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1.
Nihon Yakurigaku Zasshi ; 156(5): 303-311, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34470936

RESUMO

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor with activity against MET, VEGFR2, and AXL, among others. This drug is considered to exert excellent antitumor effects by inhibiting these targets simultaneously. Significant improvement in the primary endpoint (overall survival or PFS) were observed in patients on CAB in comparison with controls in a phase-III study in patients with renal cell carcinoma, progressed after treatment with anti-angiogenic agents, and in another phase-III study in patients with previously treated, advanced hepatocellular carcinoma. These results led to the approval of CAB in Japan in 2020 as a therapeutic agent for unresectable or metastatic renal cell carcinoma and unresectable hepatocellular carcinoma progressed after cancer chemotherapy, under the trade name of CABOMETYX® (20 mg, and 60 mg tablets). It has been suggested that CAB may modulate the immune system in favor of antitumor immunity and combined use with PD-1 checkpoint inhibitors may exert a synergistic effect. In a phase-III study that examined the efficacy of combination therapy with CAB and nivolumab in treatment-naive patients with advanced renal cell carcinoma, progression-free survival was significantly increased in patients on combination therapy over patients on sunitinib monotherapy. Three global phase-III clinical studies of combination therapy with atezolizumab and CAB in patients with non-small cell lung cancer, castration-resistant prostate cancer, and renal cell carcinoma, are in progress to confirm the efficacy of CAB.


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias Hepáticas , Neoplasias Pulmonares , Anilidas , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Piridinas
2.
Trials ; 22(1): 550, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34412682

RESUMO

OBJECTIVES: The primary objective is to evaluate the efficacy of camostat to prevent respiratory deterioration in patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Secondary objectives include assessment of the ability of camostat to reduce the requirement for Coronavirus disease 2019 (COVID-19) related hospital admission and to reduce the requirement for supplementary oxygen and ventilation as treatment for SARS-CoV-2 infection, to evaluate overall mortality related to COVID-19 and to evaluate the efficacy of camostat by effect on clinical improvement. Research objectives include to assess change in COVID-19 symptom severity, to evaluate the ability of camostat to reduce viral load throughout duration of illness as well as translational research on host and viral genomics, serum antibody production, COVID-19 diagnostics, and validation of laboratory testing methods and biomarkers. TRIAL DESIGN: SPIKE-1 is a randomised, multicentre, prospective, open label, community-based clinical trial. Eligible patients will be randomised 1:1 to the camostat treatment arm and control arm (best supportive care). The trial is designed to include a pilot phase recruiting up to 50 patients in each arm. An initial review at the end of the pilot phase will allow assessment of available data and inform the requirement for any protocol adaptations to include refinement of eligibility criteria to enrich the patient population and sample size calculations. Up to 289 additional patients will be randomised in the continuation phase of the trial. A formal interim analysis will be performed once 50% of the maximum sample size has been recruited PARTICIPANTS: The trial will recruit adults (≥ 18 years) who score moderate to very high risk according to COVID-age risk calculation, with typical symptoms of COVID-19 infection as per Public Health England guidance or equivalent organisations in the UK, Health Protection Scotland, Public Health Wales, Public Health Agency (Northern Ireland) and with evidence of current COVID-19 infection from a validated assay. The trial is being conducted in the UK and patients are recruited through primary care and hospital settings. INTERVENTION AND COMPARATOR: Eligible patients with be randomised to receive either camostat tablets, 200 mg four times daily (qds) for 14 days (treatment arm) or best supportive care (control arm). MAIN OUTCOMES: Primary outcome measure: the rate of hospital admissions requiring supplemental oxygen. Secondary outcome measures include: the rate of COVID-19 related hospital admission in patients with SARS-CoV-2 infection; the number of supplementary oxygen-free days and ventilator-free days measured at 28 days from randomisation; the rate of mortality related to COVID-19 one year from randomisation; the time to worst point on the nine-point category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019)) or deterioration of two points or more, within 28 days from randomisation. Research outcomes include the assessment of change in COVID-19 symptom severity on days 1-14 as measured by (1) time to apyrexia (maintained for 48 hrs) by daily self-assessment of temperature, time to improvement (by two points) in peripheral oxygenation saturation defined by daily self-assessment of fingertip peripheral oxygenation saturation levels, (3) assessment of COVID-19 symptoms using the Flu-iiQ questionnaire (determined by app recording and/or daily video call (or phone) consultation and (4) assessment of functional score (where possible) at screening, day 7 and 14. The ability of camostat to reduce viral load throughout duration of illness will be assessed by (1) change in respiratory (oropharyngeal/nasopharyngeal swab RT-PCR) log10 viral load from baseline to Days 7 and 14, (2) change in respiratory (saliva RT-PCR) log10 viral load from baseline to Days 1-14 and (3) change in upper respiratory viral shedding at Day 1 -14 measured as time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs by qPCR. Additional translational research outcomes include assessment of host and viral genomics, serum antibody production and COVID-19 diagnostics at baseline and on Days 7 and 14. RANDOMISATION: Eligible patients will be randomised using an interactive web response system (IWRS) in a 1:1 ratio to one of two arms: (1) treatment arm or (2) control arm. BLINDING (MASKING): The trial is open-label. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The trial is designed to include a pilot and a continuation phase. Up to 100 patients (randomised 1:1 treatment and control arm) will be recruited in the pilot phase and a maximum of 289 patients (randomised 1:1 treatment and control) will be recruited as part of the continuation phase. The total number of patients recruited will not exceed 389. TRIAL STATUS: Protocol version number v3 25 September 2020. Trial opened to recruitment on 04 August 2020. The authors anticipate recruitment to be completed by October 2021. TRIAL REGISTRATION: EudraCT 2020-002110-41; 18 June 2020 ClinicalTrials.gov NCT04455815 ; 02 July 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). Unpublished PK data provided under confidentiality agreement to the trial Sponsor has been removed from the background section of the protocol to allow for publication of the trial protocol. In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
COVID-19 , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto , Glicoproteína da Espícula de Coronavírus , Ésteres , Guanidinas , Humanos , Fusão de Membrana , Estudos Multicêntricos como Assunto , Estudos Prospectivos , SARS-CoV-2
3.
BMJ Open ; 11(8): e053876, 2021 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-34446504

