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1.
J Nanobiotechnology ; 18(1): 18, 2020 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-31964403

RESUMEN

BACKGROUND: Although accumulating evidence suggests that the crosstalk between malignant cells and cancer-associated fibroblasts (CAFs) actively contributes to tumour growth and metastatic dissemination, therapeutic strategies targeting tumour stroma are still not common in the clinical practice. Metal-based nanomaterials have been shown to exert excellent cytotoxic and anti-cancerous activities, however, their effects on the reactive stroma have never been investigated in details. Thus, using feasible in vitro and in vivo systems to model tumour microenvironment, we tested whether the presence of gold, silver or gold-core silver-shell nanoparticles exerts anti-tumour and metastasis suppressing activities by influencing the tumour-supporting activity of stromal fibroblasts. RESULTS: We found that the presence of gold-core silver-shell hybrid nanomaterials in the tumour microenvironment attenuated the tumour cell-promoting behaviour of CAFs, and this phenomenon led to a prominent attenuation of metastatic dissemination in vivo as well. Mechanistically, transcriptome analysis on tumour-promoting CAFs revealed that silver-based nanomaterials trigger expressional changes in genes related to cancer invasion and tumour metastasis. CONCLUSIONS: Here we report that metal nanoparticles can influence the cancer-promoting activity of tumour stroma by affecting the gene expressional and secretory profiles of stromal fibroblasts and thereby altering their intrinsic crosstalk with malignant cells. This potential of metal nanomaterials should be exploited in multimodal treatment approaches and translated into improved therapeutic outcomes.


Asunto(s)
Antineoplásicos/química , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Nanopartículas del Metal/química , Metástasis de la Neoplasia/tratamiento farmacológico , Aleaciones/química , Animales , Antineoplásicos/uso terapéutico , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular , Progresión de la Enfermedad , Doxorrubicina/química , Doxorrubicina/uso terapéutico , Femenino , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica , Oro/química , Humanos , Nanopartículas del Metal/uso terapéutico , Ratones Endogámicos BALB C , Metástasis de la Neoplasia/patología , Trasplante de Neoplasias , Plata/química , Microambiente Tumoral/efectos de los fármacos
2.
Medicine (Baltimore) ; 98(44): e17769, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31689840

RESUMEN

RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Melanoma/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Cutáneas/tratamiento farmacológico , Anciano de 80 o más Años , Femenino , Humanos , Melanoma/genética , Melanoma/patología , Mutación , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Resultado del Tratamiento
3.
J Cancer Res Clin Oncol ; 145(12): 3037-3045, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31646373

RESUMEN

INTRODUCTION: Because spermatocytic tumors of the testis are rare, only limited evidence exists regarding the malignant potential and the optimal management of localized and metastatic disease. MATERIALS AND METHODS: We performed a systematic review through MEDLINE, EMBASE, Scopus, Cochrane Database of Systematic Reviews and Web of Science to identify reports including patients with testicular spermatocytic tumors. RESULTS: From originally 7863 studies, we extracted data of 146 patients of which 99% were treated with radical orchiectomy. Metastases in patients with initially localised disease were diagnosed in 7% of patients and detected after a median follow-up of 5.5 months (range 2-21 months). Patients with aggressive histology (sarcoma or anaplastic subtype) were more likely to have metastatic disease (6/124 (5%) vs 9/22 (41%), p < 0.001). Patients with metastatic disease had larger primary tumors (92.5 vs 67.5 mm, p = 0.05). Life expectancy in patients with metastatic disease ranged from 1 to 25 months. CONCLUSION: The published literature does neither support the use of testis sparing surgery nor adjuvant therapy. Patients with aggressive variants or larger tumors were more likely to have metastases and develop recurrences within the first few years. Patients with metastatic disease have a limited life expectancy and metastatic spermatocytic tumors are not as responsive to chemotherapy as germ cell cancers.


