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1.
Nat Commun ; 11(1): 4858, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32978382

RESUMO

Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.


Assuntos
Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Biomarcadores Tumorais , Quimioterapia Adjuvante , Cisplatino/uso terapêutico , Metilação de DNA , Tratamento Farmacológico , Instabilidade Genômica , Humanos , Mutação , Terapia Neoadjuvante , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Transcriptoma , Neoplasias da Bexiga Urinária/patologia
2.
Medicine (Baltimore) ; 99(36): e21785, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899005

RESUMO

BACKGROUND: Concurrent cisplatin with radiotherapy (CRT) or concurrent cetuximab with radiotherapy (BRT) improves outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC) compared with radiotherapy alone. Nevertheless, a detailed comparison between CRT and BRT in locally advanced HNSCC is required due to inconclusive results. METHODS: A comprehensive literature search was conducted on PubMed, Web of Science, Cochrane databases, and EMBASE. Studies that evaluated CRT vs BRT in locally advanced HNSCC were included. The primary outcome that was overall survival (OS), whereas the secondary outcomes were progression-free survival (PFS), locoregional control (LRC), and distant metastasis-free survival (DMFS). Pooled hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) were used to evaluate prognosis. All the analyses were performed using Stata Statistical Software 12.0. RESULTS: Twenty-three studies, with a total of 8701 patients, were considered eligible and included in this meta-analysis. Our results revealed that patients treated with CRT had longer OS (HR = 0.51, 95%CI, 0.41-0.64, P < .001), PFS (HR = 0.37, 95%CI, 0.23-0.60, P < .001), LRC (HR = 0.46, 95%CI, 0.37-0.57, P < .001), and DMFS (HR = 0.56, 95%CI, 0.40-0.77, P < .001) than those treated with BRT. Furthermore, the results of the subgroup analyses were consistent with the primary analysis. CONCLUSIONS: CRT has a better OS, PFS, LRC, and DMFS than BRT in locally advanced HNSCC, and should be the preferred treatment for patients with the disease.


Assuntos
Cetuximab/uso terapêutico , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Idoso , Quimiorradioterapia/métodos , Intervalo Livre de Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
3.
Medicine (Baltimore) ; 99(38): e22297, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957389

RESUMO

RATIONALE: Growing teratoma syndrome is defined as an increase in tumor size during or after systemic chemotherapy for germ cell tumors. These cases involve normal tumor maker levels and histological features of only mature teratoma. We report a rare case of an ovarian immature teratoma in a Japanese child that was diagnosed as growing teratoma syndrome. PATIENT CONCERNS: A 12-year-old girl presented a painful abdominal mass. She underwent left salpingo-oophorectomy for grade 1 immature teratoma in the left ovary. She did not undergo additional chemotherapy or radiotherapy. Four months later, she presented with grade 3 immature teratoma disseminated into the abdomen and pelvis. Chemotherapy resulted in the tumor maker levels returning to their normal ranges, although the tumors had grown slightly. DIAGNOSIS: The specimens resected by laparotomy after the chemotherapy consisted of mature tissue predominantly, although primitive neuroepithelium was observed in a small part of the specimen. The pathological diagnosis was grade 1 immature teratoma, notwithstanding the clinical diagnosis was growing teratoma syndrome based on the clinical features and pathogenesis. INTERVENTIONS: Laparotomy was performed at 7 months after the first operation, with resection of various tumors as well as the rectum, sigmoid colon, residual left fallopian duct, and a small part of the ileum and omentum. Some small tumors at the parietal peritoneum were ablated, although many tiny tumors around the uterus were left untreated. OUTCOMES: The patient has been free from recurrence for 5 years. LESSONS: Growing teratoma syndrome can develop in children, and their tumor size is comparable to that in adolescents and adults. Furthermore, development of growing teratoma syndrome from a primary germ cell tumor is presumably faster in children than in adolescents and adults. Complete resection of all growing teratoma tissue is recommended, although fertility-sparing surgery should be considered when possible.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/terapia , Salpingo-Ooforectomia/métodos , Teratoma/terapia , Bleomicina/uso terapêutico , Criança , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Gradação de Tumores , Recidiva Local de Neoplasia , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Síndrome , Teratoma/diagnóstico por imagem , Teratoma/patologia
4.
Medicine (Baltimore) ; 99(38): e22329, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32957401