RESUMO

INTRODUCTION: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. METHODS AND ANALYSIS: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator's Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants. ETHICS AND DISSEMINATION: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact. TRIAL REGISTRATION NUMBER: ISRCTN12892056;Pre-results.


Assuntos
Acne Vulgar , Espironolactona , Acne Vulgar/tratamento farmacológico , Adulto , Ensaios Clínicos Fase III como Assunto , Método Duplo-Cego , Feminino , Humanos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Espironolactona/uso terapêutico , Resultado do Tratamento
4.
BMJ Open ; 11(8): e044885, 2021 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-34452956

RESUMO

INTRODUCTION: Immune thrombocytopaenia (ITP) is an acquired disorder of low platelets and risk of bleeding. Although many children can be observed until spontaneous remission, others require treatment due to bleeding or impact on health-related quality of life. Standard first-line therapies for those who need intervention include corticosteroids, intravenous immunoglobulin and anti-D globulin, though response to these agents may be only transient. Eltrombopag is an oral thrombopoietin receptor agonist approved for children with chronic ITP who have had an insufficient response to corticosteroids, intravenous immunoglobulin or splenectomy. This protocol paper describes an ongoing open-label, randomised trial comparing eltrombopag to standard first-line management in children with newly diagnosed ITP. METHODS AND ANALYSIS: Randomised treatment assignment is 2:1 for eltrombopag versus standard first-line management and is stratified by age and by prior treatment. The primary endpoint of the study is platelet response, defined as ≥3 of 4 weeks with platelets >50×109/L during weeks 6-12 of therapy. Secondary outcomes include number of rescue therapies needed during the first 12 weeks, proportion of patients who do not need ongoing treatment at 12 weeks and 6 months, proportion of patients with a treatment response at 1 year, and number of second-line therapies used in weeks 13-52, as well as changes in regulatory T cells, iron studies, bleeding, health-related quality of life and fatigue. A planned sample size of up to 162 randomised paediatric patients will be enrolled over 2 years at 20 sites. ETHICS AND DISSEMINATION: The study has been approved by the centralised Baylor University Institutional Review Board. The results are expected to be published in 2023. TRIAL REGISTRATION NUMBER: NCT03939637.