Asunto(s)
Metástasis de la Neoplasia/tratamiento farmacológico , Espermatocitos/efectos de los fármacos , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/cirugía , Testículo/efectos de los fármacos , Testículo/cirugía , Humanos , Masculino , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Múltiples/cirugía , Resultado del Tratamiento
4.
Anticancer Res ; 39(10): 5339-5344, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31570427

RESUMEN

BACKGROUND/AIM: Gemcitabine is standard first-line treatment for patients with advanced pancreatic cancer, however the efficacy is limited. Although acquired drug resistance and side-effects are known to limit efficacy, opposite effects of a drug, which enhance the malignancy of treated cancer, have been observed but are not well understood. The aim of the present study was to determine whether gemcitabine has such opposite effects on the BxPC-3 human pancreatic cancer cell line expressing green fluorescent protein (BxPC-3-GFP) in an orthotopic mouse model. MATERIALS AND METHODS: BxPC-3-GFP tumors grown subcutaneously in nude mice were harvested. Tumor fragments were orthotopically implanted in the tail of the pancreas of nude mice using the technique of surgical orthotopic implantation. The BxPC-3-GFP orthotopic models were divided randomly into three groups: Group 1: untreated control; Group 2: low-dose gemcitabine (weekly intraperitoneal injection at 25 mg/kg for 6 weeks); Group 3: high-dose gemcitabine (weekly intraperitoneal injection at 125 mg/kg for 6 weeks). Each group comprised eight mice. Tumor size, fluorescent area of metastases, and body weight were measured. RESULTS: Low- and high-dose gemcitabine inhibited primary tumor growth in a dose-dependent manner, and to the greatest extent by high-dose gemcitabine compared to the untreated control (p=0.0134). In contrast, the extent of metastasis on the peritoneum was significantly increased by low-dose gemcitabine compared to the untreated control (p=0.0112). The extent of metastasis showed no significant difference between the untreated control and mice treated with high-dose gemcitabine. Body weight of the treated mice was not significantly different from that of the untreated mice. CONCLUSION: The use of very bright GFP expressing of BxPC-3 cells and the orthotopic model demonstrated an unexpected increase in metastasis by low-dose gemcitabine. Future experiments will investigate the mechanism of this phenomenon.


Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Desoxicitidina/análogos & derivados , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Desoxicitidina/administración & dosificación , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Ratones , Ratones Desnudos , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Neoplasias Pancreáticas/metabolismo
5.
Medicine (Baltimore) ; 98(35): e16919, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31464927

RESUMEN

Antiangiogenic therapy has shown clinical benefit in metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of apatinib in patients who failed standard treatment and to explore potential factors related to its efficacy.A total of 47 patients were enrolled in this retrospective study. Patients who received apatinib therapy after failure of standard therapy from December 2014 and February 2018 were included. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-related adverse events were recorded and evaluated.The median PFS was 3.717 months (95% confidence interval [CI], 3.198-4.235), and the median OS was 7.335 months (95% CI, 6.738-7.932). The disease control rate was 72.34%, and the ORR was 8.51%. The most common grade 3 to 4 adverse reactions were hypertension, proteinuria, hand-foot syndrome, and diarrhea. Multivariate analysis indicated previous antiangiogenic therapy and baseline elevated neutrophil-to-lymphocyte ratio (NLR) as independent prognostic factors.Apatinib might be a reasonable treatment option with a controlled safety profile for patients with mCRC who have failed standard therapy. Patients who previously received antiangiogenic therapy and who have baseline elevated NLR are more likely to benefit from apatinib.


Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Piridinas/administración & dosificación , Administración Oral , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Masculino , Análisis Multivariante , Pronóstico , Inhibidores de Proteínas Quinasas/efectos adversos , Piridinas/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento
6.
Biomed Pharmacother ; 117: 109173, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31387176

RESUMEN

Due to the success of chimeric antigen receptors (CARs) in hematological tumors, CARs are also being studied to treat solid tumors. Improving the ability of CARs to penetrate solid tumor tissues is one of the biggest challenges. As the most malignant cancer of the female reproductive system, the survival rate of ovarian cancer has not been significantly improved by traditional therapy methods; therefore, it is necessary to develop new therapeutic targets and new immunotherapy methods for ovarian cancer. UPAR is a glysocylphosphatidylinositol (GPI) anchoring membrane protein that is differentially expressed in normal tissues and ovarian cancer tissues. It has been shown that uPAR up-regulation promotes tumor development, proliferation, invasion, and metastasis, and uPAR is also up-regulated in tumor matrix components. In our study, CARs were designed using the natural ligand binding fragment of uPAR for ovarian cancer.