RESUMO

RATIONALE: A supernumerary kidney is an extremely rare renal anomaly. Currently, <100 cases are reported in the literature. There are only 2 right unilateral supernumerary kidneys reported in the literature thus far, but no confirmed cases of urothelial carcinoma in supernumerary kidneys. We report a case of a right supernumerary with urothelial carcinoma, which is, to the best of our knowledge, reported for the first time. PATIENT CONCERNS: A 73-year-old female patient presented with intermittent, painless, whole course and gross hematuria for about 3 months. Her physical and laboratory examinations did not reveal any significant findings except positive occult blood in routine urine examination. Contrast-enhanced spiral computed tomography revealed a dysplastic supernumerary kidney under the normal right kidney. DIAGNOSES: The ureteroscopy showed that the ureter was Y-shaped in the middle part. The medial ureter led to a normal kidney. The lateral ureter was just 2 cm and led to a small cavity in which there was a mass whose biopsy showed urothelial carcinoma. The patient was subsequently diagnosed with a right supernumerary kidney with urothelial carcinoma. INTERVENTION: Nephroureterectomy, including the right normal and supernumerary kidneys, and partial cystectomy by laparoscopy were performed after the ureteroscopy. The patient then received 6 cycles of gemcitabine and cisplatin regimen chemotherapy and regular intravesical epirubicin chemotherapy. OUTCOMES: No recurrence or metastasis was found on follow-up computed tomography performed 13 months postoperatively. LESSONS: A supernumerary kidney is an extremely rare renal anomaly. Malignancy can occur in supernumerary kidneys.


Assuntos
Carcinoma de Células de Transição/terapia , Neoplasias Renais/terapia , Rim/anormalidades , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/diagnóstico por imagem , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Humanos , Rim/diagnóstico por imagem , Neoplasias Renais/diagnóstico por imagem , Neoplasias Renais/patologia , Nefroureterectomia , Ureter/anormalidades
6.
Anticancer Res ; 40(10): 5829-5835, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988912

RESUMO

BACKGROUND: Preoperative chemotherapy with surgery is the most effective treatment modality in Japan for advanced oesophageal squamous cell carcinoma (OSCC). We evaluated the long-term outcomes associated with preoperative docetaxel/cisplatin/5-fluorouracil (DCF) administration followed by oesophagectomy in OSCC. PATIENTS AND METHODS: Overall, 76 consecutive patients with cStage IB-IIIC OSCC were enrolled. After two cycles of preoperative DCF, oesophagectomy was performed. Survival monitoring was performed and relevant risk factors were analysed. RESULTS: The median follow-up period was 88.3 months. The 5-year overall and recurrence-free survival rates were 51% and 43%, respectively. In the multivariable analysis, cT3 stage [hazard ratio (HR)=1.81, 95% confidence interval (CI)=1.08-6.16], incomplete chemotherapy (HR=2.35, 95% CI=1.37-4.02), poor clinical response (HR=1.82, 95% CI=1.01-3.29), and postoperative complications (HR=2.11, 95% CI=1.14-3.90) were independent predictors of poorer overall survival. CONCLUSION: The 5-year outcomes of preoperative DCF with oesophagectomy were favourable. Our findings can aid in the formulation of strategies aimed at improving prognosis in OSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Metástase Linfática/tratamento farmacológico , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Cisplatino/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Esofagectomia/métodos , Feminino , Fluoruracila/uso terapêutico , Humanos , Japão/epidemiologia , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Resultado do Tratamento
7.
Anticancer Res ; 40(10): 5861-5868, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988916

RESUMO

AIM: To evaluate our experience with radical radiotherapy and chemotherapy in patients with muscle-invasive bladder cancer. PATIENTS AND METHODS: The study consisted of 27 patients treated with cisplatin-based chemoradiation (CCRT), 48 treated with radiation alone (RT), and 42 with locally advanced disease treated with neoadjuvant chemotherapy and radiation (neoCRT). RESULTS: The incidence of acute grade 3 or more genitourinary (GU) toxicity in the RT, CCRT and neoCRT groups was: 25%, 11% and 19%, respectively (p=0.029). The 3-year freedom from grade 2 or more GU toxicity was: 81%, 89%, 54%, respectively (p=0.36). The long-term outcomes of 3-year local control, overall survival, and disease-free survival were as follows: RT group: 74%, 61% and 55%; CCRT group: 76%, 76% and 56%; neoCRT group: 31%, 43% and 18%, respectively. CONCLUSION: The preferable bladder-conserving approach is CRT, however RT alone might also be an option for appropriately selected patients. NeoCRT for those with locally advanced tumors remain unsatisfactory; adequate selection of patients for radical treatment is of importance.