Assuntos
Púrpura Trombocitopênica Idiopática , Benzoatos/uso terapêutico , Criança , Ensaios Clínicos Fase III como Assunto , Humanos , Hidrazinas/uso terapêutico , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Pirazóis , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
5.
Mol Ther ; 29(9): 2794-2805, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34365034

RESUMO

The numbers of cases and deaths from coronavirus disease 2019 (COVID-19) are continuously increasing. Many people are concerned about the efficacy and safety of the COVID-19 vaccines. We performed a comprehensive analysis of the published trials of COVID-19 vaccines and the real-world data from the Vaccine Adverse Event Reporting System. Globally, our research found that the efficacy of all vaccines exceeded 70%, and RNA-based vaccines had the highest efficacy of 94.29%; moreover, Black or African American people, young people, and males may experience greater vaccine efficacy. The spectrum of vaccine-related adverse drug reactions (ADRs) is extremely broad, and the most frequent ADRs are pain, fatigue, and headache. Most ADRs are tolerable and are mainly grade 1 or 2 in severity. Some severe ADRs have been identified (thromboembolic events, 21-75 cases per million doses; myocarditis/pericarditis, 2-3 cases per million doses). In summary, vaccines are a powerful tool that can be used to control the COVID-19 pandemic, with high efficacy and tolerable ADRs. In addition, the spectrum of ADRs associated with the vaccines is broad, and most of the reactions appear within a week, although some may be delayed. Therefore, ADRs after vaccination need to be identified and addressed in a timely manner.


Assuntos
Vacinas contra COVID-19/efeitos adversos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , SARS-CoV-2/imunologia , Vacinação/métodos , Vacinas Sintéticas/efeitos adversos , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano , Idoso , Idoso de 80 Anos ou mais , COVID-19/etnologia , COVID-19/virologia , Ensaios Clínicos Fase III como Assunto , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Imunogenicidade da Vacina , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
6.
Vaccimonitor (La Habana, Print) ; 30(2)mayo.-ago. 2021. tab, graf
Artigo em Espanhol | LILACS, CUMED | ID: biblio-1252326

RESUMO

Este reporte corresponde al análisis de la calidad de vida de los pacientes que se incluyeron en el ensayo clínico fase III de evaluación de la vacuna CIMAvaxEGF® en cáncer de pulmón de células no pequeñas. La calidad de vida se evaluó empleando los cuestionarios EORTC QLQ-C30 y QLQ-C13, al inicio y cada 3 meses hasta el fallecimiento del paciente a criterio del investigador. Para comparar las medianas entre los dos grupos se utilizó la prueba no paramétrica de Mann-Whitney. Las comparaciones entre el nivel basal y los diferentes tiempos de seguimiento se realizaron a través de la prueba no paramétrica de Wilcoxon. El cuestionario QLQ-C30 evidenció un beneficio en cuanto a calidad de vida para el grupo vacunado con la vacuna CIMAvaxEGF® en las escalas funcionales (global, rol y social), en las escalas de síntomas de la enfermedad y del tratamiento (dolor) se observó que mejora la calidad de los mismos a favor de los pacientes tratados con la vacuna CIMAvaxEGF®. El cuestionario QLQ-C13, también evidenció ventajas para el grupo vacunado desde el punto de vista de beneficio clínico en los síntomas (disnea, disfagia, alopecia y dolor en el pecho). Se señala como significativo que disminuye la hemoptisis y la tos en el grupo vacunado, observándose un empeoramiento en el grupo control(AU)


This report corresponds to quality of life analysis of patient with non-small cell lung cancer included in the phase III clinical trials Evaluation of CIMAvaxEGF® vaccine in lung cancer. The quality of life was evaluate using the EORTC questionnaires QLQ-C30 y QLQ-C13, at the beginning and every 3 months. To compare the median between two groups the Mann-Whitney non-parametric test was used. To compare the baseline and different follows times the Wilcoxon non-parametric test was used. The QLQ-C30 questionnaire showed a benefit in terms of the quality of life for the CIMAvaxEGF® vaccine group on the functional scores (global, role and social) and symptoms of the disease (pain). The QLQ-LC13 questionnaire showed a benefit in terms of the quality of life for the CIMAvaxEGF® vaccine group on the symptoms scores (dyspnea, dysphagia, alopecia and chest pain). It is noted as significant that the hemoptysis decreases in the group vaccinated as well as the dysphagia, the cough and the dyspnea observing a worsening in the control group(AU)


Assuntos
Humanos , Masculino , Feminino , Qualidade de Vida , Inquéritos e Questionários , Ensaios Clínicos Fase III como Assunto , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Vacinas Anticâncer
7.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299337

RESUMO

Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.