Asunto(s)
Proteínas de la Membrana/metabolismo , Neoplasias Ováricas/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Adulto , Anciano , Antineoplásicos/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Inmunoterapia/métodos , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/terapia , Regulación hacia Arriba/efectos de los fármacos , Adulto Joven
7.
Eur J Dermatol ; 29(3): 315-321, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-31389790

RESUMEN

BACKGROUND: Anti-PD1 antibodies have revolutionized the management of patients with advanced melanoma. In clinical trials, the efficacy of nivolumab is being tested in selected populations of patients. OBJECTIVES: The aim of this study was to analyse the efficacy and safety of nivolumab in patients with advanced melanoma under real-life conditions. MATERIALS AND METHODS: A retrospective, observational study was conducted in patients treated with nivolumab for advanced melanoma included in the RIC-Mel network. Overall survival and progression-free survival (PFS) were assessed using the Kaplan-Meier method. RESULTS: Eighty-seven patients were included with a median follow-up of 31 months. The median PFS was 13 months (95% CI: 7-28). Objective response rate was 33.3%. Among patients achieving a complete response, the response was maintained after treatment discontinuation in 80.7% of patients for a median duration of 21.7 months. Multivariate analysis showed that an increased lactate dehydrogenase level (p = 0.03; HR: 1.21; 95% CI: 1.02-1.45) and brain metastases (p = 0.024; HR: 2.78; 95% CI: 1.14-6.77) were correlated with a decrease in PFS. Grade 3 or 4 adverse events were found in 10.3% of patients. CONCLUSION: Based on our study, the efficacy and safety of nivolumab in patients with advanced melanoma are consistent with previously published data.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/mortalidad , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/patología , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica/patología , Metástasis de la Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Nivolumab/efectos adversos , Seguridad del Paciente , Estudios Retrospectivos , Medición de Riesgo , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Resultado del Tratamiento
8.
BMC Cancer ; 19(1): 847, 2019 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-31462288

RESUMEN

BACKGROUND: Studies over the past 10 years strongly support an association between skeletal muscle mass (SMM) depletion and outcome in metastatic colorectal cancer (mCRC). Factors influencing SMM changes over time are, however, poorly studied. We analyzed the impact of SMM on overall survival and chemotherapy toxicities in mCRC patients treated with first-line chemotherapy. Changes in weight and body composition were evaluated during follow-up. METHODS: Patients enrolled in the randomized phase II ACCORD trial comparing two chemotherapy regimens were screened. Body composition parameters (SMM, adipose tissue) were assessed prospectively with computed tomography (CT) imaging, and toxicities were recorded. Mixed models were used to assess weight and BC changes during 4 months of treatment follow-up. RESULTS: Among 145 patients included in ACCORD, 76 had available baseline CT scans and were included in the current study. Mean age was 60.6 ± 10.0 years, 50% were women, 82% had colon cancer, and 62% had two or more metastatic sites. At baseline, 49% had lost at least 5% of their initial weight, including 26% who had lost more than 10%; 53% had SMM depletion. In this homogenous cohort, there were no statistically significant associations between SMM depletion and overall survival, progression-free survival or chemotherapy toxicity. There were no decreases in weight or SMM during follow-up. Weight and SMM changes were not influenced by diarrhea either grade 3-4 or any grade (reported in 74% of patients). For patients with weight loss ≥10% at baseline, SMM increased significantly after 4 months of follow-up and after disease stabilization following chemotherapy (P = 0.008). CONCLUSIONS: In a homogenous mCRC cohort, SMM depletion was not associated with survival or chemotherapy toxicity. Despite most patient experiencing diarrhea, no changes in weight or SMM were found during 4 months of follow-up. However, hypotheses deriving from our exploratory study have to be tested in further larger sample size studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT00423696 (2011).