Assuntos
Cisplatino/uso terapêutico , Músculo Esquelético/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/radioterapia , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/patologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/cirurgia
8.
Int J Nanomedicine ; 15: 4793-4810, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764921

RESUMO

Background: Platinum resistance is a major challenge in the management of ovarian cancer. Even low levels of acquired resistance at the cellular level lead to impaired response to cisplatin. In ovarian cancer intraperitoneal therapy, nanoparticle formulation can improve the cisplatin's pharmacokinetics and safety profile. Purpose: This work aimed to investigate the chemo-sensitivity of ovarian cancer SKOV3 cells upon short-term (72h) single treatment of cisplatin and cisplatin-loaded biodegradable nanoparticles (Cis-NP). The aim was then to determine the therapeutic properties of Cis-NP in vivo using a SKOV3-luc cells' xenograft model in mice. Methods: Cell cytotoxicity was assessed after the exposure of the cell culture to cisplatin or Cis-NP. The effect of treatments on EMT and CSC-like phenotype was studied by analyzing a panel of markers by flow cytometry. Intracellular platinum concentration was determined by inductively coupled plasma mass spectrometry (ICS-MS), and gene expression was evaluated by RNAseq analysis. The efficacy of intraperitoneal chemotherapy was evaluated in a SKOV3-luc cells' xenograft model in mice, through a combination of bioluminescence imaging, histological, and immunohistochemical analyses. Results: We observed in vitro that short-term treatment of cisplatin has a critical role in determining the potential induction of chemoresistance, and a nanotechnology-based drug delivery system can modulate it. The RNAseq analysis underlines a protective effect of nanoparticle system according to their ability to down-regulate several genes involved in chemoresistance, cell proliferation, and apoptosis. The highest intracellular platinum concentration obtained with Cis-NP treatment significantly improved the efficacy. Consistent with in vitro results, we found that Cis-NP treatment in vivo can significantly reduce tumor burden and aggressiveness compared to the free drug. Conclusion: Nanoparticle-mediated cisplatin delivery may serve as an intracellular depot impacting the cisplatin pharmacodynamic performance at cellular levels. These features may contribute to improving the drawbacks of conventional intraperitoneal therapy, and therefore will require further investigations in vivo.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Portadores de Fármacos/química , Espaço Intracelular/metabolismo , Nanomedicina/métodos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cisplatino/química , Cisplatino/metabolismo , Cisplatino/uso terapêutico , Regulação para Baixo/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Medicine (Baltimore) ; 99(31): e20500, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756075

RESUMO

BACKGROUND: Chinese herbal injections (CHIs) have been proven beneficial to patients with non-small cell lung cancer (NSCLC) in combination with chemotherapy. The network meta-analysis (NMA) was designed to update and expand on previous work to better evaluate the effectiveness and safety of different Yiqi Fuzheng (YQFZ) CHIs combined with the Vinorelbine plus cisplatin (NP) regimen versus NP alone for NSCLC. METHODS: We searched multiple electronic databases and identified randomized controlled trials (RCTs) concerning different YQFZ CHIs combined with the NP regimen for treating NSCLC up to March 1st, 2019. The outcomes are the objective response rate, performance status and adverse reactions (ADRs). Two individuals accomplished the quality assessment of this NMA based on the Cochrane risk of bias tool and the methodological section of the CONSORT statement. Random effects models were generated to estimate efficacy and safety outcomes. Odds ratios and corresponding 95% confidence intervals were calculated via Stata 14 software. Furthermore, the rankings for the efficacy and safety of different YQFZ CHIs for each outcome were determined by the surface under the cumulative ranking curve (SUCRA). RESULTS: Initially, a total of 4775 citations were retrieved through comprehensive searching, and 88 eligible articles involving 6695 participants and 8 CHIs were ultimately included. The cluster analysis results of the current evidence indicated that the NP regimen combined with Delisheng, Shenfu and Shenmai injections have a higher clinical effectiveness rate and better performance status compared with the NP regimen alone. Additionally, the NP regimen combined with Shenqifuzheng, Shengmai and Shenfu injections may be considered a favorable choice for reliving ADRs among patients with NSCLC. CONCLUSIONS: The current evidence demonstrated that the combination of Shenfu injection plus NP regimen could produce better outcomes than other YQFZ CHIs groups in terms of efficacy and safety. However, meticulously designed, strictly executed, high-quality trials are still required to further assess and confirm the results due to the inadequacy of the included RCTs.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Vinorelbina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Injeções , Metanálise em Rede , Vinorelbina/uso terapêutico
10.
Medicine (Baltimore) ; 99(34): e21936, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846862