Assuntos
Neoplasias Colorretais/terapia , Medicina de Precisão/métodos , Proteínas ras/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/química , Biomarcadores Farmacológicos/metabolismo , Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais/enzimologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Mutação , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas ras/metabolismo
8.
J Stroke Cerebrovasc Dis ; 30(9): 105996, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34303090

RESUMO

OBJECTIVE: We hypothesize that procedure deployment rates and technical performance with minimally invasive surgery and thrombolysis for intracerebral hemorrhage (ICH) evacuation (MISTIE) can be enhanced in post-trial clinical practice, per Phase III trial results and lessons learned. MATERIALS AND METHODS: We identified ICH patients and those who underwent MISTIE procedure between 2017-2021 at a single site, after completed enrollments in the Phase III trial. Deployment rates, complications and technical outcomes were compared to those observed in the trial. Initial and final hematoma volume were compared between site measurements using ABC/2, MISTIE trial reading center utilizing manual segmentation, and a novel Artificial Intelligence (AI) based volume assessment. RESULTS: Nineteen of 286 patients were eligible for MISTIE. All 19 received the procedure (6.6% enrollment to screening rate 6.6% compared to 1.6% at our center in the trial; p=0.0018). Sixteen patients (84%) achieved evaculation target < 15 mL residual ICH or > 70% removal, compared to 59.7% in the trial surgical cohort (p=0.034). No poor catheter placement occurred and no surgical protocol deviations. Limitations of ICH volume assessments using the ABC/2 method were shown, while AI based methodology of ICH volume assessments had excellent correlation with manual segmentation by experienced reading centers. CONCLUSIONS: Greater procedure deployment and higher technical success rates can be achieved in post-trial clinical practice than in the MISTIE III trial. AI based measurements can be deployed to enhance clinician estimated ICH volume. Clinical outcome implications of this enhanced technical performance cannot be surmised, and will need assessment in future trials.


Assuntos
Hemorragia Cerebral/terapia , Procedimentos Neurocirúrgicos , Terapia Trombolítica , Adulto , Idoso , Idoso de 80 Anos ou mais , Inteligência Artificial , Hemorragia Cerebral/diagnóstico por imagem , Ensaios Clínicos Fase III como Assunto , Bases de Dados Factuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos/efeitos adversos , Valor Preditivo dos Testes , Interpretação de Imagem Radiográfica Assistida por Computador , Estudos Retrospectivos , Terapia Trombolítica/efeitos adversos , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
9.
Cancer Treat Rev ; 99: 102254, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34242928

RESUMO

PURPOSE: Radiation therapy (RT) and endocrine therapy (ET) are standard treatments for hormone receptor-positive (HR+) breast cancer after breast-conserving surgery (BCS). However, many older patients are at greater risk of treatment-related toxicities and non-cancer related death, and less likely to benefit from these standard treatments. A systematic review was performed evaluating outcomes of omitting RT or ET in older patients aged ≥50 treated with BCS for lower-risk breast cancer. METHODS: Medline, Embase, and the Cochrane Register of Controlled Trials were queried from 1980 to April 30th, 2020 for randomized controlled studies (RCTs) and prospective cohort studies (PCSs) evaluating omission of RT and/or ET compared to RT plus ET in patients. Meta-analysis was performed using random-effects models with findings reported as risk ratios (RR) with 95% confidence intervals (CI). RESULTS: From 3860 citations, 10 prospective studies met eligibility criteria. Omission of RT alone was evaluated in 7 RCTs (n = 4604) and one PCS (n = 667); omission of ET alone was assessed in 1 PCS (n = 271); and omission of either ET or RT was compared to ET plus RT in 1 RCT (n = 495). Adjuvant RT compared to no RT reduced 5- and 10-year in-breast tumor recurrence [5-year: RR 0.16, 95 %CI 0.09-0.27 l 10-year: 0.28, 95 %CI 0.16-0.5], but had no effect on survival [5-year: RR 0.94, 95 %CI 0.77-1.15; 10-year: 1.01, 95 %CI 0.9-1.12]. CONCLUSION: The current body of evidence suggests that RT can be omitted in older patients with lower-risk disease. However, more trials on the omission of ET are required to better inform treatment decisions.