Asunto(s)
Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Músculo Esquelético/diagnóstico por imagen , Metástasis de la Neoplasia/tratamiento farmacológico , Anciano , Antineoplásicos/farmacología , Composición Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Estudios Prospectivos , Análisis de Supervivencia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
9.
N Engl J Med ; 381(4): 338-348, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31340094

RESUMEN

BACKGROUND: Alterations in the gene encoding fibroblast growth factor receptor (FGFR) are common in urothelial carcinoma and may be associated with lower sensitivity to immune interventions. Erdafitinib, a tyrosine kinase inhibitor of FGFR1-4, has shown antitumor activity in preclinical models and in a phase 1 study involving patients with FGFR alterations. METHODS: In this open-label, phase 2 study, we enrolled patients who had locally advanced and unresectable or metastatic urothelial carcinoma with prespecified FGFR alterations. All the patients had a history of disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy. Prior immunotherapy was allowed. We initially randomly assigned the patients to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen (selected-regimen group), with provision for a pharmacodynamically guided dose escalation to 9 mg. The primary end point was the objective response rate. Key secondary end points included progression-free survival, duration of response, and overall survival. RESULTS: A total of 99 patients in the selected-regimen group received a median of five cycles of erdafitinib. Of these patients, 43% had received at least two previous courses of treatment, 79% had visceral metastases, and 53% had a creatinine clearance of less than 60 ml per minute. The rate of confirmed response to erdafitinib therapy was 40% (3% with a complete response and 37% with a partial response). Among the 22 patients who had undergone previous immunotherapy, the confirmed response rate was 59%. The median duration of progression-free survival was 5.5 months, and the median duration of overall survival was 13.8 months. Treatment-related adverse events of grade 3 or higher, which were managed mainly by dose adjustments, were reported in 46% of the patients; 13% of the patients discontinued treatment because of adverse events. There were no treatment-related deaths. CONCLUSIONS: The use of erdafitinib was associated with an objective tumor response in 40% of previously treated patients who had locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations. Treatment-related grade 3 or higher adverse events were reported in nearly half the patients. (Funded by Janssen Research and Development; BLC2001 ClinicalTrials.gov number, NCT02365597.).


Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirazoles/administración & dosificación , Quinoxalinas/administración & dosificación , Receptores de Factores de Crecimiento de Fibroblastos/antagonistas & inhibidores , Receptores de Factores de Crecimiento de Fibroblastos/genética , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/tratamiento farmacológico , Supervivencia sin Progresión , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirazoles/efectos adversos , Quinoxalinas/efectos adversos , Resultado del Tratamiento , Neoplasias Urológicas/genética , Neoplasias Urológicas/patología , Urotelio
10.
Ceska Slov Farm ; 68(2): 43-47, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31331174

RESUMEN

Targeted therapy is a significant benefit in the treatment of cancer patients. Bevacizumab improves overall survival (OS) and progression free survival (PFS) in the treatment of metastatic colorectal cancer (mCRC). The clinical effectiveness of bevacizumab is similar to its efficacy in randomised controlled trials. However, the costs of bevacizumab treatment as well as other agents of targeted treatment are discussed between the health care payers, the regulatory authorities and the members of professional societies. Biomarkers of bevacizumab treatment helpful in the selection of eligible groups of patients are still missing. This review focuses on current bevacizumab therapy of mCRC from the pharmacoeconomic perspective. The cost per a 14-day bevacizumab treatment cycle is approximately 31,000 CZK in the Czech Republic. External published pharmacoeconomics analyses have no clear conclusions. Their results are usually expressed as the cost per QALY gained in comparison with a comparator. They differ according to the economic situation of the particular countries. The pharmacoeconomic results have to be confirmed in the real clinical practice, and then the decision should be reassessed by using the uniform methodology, e.g. the Health Technology Assessment (HTA).


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Anticuerpos Monoclonales , Neoplasias Colorrectales/patología , Análisis Costo-Beneficio , República Checa , Humanos , Metástasis de la Neoplasia/tratamiento farmacológico , Años de Vida Ajustados por Calidad de Vida
11.
Acta Gastroenterol Belg ; 82(2): 322-325, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31314196

RESUMEN

Colorectal cancer is one of the most frequently diagnosed malignancies worldwide. One of the most important developments in the management of metastatic colorectal cancer is targeted therapy. Bevacizumab, a monoclonal antibody inhibiting VEGF induced angiogenesis, has been accepted as safe and efficient in the treatment of metastatic colorectal cancer for more than a decade. Addition of bevacizumab to fluorouracil-based chemotherapy is also associated with severe adverse events. We present a case of bevacizumab-induced bowel ischaemia associated with gastrointestinal haemorrhage.