RESUMO

RATIONALE: IgG4-related disease (IgG4-RD) is a systemic disease that can involve various organs and is characterized by the infiltrations of IgG4-positive plasma cells and lymphocytes, fibrosis, and elevated serum IgG4 levels. IgG4-related sclerosing cholangitis (IgG4-RSC) is a subtype of IgG4-RD. No certain relationship between IgG4-RSC and cholangiocarcinoma has been established as yet, and there have been few reports of the simultaneous diagnosis of IgG4-RSC and cholangiocarcinoma. PATIENT CONCERNS: A 76-year-old male visited our gastroenterology department due to the recent occurrence of pruritus and jaundice. DIAGNOSIS: Computed tomography (CT) scan showed ductal wall swelling and enhancement from both intrahepatic duct confluence to the common bile duct, upper biliary dilatation, and accompanying autoimmune pancreatitis (a sub type of IgG4-RD). Biopsy of the distal common bile duct by endoscopic retrograde cholangiopancreatography (ERCP) resulted in a diagnosis of IgG4-RSC. Subsequently, adenocarcinoma was identified by repeated cytology of bile juice. Finally, Klatskin tumor type IIIA and IgG4-RSC were concurrently diagnosed. INTERVENTIONS: IgG4-RSC was treated with steroid and Klatskin tumors by gemcitabine + cisplatin chemotherapy. OUTCOMES: The jaundice had improved and CT showed substantial improvement of the intrahepatic duct dilatation. LESSONS: IgG4-RSC and cholangiocarcinoma are easily confused, but their treatments are quite different, and thus, care must be taken during diagnosis. Furthermore, these 2 diseases may co-exist. Therefore, even if IgG4-RSC is diagnosed first, the possibility of accompanying cholangiocarcinoma should be thoroughly investigated.


Assuntos
Colangiocarcinoma/complicações , Colangite Esclerosante/patologia , Imunoglobulina G/imunologia , Tumor de Klatskin/complicações , Tumor de Klatskin/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colangiocarcinoma/patologia , Colangiopancreatografia Retrógrada Endoscópica , Colangite Esclerosante/diagnóstico por imagem , Colangite Esclerosante/tratamento farmacológico , Cisplatino/uso terapêutico , Ducto Colédoco/patologia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Diagnóstico Diferencial , Humanos , Doença Relacionada a Imunoglobulina G4/patologia , Icterícia/diagnóstico , Icterícia/etiologia , Tumor de Klatskin/classificação , Tumor de Klatskin/tratamento farmacológico , Masculino , Prurido/diagnóstico , Prurido/etiologia , Esteroides/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
11.
Medicine (Baltimore) ; 99(31): e21539, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756206