Assuntos
Neoplasias da Mama/terapia , Receptores de Estrogênio/metabolismo , Fatores Etários , Antineoplásicos Hormonais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Mastectomia Segmentar/métodos , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco
10.
Cancer Treat Rev ; 99: 102258, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252720

RESUMO

BACKGROUND: Locoregional treatments (LRT) including radioembolisation (SIRT), transarterial chemo-embolisation (TACE), hepatic arterial infusion (HAI) of chemotherapy, external beam radiotherapy (EBRT) and ablation have been studied for the management of intrahepatic cholangiocarcinoma (iCC). The aim of this systematic review was to provide outcome benchmarks for clinical trial design. METHODS: Identification of studies reporting outcomes of patients treated with LRT for iCC was performed using PubMed and Embase. Pooled weighted means were calculated for progression-free survival (PFS) and overall survival (OS); meta-analysis of proportions was used for estimation of pooled response rate. RESULTS: 6325 entries were reviewed; 93 studies were eligible, representing 101 cohorts and 3990 patients: 15 cohorts (645 patients) for ablation, 18 cohorts (541 patients) for EBRT, 27 cohorts (1232 patients) for SIRT, 22 cohorts (1145 patients) for TACE, 16 cohorts (331 patients) for HAI and 3 cohorts (96 patients) not pooled. 74% of the studies were retrospective, 99% non-randomised. The pooled mean weighted OS was 30.2 months (95% confidence interval (CI): 21.8-38.6) for ablation, 18.9 (14.2-23.5) for EBRT, 14.1 (12.1-16.0) for SIRT, 15.9 (12.9-19.0) for TACE and 21.3 (15.4-27.1) for HAI. The pooled complete response rate was 93.9% for ablation. When analysed together, SIRT, TACE and HAI had a pooled mean weighted OS of 15.7 months, and 25.2 months for patients treated in first-line with concomitant systemic chemotherapy. CONCLUSIONS: Available literature on LRT for iCC was heterogeneous and of insufficient quality to make strong recommendations. Ablation achieved satisfactory outcomes, and may be recommended when surgery is not feasible.


Assuntos
Técnicas de Ablação/métodos , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/terapia , Embolização Terapêutica/métodos , Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/radioterapia , Quimioembolização Terapêutica , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/radioterapia , Colangiocarcinoma/cirurgia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Estudos de Coortes , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Ensaios Clínicos Controlados Aleatórios como Assunto , Radioisótopos de Ítrio/administração & dosagem
11.
Cancer Treat Rev ; 99: 102256, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34261032

RESUMO

The evaluation of the homologous recombination repair (HRR) status is emerging as a predictive tumor agnostic biomarker for poly (ADP-ribose) polymerase (PARP) inhibition across different tumor types and testing for HRR-signature is currently a developing area with promising therapeutic implications. Treatment with PARP inhibitors (PARPi) either as single agent or in combination with chemotherapy have shown so far limited activity in patients with thoracic malignancies. A deeper understanding of the biological background underlying HRR-deficient tumors, along with the recent advent of new effective targeted and immunotherapeutic agents, prompted the design of a new generation of clinical trials investigating novel PARPi-combinations in patients with lung cancer as well as malignant pleural mesothelioma. In this review we briefly summarize the biological basis of the DNA damage response pathway inhibition and provide an updated and detailed overview of clinical trials testing different PARPi-combinations strategies in patients with thoracic malignancies.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias Torácicas/tratamento farmacológico , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma Maligno/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Reparo de DNA por Recombinação , Neoplasias Torácicas/genética
12.
Cancer Treat Rev ; 99: 102255, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34332292

RESUMO

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as "synthetically lethal" in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This review summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Quimioterapia de Manutenção , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Molecules ; 26(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299503