Asunto(s)
Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Bevacizumab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Metástasis de la Neoplasia/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/uso terapéutico , Hemorragia Gastrointestinal , Humanos
12.
BMC Cancer ; 19(1): 687, 2019 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-31307428

RESUMEN

BACKGROUND: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen. METHODS: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8+ T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). RESULTS: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8+ cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4+ subset. 2) A low proportion of circulating Tregs among CD4+ cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high. CONCLUSIONS: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Linfocitos T Citotóxicos/metabolismo , Linfocitos T Reguladores/metabolismo , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Adenocarcinoma/sangre , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Bevacizumab/administración & dosificación , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Estudios de Seguimiento , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos , Proteínas Proto-Oncogénicas p21(ras)/análisis , Tasa de Supervivencia
13.
BMC Cancer ; 19(1): 688, 2019 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-31307432

RESUMEN

BACKGROUND: The differences in progression-free survival (PFS) and cancer-specific survival (CSS) of metastatic renal cell carcinoma (mRCC) patients according to treatment, type of metastasis, and Heng criteria risk are unclear. In this study, we compared survival according to various such parameters. METHODS: Between 2000 to 2014, 214 mRCC patients, of whom 171 (79.9%) were intermediate-risk and 43 (20.1%) were poor-risk, were retrospectively selected; 126 (58.9%) patients were treated with immunotherapy (IT) and 88 (41.1%) with targeted therapy (TT). Moreover, 144 patients had synchronous mRCCs (67.3%, SM) and 70 had metachronous mRCCs (32.7%, MM). The Kaplan-Meier method and log-rank test were used to compare progression-free survival (PFS) and CSS. RESULTS: During a median 4.2 (1.0-70.4) months of systemic treatment and 98.3 (4.8-147.6) months of follow-up, the median PFS and CSS were 4.7 (95% confidence interval [CI]: 3.8-5.5) and 13.8 (95% CI, 9.8-18.3) months, respectively. The PFS and CSS were significantly better in the MM (5.9 and 21.3 months) and intermediate-risk groups (5.2 and 18.3 months) than those in the SM (4.4 and 9.6 months) and poor-risk groups (2.7 and 5.8 months), respectively (p < 0.05). Further stratification showed that TT produced significantly better PFS than IT in intermediate-risk patients with SM and a treatment-free interval (TFI) < 1 year, and in those with MM with a TFI ≥1 year (p < 0.05). There were no differences in survival outcomes according to various other subgroup stratifications (p > 0.05). CONCLUSION: Dividing patients into specific subcategories helps to better predict therapeutic outcomes.


Asunto(s)
Carcinoma de Células Renales/patología , Inmunoterapia , Neoplasias Renales/patología , Terapia Molecular Dirigida , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Primarias Múltiples/tratamiento farmacológico , Neoplasias Primarias Secundarias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Estudios Retrospectivos
14.
Biochim Biophys Acta Gene Regul Mech ; 1862(8): 822-833, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31167152

RESUMEN

Muscle invasive bladder cancer (MIBC) is characterized by a poor overall survival rate in patients. Therefore, innovation and evaluation of idea anti-cancer compounds is of importance for reducing the mortality of MIBCs. The chemotherapeutic activity of ChlA-F, a novel C8 fluoride derivative of cheliensisin A with potent anti-neoplastic properties, was barely investigated. We reported here that ChlA-F treatment significantly induced miR-494 expression and suppressed cell invasion in human MIBC cells. Our results indicated that miR-494 was downregulated in M1 metastatic BC patients in comparison to non-metastatic (M0) BC patients, and such downregulation was also well correlated with over survival rate for MIBC patients. Mechanistically, ChlA-F-induced upregulation of miR-494 was due to a HuR-mediated increase in JunB mRNA stabilization and protein expression, which led to an increase in miR-494 transcription via directly binding to the miR-494 promoter region, while the upregulated miR-494 was able to bind the 3'-UTR region of c-Myc mRNA, resulting in decreased c-Myc mRNA stability and protein expression and further reducing the transcription of c-Myc-regulated MMP-2 and ultimately inhibiting BC invasion. Our results provide the first evidence showing that miR-494 downregulation was closely associated with BC metastatic status and overall BC survival, and ChlA-F was able to reverse the level of miR-494 with a profound inhibition of human BC invasion in human invasive BC cells. Our studies also reveal that ChlA-F is a promising therapeutic compound for BCs and miR-494 could also serve as a promising therapeutic target for the treatment of MIBC patients.