RESUMO

BACKGROUND: The main component of cinobufacini injection is dry toad skin, which is used as adjuvant therapy for stage III/IV non-small cell lung cancer patients in long-term combination with vinorelbine and cisplatin. However, the efficacy and safety of this combination therapy remain unclear. METHODS: A systematic review and meta-analysis will be conducted following the preferred reported items for systematic review and meta-analysis guidelines. Two independent reviewers (LRL and ZLN) will carry out a comprehensive search of the PubMed, Web of Science, Cochrane Library, EMBASE, the Chinese Science and Technology Periodical Database, China National Knowledge Infrastructure, Wanfang Databases, China Biology Medicine. The last search date will be July 30, 2020. Reference list of all selected articles will independently screened to identify additional studies left out in the initial search. The Cochrane Risk of Bias Tool will be used to evaluate the risk of bias of the randomized controlled trials. Outcome index: The main efficacy indicators were based on the objective efficacy evaluation criteria of the World Health Organization antineoplastic drugs or the objective efficacy evaluation criteria of solid tumors established by RECIST. Secondary criteria Karnofsky performance scale (KPS) score, pain efficacy criteria, side effects of chemotherapy such as myelosuppression and gastrointestinal symptoms. Assessment of risk of bias and data synthesis will be conducted using Review Manager V5.3 software. RESULTS: This study will systematically evaluate the efficacy and safety of cinobufacini combined with vinorelbine and cisplatin in the treatment of stage III/IV non-small cell lung cancer. The results of this systematic review will be published in peer-reviewed scientific journals. ETHICS: The ethical approval is not required since systematic review is based on published studies. INPLASY REGISTRATION NUMBER: INPLASY202060091.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bufanolídeos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bufanolídeos/administração & dosagem , Bufanolídeos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/uso terapêutico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/efeitos adversos , Humanos , Neoplasias Pulmonares/patologia , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Vinorelbina/uso terapêutico
12.
PLoS One ; 15(8): e0237098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745124

RESUMO

The EGFR-targeting cancer therapies are commonly facing drug resistance, mostly due to mutations. Gene therapy with artificial microRNA targeting EGFR conserved sequence may avoid such problem. In this study, we constructed a recombinant adenovirus expressing EGFR-targeting artificial microRNA and active revCASP3 (Ad-EC), under the control of tumor-specific SLPI promoter, and evaluated its inhibitory effect on HEP-2 cancer cells both in vitro and in vivo. MTT assay showed that cell growth inhibition rate at 72h was 44.0% in Ad-EC group at MOI 50, while the rate was 7.7% in the control virus Ad-GFP group and 3.6% in Cetuximab (500 µg/ml) group respectively. Flow cytometry analysis revealed the late apoptotic cells rate was 36.1% in Ad-EC group, significantly higher than 6.5% of Ad-GFP group (p < 0.001). When Ad-EC (MOI 50) was combined with CDDP (0.25 µg/ml), late apoptotic cells rate increased to 61.2%, significantly higher than each monotherapy group (P < 0.001). The real-time xCELLigence system recorded an effective cell growth inhibition in Ad-EC and CDDP groups, and more enhanced effect in Ad-EC plus CDDP group. Western blot revealed that Ad-EC could inhibit the activation of AKT pathway and ERK1/2 pathway, while Cetuximab had the AKT pathway over-activated. In vivo experiments with HEP-2 xenograft in nude mice confirmed the tumor inhibition in Ad-EC, CDDP and Ad-EC plus CDDP groups compared with PBS group (P < 0.01). Collectively, these data support the effective inhibition of cancer cells by this novel gene therapy strategy.


Assuntos
Caspase 3/metabolismo , Receptores ErbB/genética , MicroRNAs/genética , Neoplasias Experimentais/terapia , Terapêutica com RNAi/métodos , Adenoviridae/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo
13.
Int J Nanomedicine ; 15: 5561-5571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801704

RESUMO

Purpose: Platinum/paclitaxel-based chemotherapy is the strategy for ovarian cancer, but chemoresistance, inherent or acquired, occurs and hinders therapy. Therefore, further understanding of the mechanisms of drug resistance and adoption of novel therapeutic strategies are urgently needed. Methods: In this study, we report that sphingosine-1-phosphate receptor-1 (S1PR1)-mediated chemoresistance for ovarian cancer. Then we developed nanoparticles with a hydrophilic PEG2000 chain and a hydrophobic DSPE and biodegradable CaP (calcium ions and phosphate ions) shell with pH sensitivity as a delivery system (CaP-NPs) to carry BAF312, a selective antagonist of S1PR1 (BAF312@CaP-NPs), to overcome the cisplatin (DDP) resistance of the ovarian cancer cell line SKOV3DR. Results: We found that S1PR1 affected acquired chemoresistance in ovarian cancer by increasing the phosphorylated-signal transduction and activators of transcription 3 (P-STAT3) level. The mean size and zeta potential of BAF312@CaP-NPs were 116 ± 4.341 nm and -9.67 ± 0.935 mV, respectively. The incorporation efficiency for BAF312 in the CaP-NPs was 76.1%. The small size of the nanoparticles elevated their enrichment in the tumor, and the degradable CaP shell with smart pH sensitivity of the BAF312@CaP-NPs ensured the release of BAF312 in the acidic tumor niche. BAF312@CaP-NPs caused substantial cytotoxicity in DDP-resistant ovarian cancer cells by downregulating S1PR1 and P-STAT3 levels. Conclusion: We found that BAF312@CaP-NPs act as an effective and selective delivery system for overcoming S1PR1-mediated chemoresistance in ovarian carcinoma by inhibiting S1PR1 and P-STAT3.