RESUMO

Naturally occurring flavonoids are found as secondary metabolites in a wide number of plants exploited for both medicine and food and have long been known to be endowed with multiple biological activities, making them useful tools for the treatment of different pathologies. Due to the versatility of the scaffolds and the vast possibilities of appropriate decoration, they have also been regarded as fruitful sources of lead compounds and excellent chemical platforms for the development of bioactive synthetic compounds. Flavone-8-acetic acid (FAA) and 5,6-dimethylxanthone acetic acid (DMXAA) emerged for their antitumour potential due to the induction of cytokines and consequent rapid haemorrhagic necrosis of murine tumour vasculature, and different series of derivatives have been designed thereafter. Although the promising DMXAA failed in phase III clinical trials because of strict species-specificity, a boost in research came from the recent identification of the stimulator of interferon genes (STING), responsible for supporting tumoural innate immune responses, as a possible biological target. Consequently, in the last decade a renewal of interest for these flavonoid-based structures was noticed, and novel derivatives have been synthesised and evaluated for a deeper understanding of the molecular features needed for affecting human cells. Undoubtedly, these natural-derived molecules deserve further investigation and still appear attractive in an anticancer perspective.


Assuntos
Flavonoides/farmacologia , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Ensaios Clínicos Fase III como Assunto , Humanos , Xantenos/farmacologia , Xantonas/farmacologia
15.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299189

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Transdução de Sinais
16.
Mayo Clin Proc ; 96(8): 2095-2101, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34226027

RESUMO

OBJECTIVE: To assess the readability of the informed consent forms from the phase 3 COVID-19 vaccine trials conducted in the United States. PATIENTS AND METHODS: English consent forms were used for patients in phase 3 COVID-19 vaccine clinical trials. Consent forms were obtained in October 2020. Using Microsoft Word tools, we analyzed the readability (ie, the ease of reading) of written consent forms and informational documents from phase 3 COVID-19 vaccine clinical trials in the United States from the following manufacturers: AstraZeneca, Moderna, Pfizer, Johnson & Johnson, and Novavax. RESULTS: Owing to low readability and several format factors, this study determined that none of the consent forms or informational documents from the recent phase 3 COVID-19 vaccine clinical trials conducted in the United States met readability standards at the recommended 7th grade readability level for the average vaccine research volunteer in any readability category. The average English-speaking vaccine trial volunteer would have great difficulty comprehending the information provided in the consent forms and informational documents. To ensure that study subjects receive and fully comprehend information regarding a clinical study and can provide reliable consent, greater attention should be given to the development and use of simplified consent forms, multimedia formatting, personal discussion, and comprehension assessments.


Assuntos
Vacinas contra COVID-19 , Compreensão , Informação de Saúde ao Consumidor , Letramento em Saúde , Consentimento Livre e Esclarecido , Ensaios Clínicos Fase III como Assunto , Humanos , Estados Unidos
17.
Trials ; 22(1): 475, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294114

RESUMO

BACKGROUND: A previously performed phase III trial on 112 subjects investigating prophylactic nimodipine treatment in vestibular schwannoma (VS) surgery showed no clear beneficial effects on preservation of facial and cochlear nerve functions, though it should be considered that protection of facial nerve function was the primary outcome. However, the risk for postoperative hearing loss was halved in the nimodipine group compared to the control group (OR 0.49; 95% CI 0.18-1.30; p = 0.15). Accordingly, this phase III extension trial investigates the efficacy and safety of prophylactic nimodipine for hearing preservation in VS surgery. METHODS: This is a randomized, multi-center, two-armed, open-label phase III trial with blinded expert review and two-stage with interim analysis. Three hundred thirty-six adults with the indication for microsurgical removal of VS (Koos I-IV) and serviceable preoperative hearing (Gardner-Robertson scale (GR) 1-3) are assigned to either the therapy (intravenous nimodipine 1-2 mg/h from the day before surgery until the fifth postoperative day and standard of care) or the control group (surgery only and standard of care). The primary endpoint of the trial is postoperative cochlear nerve function measured before discharge according to GR 1-3 versus GR 4-5 (binary). Hearing function will be determined by pre- and postoperative audiometry with speech discrimination, which will be evaluated by a blinded expert reviewer. Furthermore, patient-reported outcomes using standardized questionnaires will be analyzed. DISCUSSION: Prophylactic parenteral nimodipine treatment may have a positive effect on hearing preservation in VS surgery and would improve patient's quality of life. Further secondary analyses are planned. Except for dose-depending hypotension, nimodipine is known as a safe drug. In the future, prophylactic nimodipine treatment may be recommended as a routine medication in VS surgery. VS can be considered as an ideal model for clinical evaluation of neuroprotection, since hearing outcome can be classified by well-recognized criteria. The beneficial effect of nimodipine may be transferable to other surgical procedures with nerves at risk and may have impact on basic research. TRIAL REGISTRATION: EudraCT 2019-002317-19, DRKS00019107 . 8th May 2020.