Asunto(s)
Proteína 1 Similar a ELAV/metabolismo , Lactonas/farmacología , MicroARNs/genética , Metástasis de la Neoplasia/genética , Factores de Transcripción/metabolismo , Neoplasias de la Vejiga Urinaria/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Invasividad Neoplásica , Metástasis de la Neoplasia/tratamiento farmacológico , Pronóstico , Proteínas Proto-Oncogénicas c-myc/química , Proteínas Proto-Oncogénicas c-myc/genética , Estabilidad del ARN/efectos de los fármacos , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo
15.
N Engl J Med ; 381(4): 317-327, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31157963

RESUMEN

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Quimioterapia de Mantención , Neoplasias Pancreáticas/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Estimación de Kaplan-Meier , Quimioterapia de Mantención/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Supervivencia sin Progresión
16.
Cancer Sci ; 110(8): 2493-2506, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31215139

RESUMEN

Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.


Asunto(s)
Antineoplásicos/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Inhibidores de Histona Desacetilasas/farmacología , Proteínas Nucleares/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular , División Celular/efectos de los fármacos , Línea Celular , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Fase G2/efectos de los fármacos , Neoplasias de la Vesícula Biliar/patología , Células HEK293 , Humanos , Masculino , Ratones , Ratones Desnudos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/patología , Vorinostat/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
17.
Int J Oncol ; 54(6): 2250-2256, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31081056

RESUMEN

Aberrant expression of cell division cycle 20 (CDC20) is associated with malignant progression and poor prognosis in various types of cancer. The development of specific CDC20 inhibitors may be a novel strategy for the treatment of cancer with elevated expression of CDC20. The aim of the current study was to elucidate the role of CDC20 in cancer cell invasiveness and to identify novel natural inhibitors of CDC20. The authors found that CDC20 knockdown inhibited the migration of chemoresistant PANC­1 pancreatic cancer cells and the metastatic MDA­MB­231 breast cancer cell line. By contrast, the overexpression of CDC20 by plasmid transfection promoted the metastasizing capacities of the PANC­1 cells and MCF­7 breast cancer cells. It was also identified that a triterpene mixture extracted from the mushroom Poria cocos (PTE), purified triterpenes dehydropachymic acid, and polyporenic acid C (PPAC) downregulated the expression of CDC20 in PANC­1 cells dose­dependently. Migration was also suppressed by PTE and PPAC in a dose­dependent manner, which was consistent with expectations. Taken together, the present study is the first, to the best of our knowledge, to demonstrate that CDC20 serves an important role in cancer metastasis and that triterpenes from P. cocos inhibit the migration of pancreatic cancer cells associated with CDC20. Further investigations are in progress to investigate the specific mechanism associated with CDC20 and these triterpenes, which may have future potential use as natural agents in the treatment of metastatic cancer.


Asunto(s)
Agaricales/química , Neoplasias de la Mama/genética , Proteínas Cdc20/genética , Metástasis de la Neoplasia/genética , Neoplasias Pancreáticas/genética , Triterpenos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Proteínas Cdc20/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Células MCF-7 , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plásmidos/genética , Triterpenos/química
18.
Int J Mol Sci ; 20(10)2019 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-31100782

RESUMEN

Increased health awareness among the public has highlighted the health benefits of dietary supplements including flavonoids. As flavonoids target several critical factors to exert a variety of biological effects, studies to identify their target-specific effects have been conducted. Herein, we discuss the basic structures of flavonoids and their anticancer activities in relation to the specific biological targets acted upon by these flavonoids. Flavonoids target several signaling pathways involved in apoptosis, cell cycle arrest, mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/AKT kinase, and metastasis. Polo-like kinase 1 (PLK1) has been recognized as a valuable target in cancer treatment due to the prognostic implication of PLK1 in cancer patients and its clinical relevance between the overexpression of PLK1 and the reduced survival rates of several carcinoma patients. Recent studies suggest that several flavonoids, including genistein directly inhibit PLK1 inhibitory activity. Later, we focus on the anticancer effects of genistein through inhibition of PLK1.