Assuntos
Azetidinas/administração & dosagem , Compostos de Benzil/administração & dosagem , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Nanopartículas/química , Neoplasias Ovarianas/tratamento farmacológico , Fator de Transcrição STAT3/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/genética , Azetidinas/farmacocinética , Compostos de Benzil/farmacocinética , Fosfatos de Cálcio/química , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Polietilenoglicóis/química , Fator de Transcrição STAT3/metabolismo , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Receptores de Esfingosina-1-Fosfato/metabolismo
14.
J Cancer Res Ther ; 16(3): 478-484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719254

RESUMO

Context: As the number of head-and-neck cancer (HNC) patients are high in our subcontinent, the study was designed to reduce the treatment time and increase efficacy. Aims: Comparative evaluation of the efficacy, toxicity, local control, and survival of concomitant boost radiotherapy (CBRT), CBRT with concurrent chemoradiation (CBRT + CCT) and conventionally fractionated radiotherapy with concomitant chemotherapy (CFRT + CCT) in locally advanced HNC (LAHNC). Materials and Methods: Patients with LAHNC were randomly assigned to 3-groups of 30-patients each. Group I (CBRT) received, 45 Gy/25#/5-weeks and 18 Gy/10# concomitant boost in the last 2-week of treatment, receiving a total dose of 63 Gy. Group II (CBRT + CCT) received CBRT with concomitant cisplatin 75 mg/m 2 on day 1, 17, and 34. Group III (CFRT + CCT) received 64 Gy/32#/6.2 weeks, concurrent with injection cisplatin 75 mg/m 2 on day 1, 22, and 42. Statistical Analysis Used: Stata 9.0 SPSS and Chi-square test were used for analysis and disease-free survival (DFS) rates were calculated using the Kaplan-Meier method. Results: The median follow-up period was 8.2 months. At last follow-up, locoregional control was 36%, 57%, and 40% and DFS was seen in 33%, 53%, and 40% of patients in Group I, II, and III, respectively. Grade-3 cutaneous reactions were significantly higher in Group-II as compared to that of Group-III (P = 0.033) and Group-I (P = 0.715). Conclusion: All three groups have similar response rates and DFS with manageable toxicity.


Assuntos
Carcinoma de Células Escamosas/mortalidade , Quimiorradioterapia/mortalidade , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segurança do Paciente , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento
15.
Yonsei Med J ; 61(7): 587-596, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32608202

RESUMO

PURPOSE: The current study aimed to investigate the synergistic antitumor effect of combined treatment with 17-DMAG (HSP90 inhibitor) and NVP-BEZ235 (PI3K/mTOR dual inhibitor) on cisplatin-resistant human bladder cancer cells. MATERIALS AND METHODS: Human bladder cancer cells exhibiting cisplatin resistance (T24R2) were exposed to escalating doses of 17-DMAG (2.5-20 nM) with or without NVP-BEZ236 (0.5-4 µM) in combination with cisplatin. Antitumor effects were assessed by CCK-8 analysis. Based on the dose-response study, synergistic interactions between the two regimens were evaluated using clonogenic assay and combination index values. Flow cytometry and Western blot were conducted to analyze mechanisms of synergism. RESULTS: Dose- and time-dependent antitumor effects for 17-DMAG were observed in both cisplatin-sensitive (T24) and cisplatin-resistant cells (T24R2). The antitumor effect of NVP-BEZ235, however, was found to be self-limiting. The combination of 17-DMAG and NVP-BEZ235 in a 1:200 fixed ratio showed a significant antitumor effect in cisplatin-resistant bladder cancer cells over a wide dose range, and clonogenic assay showed compatible results with synergy tests. Three-dimensional analysis revealed strong synergy between the two drugs with a synergy volume of 201.84 µM/mL²%. The combination therapy resulted in G1-phase cell cycle arrest and caspase-dependent apoptosis confirmed by the Western blot. CONCLUSION: HSP90 inhibitor monotherapy and in combination with the PI3K/mTOR survival pathway inhibitor NVP-BEZ235 shows a synergistic antitumor effect in cisplatin-resistant bladder cancers, eliciting cell cycle arrest at the G1 phase and induction of caspase-dependent apoptotic pathway.