Assuntos
Neuroma Acústico , Nimodipina , Adulto , Ensaios Clínicos Fase III como Assunto , Audição , Humanos , Estudos Multicêntricos como Assunto , Neuroma Acústico/diagnóstico , Neuroma Acústico/cirurgia , Nimodipina/efeitos adversos , Complicações Pós-Operatórias , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento
18.
Cancer Metastasis Rev ; 40(2): 537-547, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34101053

RESUMO

Immunotherapy has become a mainstay of cancer treatment in many malignancies, though its application in breast cancer remains limited. Of the breast cancer subtypes, triple-negative breast cancers (TNBCs) are characterized by immune activation and infiltration and more commonly express biomarkers associated with response to immunotherapy. Checkpoint inhibitor therapy has shown promising activity in metastatic TNBC. In 2019, the US FDA granted accelerated approval of atezolizumab, a programmed death-ligand 1 (PD-L1) inhibitor, in combination with nab-paclitaxel for unresectable locally advanced or metastatic PD-L1-positive TNBC, based on the results of the phase III IMpassion130 trial. In 2020, the FDA also granted accelerated approval of pembrolizumab, a PD-1 inhibitor, in combination with chemotherapy for locally recurrent unresectable and metastatic PD-L1-positive TNBC, based on results of the phase III KEYNOTE-355 trial. Additional combination strategies are being explored in the treatment of metastatic TNBC, with the goal of augmenting antitumor activity. In this review, the clinical development of checkpoint inhibitors in the treatment of metastatic TNBC will be discussed, including clinical outcomes with monotherapy and combination therapy regimens, biomarkers that may predict for benefit, and future directions in the field.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Cancer Treat Rev ; 99: 102228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34111642

RESUMO

Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC) and a distinct entity, although heterogenous, associated with poor outcomes. The treatment landscape of metastatic pRCC (mpRCC) relied so far on targeted therapies, mimicking previous developments in metastatic clear-cell renal cell carcinoma. However, antiangiogenics as well as mTOR inhibitors retain only limited activity in mpRCC. As development of immune checkpoint inhibitors (ICI) is now underway in patients with mpRCC, we aimed at discussing early activity data and potential for future therapeutic strategies in monotherapy or combination. Expression of immune checkpoints such as PD-L1 and infiltrative immune cells in pRCC could provide insights into their potential immunogenicity, although this is currently poorly described. Based on retrospective and prospective data, efficacy of ICI as single agent remains limited. Combinations with tyrosine-kinase inhibitors, notably with anti-MET inhibitors, harbor promising response rates and may enter the standard of care in untreated patients. Collaborative work is needed to refine the molecular and immune landscape of pRCC, and pursue efforts to set up predictive biomarker-driven clinical trials in these rare tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Papilar/tratamento farmacológico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Carcinoma Papilar/imunologia , Carcinoma de Células Renais/imunologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/administração & dosagem , Neoplasias Renais/imunologia , Inibidores de Proteínas Quinases/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
Cancer Treat Rev ; 99: 102240, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34119803

RESUMO

The development of cancer therapies using monoclonal antibodies has been successful during the last 30 years. Recently much progress was achieved with technologies involving bispecific and multi-specific antibodies. Bispecific antibodies (BsAbs) are antibodies that bind two distinct epitopes, and a large number of potential clinical applications of BsAbs have been described. Here we review mechanism of action, clinical development and future challenges of BsAbs which could be a serve as a valuable arsenal in cancer patients.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Neoplasias/imunologia , Neoplasias/terapia , Anticorpos Biespecíficos/imunologia , Antineoplásicos Imunológicos/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
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