapy drugs. The apoptosis involved the caspase-dependent pathway, while the necroptosis involved the activation of the RIPK3-MLKL pathway. We hope our findings might provide a new insight for the potential of BBR as a therapeutic agent in the treatment of ovarian cancer.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Berberina/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Berberina/farmacologia , Caspases , Linhagem Celular Tumoral/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Necrose
17.
J Cancer Res Clin Oncol ; 145(8): 2157-2166, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273512

RESUMO

PURPOSE: Adjuvant chemotherapy for gastric cancer, particularly stage III, improves survival after curative D2 gastrectomy. We investigated the clinical value of the lymph-node ratio (LNR; number of metastatic lymph nodes/number of lymph nodes examined) for selecting the appropriate adjuvant chemotherapy regimen in patients with D2-resected stage II/III gastric cancer. METHODS: We reviewed the data of 819 patients who underwent curative D2 gastrectomy followed by adjuvant chemotherapy. Of them, 353 patients received platinum-based chemotherapy and 466 received TS-1. The patients were categorized into three groups according to their LNR (LNR 1, 0-0.1; LNR 2, > 0.1-0.25; and LNR 3, > 0.25), and their disease-free survival (DFS) was evaluated. RESULTS: The DFS curves of the patients were well separated according to stage and LNR. In multivariate analyses, an LNR > 0.1 was strongly associated with the 3-year DFS (hazard ratio 2.402, 95% confidence interval 1.607-3.590, P < 0.001). Platinum-based chemotherapy improved the 3-year DFS compared to TS-1 in patients with LNR 3 group in stage III gastric cancer (platinum vs. TS-1, median DFS 26.87 vs. 16.27 months, P = 0.028). An LNR > 0.1 was associated with benefiting from platinum-based adjuvant chemotherapy in stage III gastric cancer patients with lymphovascular invasion (platinum vs. TS-1, median DFS 47.57 vs. 21.77 months, P = 0.011). CONCLUSIONS: The LNR can be used to select the appropriate adjuvant chemotherapy regimen for patients with D2-resected gastric cancer, particularly in stage III.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Comportamento de Escolha , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Gastrectomia , Linfonodos/patologia , Neoplasias Gástricas/terapia , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/classificação , Cisplatino/uso terapêutico , Terapia Combinada , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Gastrectomia/métodos , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Tegafur/uso terapêutico , Uracila/uso terapêutico
18.
Gan To Kagaku Ryoho ; 46(4): 701-704, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164510

RESUMO

A 74-year-old man with bloody vomit was diagnosed as having clinical Stage Ⅳ advanced gastric cancer with lymph node metastasis around the abdominal aorta. Initially, for curative surgery, he was administered neoadjuvant chemotherapy. On day 32, in the second course of chemotherapy containing S-1 after 12 courses of chemotherapy containing S-1 and cisplatin, he developed pan-peritonitis owing to the perforation of gastric cancer caused by chemotherapy, and thus, we performed emergency omental implantation and peritoneal drainage. He was discharged from the hospital after 14 days with no trouble. His gastric cancer was judged to be resectable without retaining metastatic lymph nodes based on intraoperative findings and abdominal computed tomography. Therefore, 3 months after the emergency surgery, he underwent total gastrectomy with D1+(+No. 11d)lymphadenectomy. The postoperative course was uneventful. He rejected adjuvant chemotherapy despite our recommendation. Regrettably, intraabdominal dissemination was observed 15 months after total gastrectomy, and he then received chemotherapy again. He has remained alive for 57 months after the first visit to our hospital.


Assuntos
Gastrectomia , Neoplasias Gástricas , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Combinação de Medicamentos , Humanos , Excisão de Linfonodo , Metástase Linfática , Masculino , Terapia Neoadjuvante , Ácido Oxônico , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/cirurgia
19.
Gan To Kagaku Ryoho ; 46(4): 775-777, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164532

RESUMO

A 47-year-old woman who had unresectable locally advanced gallbladder cancer(GBC)accompanied with liverinvasion, duodenum invasion, transverse colon invasion, and surrounding lymphatic metastasis received 5 courses of chemotherapy with gemcitabine plus cisplatin. Afterthe chemotherapy, imaging showed down-staging of the GBC, indicating tumor shrinkage. The initial laparoscopic examination revealed no peritoneal seeding or distant metastasis. Subsequently, we performed cholecystectomy with a partial hepatectomy at the gallbladder bed. Malignant findings were not observed in the histopathological examination and the pathological diagnosis was CR with pT0N0M0, Stage 0. The patient was discharged on day 11 after the operation. There has been no recurrence at 14 months after surgery. Although the prognosis of advanced GBC with local invasion is generally poor, chemotherapy might be an effective treatment for patients with initially unresectable locally advanced gallbladder carcinoma.


Assuntos
Neoplasias da Vesícula Biliar , Antineoplásicos/uso terapêutico , Colecistectomia , Cisplatino/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Hepatectomia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia
20.
Cancer Sci ; 110(9): 2867-2874, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31237050

RESUMO

This study aimed to evaluate the feasibility of combining helical tomotherapy (HT) and intensity-modulated proton therapy (IMPT) in treating patients with nasopharynx cancer (NPC). From January 2016 to March 2018, 98 patients received definitive radiation therapy (RT) with concurrent chemotherapy (CCRT). Using simultaneous integrated boost and adaptive re-plan, 3 different dose levels were prescribed: 68.4 Gy in 30 parts to gross tumor volume (GTV), 60 Gy in 30 parts to high-risk clinical target volume (CTV), and 36 Gy in 18 parts to low-risk CTV. In all patients, the initial 18 fractions were delivered by HT, and, after rival plan evaluation on the adaptive re-plan, the later 12 fractions were delivered either by HT in 63 patients (64.3%, HT only) or IMPT in 35 patients (35.7%, HT/IMPT combination), respectively. Propensity-score matching was conducted to control differences in patient characteristics. In all patients, grade ≥ 2 mucositis (69.8% vs 45.7%, P = .019) and grade ≥ 2 analgesic usage (54% vs 37.1%, P = .110) were found to be less frequent in HT/IMPT group. In matched patients, grade ≥ 2 mucositis were still less frequent numerically in HT/IMPT group (62.9% vs 45.7%, P = .150). In univariate analysis, stage IV disease and larger GTV volume were associated with increased grade ≥ 2 mucositis. There was no significant factor in multivariate analysis. With the median 14 month follow-up, locoregional and distant failures occurred in 9 (9.2%) and 12 (12.2%) patients without difference by RT modality. In conclusion, comparable early oncologic outcomes with more favorable acute toxicity profiles were achievable by HT/IMPT combination in treating NPC patients.


Assuntos
Quimiorradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Recidiva Local de Neoplasia/epidemiologia , Terapia com Prótons/métodos , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso , Quimiorradioterapia/efeitos adversos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mucosite/epidemiologia , Mucosite/etiologia , Neoplasias Nasofaríngeas/mortalidade , Recidiva Local de Neoplasia/prevenção & controle , Terapia com Prótons/efeitos adversos , Lesões por Radiação/epidemiologia , Lesões por Radiação/etiologia , Radiossensibilizantes/uso terapêutico , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Resultado do Tratamento , Adulto Jovem
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