Assuntos
Antineoplásicos/uso terapêutico , Benzoquinonas/uso terapêutico , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Lactamas Macrocíclicas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Benzoquinonas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cisplatino/farmacologia , Dano ao DNA/efeitos dos fármacos , Humanos , Imidazóis , Lactamas Macrocíclicas/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Quinolinas , Serina-Treonina Quinases TOR/metabolismo
16.
Anticancer Res ; 40(8): 4773-4777, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727804

RESUMO

BACKGROUND/AIM: Recent studies have demonstrated the efficacy of salvage surgery following downstaging of hepatocellular carcinoma (HCC). The aim was to assess the outcomes of salvage surgery after successful downstaging using hepatic arterial infusion chemotherapy (HAIC). PATIENTS AND METHODS: Patients whose diagnosis was unresectable locally advanced HCC and who were resected after conversion to a resectable status by HAIC were included. The overall survival (OS) rate, and disease-free survival (DFS) rate were analyzed by stratifying patients into those with Vp3/4, Vv2/3, and those without major vascular invasion (MVI). RESULTS: Eighteen patients were censored. Among them, six patients had Vp3/4, four patients had Vv2/3, and eight patients had no MVI. The 5-year OS rates of patients with Vp3/4 and those without MVI were 83% and 73%, respectively, whereas those with Vv2/3 had 0% (p<0.001). CONCLUSION: Salvage surgery has the potential to provide excellent outcomes in resectable HCC patients, except for those with Vv2/3.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Hepatectomia/métodos , Humanos , Infusões Intra-Arteriais/métodos , Masculino , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Taxa de Sobrevida , Resultado do Tratamento
17.
Anticancer Res ; 40(7): 4011-4015, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620645

RESUMO

BACKGROUND/AIM: The aim of this monocentric study was to evaluate the efficacy and tolerability of a polychemotherapy regimen based on gemcitabine, docetaxel, capecitabine, cisplatin (PDGX) as second-line for advanced pancreatic cancer after FOLFIRINOX. PATIENTS AND METHODS: Patients received FOLFIRINOX as first-line regimen were retrospectively identified between January 2016 and January 2019. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were treated in our center by PDGX. RESULTS: During this period, 18 patients received PDGX regimen as second-line therapy. Main grade 3 toxicities were hematologic, which required dose adaptation in 14/18 patients. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2,91 and 5,3 months, respectively. Total OS from the initiation of first-line was and 11,9 months. CONCLUSION: Second-line PDGX regimen after FOLFIRINOX failure is feasible, with notable toxicity profile and is associated with poor clinical outcomes.


Assuntos
Adenocarcinoma/tratamento farmacológico , Capecitabina/uso terapêutico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Docetaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/efeitos adversos , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Docetaxel/efeitos adversos , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Resultado do Tratamento
18.
Anticancer Res ; 40(7): 4183-4190, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32620668

RESUMO

BACKGROUND/AIM: The present study aimed to analyze the treatment outcome after definitive radiotherapy (dRT) using volumetric-modulated arc therapy (VMAT) in patients with hypopharyngeal cancer (HPC), including an examination of late toxicities. PATIENTS AND METHODS: A total of 62 patients with HPC, who underwent dRT using VMAT, were analyzed. Overall survival (OS), progression-free survival (PFS), laryngoesophageal dysfunction-free survival (LEDFS), and locoregional control (LRC) were calculated. RESULTS: The median follow-up period was 49 months. The 3- and 5-year OS, PFS, LEDFS, and LRC rates were 77% and 60%, 61% and 56%, 66% and 53%, and both 79%, respectively. Regarding late toxicities, 11 (17.7%) patients developed grade ≥2 late toxicity. Grade 3 dysphagia was observed in 4 (6.5%) patients, and grade 2 xerostomia in 6 (9.7%). CONCLUSION: VMAT was an effective treatment for HPC, with a low incidence of late toxicities.