Asunto(s)
Antineoplásicos/farmacología , Flavonoides/química , Flavonoides/farmacología , Genisteína/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/metabolismo , Flavanonas/farmacología , Humanos , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Metástasis de la Neoplasia/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos
19.
Medicina (Kaunas) ; 55(5)2019 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-31100964

RESUMEN

Background and Objective: Radium-223 dichloride (Xofigo®) is a calcium mimetic agent approved for the treatment of castration-resistant prostate cancer patients with symptomatic bone metastases and no known visceral metastatic disease. This targeted, α-particle-emitting therapy has demonstrated significant survival benefit accompanied by a favorable safety profile. Nevertheless, recent evidence suggests that its combined use with abiraterone and prednisone/prednisolone may be associated with increased risk of death and fractures. While the precise pathophysiologic mechanisms of these events are not yet clear, collecting evidence from more clinical trials and translational studies is necessary. The aim of our present study is to assess whether accessible sources of patient outcome data can help gain additional clinical insights to radium-223 dichloride's safety profile. Materials and Methods: We performed a retrospective analysis of cases extracted from the FDA Adverse Event Reporting System and characterized side effect occurrence by using reporting ratios. Results: A total of ~1500 prostate cancer patients treated with radium-223 dichloride was identified, and side effects reported with the use of radium-223 dichloride alone or in combination with other therapeutic agents were extracted. Our analysis demonstrates that radium-223 dichloride may often come with hematological-related reactions, and that, when administered together with other drugs, its safety profile may differ. Conclusions: While more prospective studies are needed to fully characterize the toxicological profile of radium-223 dichloride, the present work constitutes perhaps the first effort to examine its safety when administered alone and in combination with other agents based on computational evidence from public real-world post marketing data.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias de la Próstata/tratamiento farmacológico , Radio (Elemento)/uso terapéutico , Adulto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Masculino , Metástasis de la Neoplasia/fisiopatología , Estudios Prospectivos , Neoplasias de la Próstata/complicaciones , Neoplasias de la Próstata/fisiopatología , Radio (Elemento)/farmacología , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento
20.
Urologe A ; 58(10): 1185-1197, 2019 Oct.
Artículo en Alemán | MEDLINE | ID: mdl-31127324

RESUMEN

BACKGROUND: Androgen deprivation therapy (ADT) alone has long been the standard of care in the treatment of metastatic prostate cancer (mCSPC). A paradigm shift in the treatment of patients with mCSPC has now been initiated by the results of three major phase 3 clinical trials (CHAARTED, STAMPEDE, LATITUDE): They demonstrated a significant advantage of ADT in combination with docetaxel or abiraterone/prednisone over ADT alone. OBJECTIVES: This review presents the current evidence for the use of docetaxel or abiraterone/prednisone in combination with ADT and discusses-in the absence of directly comparing studies-which patients may have an advantage of ADT plus abiraterone/prednisone over ADT plus docetaxel or vice versa. METHODS: A systematic review based on bibliographic literature search was conducted. RESULTS: Both the combinations of ADT with docetaxel and with abiraterone/prednisone represent a major advance in the treatment of patients with mCSPC, in particular of patients with multiple metastases. Compared to chemotherapy, the use of abiraterone in addition to ADT avoids (rare) neutropenic complications and treatment-associated deaths. Long-term oral treatment with abiraterone/prednisone as a complementary therapy to ADT replaces short-term intravenous treatment (docetaxel). CONCLUSION: In patients with mCSPC, ADT plus docetaxel or ADT plus abiraterone/prednisone is recommended. In particular in patients with pre-existing cardiovascular disease, ADT should be considered with a GnRH (gonadotropin-releasing hormone) antagonist to reduce the risk of cardiotoxic side effects.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Androstenos/uso terapéutico , Antineoplásicos/uso terapéutico , Docetaxel/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Humanos , Masculino , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias de la Próstata/patología , Resultado del Tratamiento
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