Assuntos
Neoplasias Hipofaríngeas/radioterapia , Radioterapia de Intensidade Modulada , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Feminino , Humanos , Neoplasias Hipofaríngeas/tratamento farmacológico , Neoplasias Hipofaríngeas/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada/efeitos adversos
19.
Bull Cancer ; 107(5S): eS8-eS15, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32620213

RESUMO

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy (NAC) is the standard of care in localized muscle-invasive bladder cancer (MIBC). However, 60-70% of patients have residual tumor after NAC. Based on the overall response rate observed in the metastatic setting, ddMVAC is the most commonly used NAC regimen in Europe. The emergence of immune checkpoint inhibitor (ICI) in the metastatic setting raises the question if the combination of chemo plus ICI could increase the pCR rate. METHODS/DESIGN: NEMIO is a French open-label randomized phase I/II trial assessing in the neoadjuvant setting the combination of ddMVAC plus durvalumab alone or with tremelimumab: 4 cycles of ddMVAC/2 weeks + 2 cycles of Durvalumab +/- Tremelimumab/4 weeks. Cystectomy is performed 4-8 weeks after the last dose of ddMVAC. Six pts will be included in each arm in a safety run-in cohort to evaluate the toxicity rate. Each arm will be expanded to a maximum of 60 pts. The primary endpoint of the safety run-in phase will be the rate of grade 3/4 treatment-related adverse events G3/4 TRAE. The primary endpoint of the phase II will be the pathological response rate and G 3/4 TRAE. Exploratory endpoints will include biomarkers of response and resistance to the combo. A total of 120 patients will be included in 15 French centers and we expect the recruitment to be completed in 2021. DISCUSSION: NEMIO trial will assess for the first time the tolerance and the efficacy of ddMVAC regimen associated with checkpoints inhibitors as neoadjuvant treatment in localized MIBC. NCT number: NCT03549715. Registered on June 8, 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células de Transição/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Neoplasias da Bexiga Urinária/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células de Transição/patologia , Cisplatino/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Metotrexato/uso terapêutico , Terapia Neoadjuvante , Invasividade Neoplásica , Resultado do Tratamento , Neoplasias da Bexiga Urinária/patologia , Vimblastina/uso terapêutico
20.
Hinyokika Kiyo ; 66(6): 171-176, 2020 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-32605355

RESUMO

A 49-year-old male visited our department of gastroenterology with chief complaints of blackish feces and ill complexion in February 1997. Computed tomography (CT) revealed a right retroperitoneal tumor, which was removed the same month. Histopathological examination showed teratoma and yolk sac tumor. He was diagnosed with primary retroperitoneal extragonadal germ cell tumor, and received three cycles of chemotherapy (bleomycin/etoposide/cisplatin ; BEP) starting in March 1997. Periodic imaging and determination of tumor markers (α fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase) showed no recurrence or metastasis for five years after treatment. After his visit in April 2002 he stopped visiting our outpatient ward. In November 2017, the patient visited our department with chief complaints of indolent right scrotum enlargement and a right inguinal mass. Past history showed that he had undergone hydrocele of the right testicle in August 1999. Contrast enhanced CT showed a 35-mm contrast effect with uneven contents in the right testis, and enlarged nodes that were suspicious of metastases in the right inguinal and right external iliac lymph nodes. All tumor markers were within the normal ranges. He underwent right high orchiectomy and resection of the right inguinal lymph nodes in the same month. Histopathological findings revealed seminoma (pT1, pN2, M0, S0, and clinical Stage IIA). He received postoperative chemotherapy starting in January 2018 ; one cycle of BEP therapy and three cycles of etoposide and cisplatin (EP) therapy. Post-chemotherapeutic CT confirmed clinical complete response at the right external iliac lymph nodes, and this response was confirmed 12 months later. Neither recurrence nor metastasis has occurred so far.


Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Retroperitoneais , Neoplasias Testiculares/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica , Bleomicina , Cisplatino/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Orquiectomia
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