RESUMEN
BACKGROUND: Temporary drug treatment cessation might alleviate toxicity without substantially compromising efficacy in patients with cancer. We aimed to determine if a tyrosine kinase inhibitor drug-free interval strategy was non-inferior to a conventional continuation strategy for first-line treatment of advanced clear cell renal cell carcinoma. METHODS: This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done at 60 hospital sites in the UK. Eligible patients (aged ≥18 years) had histologically confirmed clear cell renal cell carcinoma, inoperable loco-regional or metastatic disease, no previous systemic therapy for advanced disease, uni-dimensionally assessed Response Evaluation Criteria in Solid Tumours-defined measurable disease, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) at baseline to a conventional continuation strategy or drug-free interval strategy using a central computer-generated minimisation programme incorporating a random element. Stratification factors were Memorial Sloan Kettering Cancer Center prognostic group risk factor, sex, trial site, age, disease status, tyrosine kinase inhibitor, and previous nephrectomy. All patients received standard dosing schedules of oral sunitinib (50 mg per day) or oral pazopanib (800 mg per day) for 24 weeks before moving into their randomly allocated group. Patients allocated to the drug-free interval strategy group then had a treatment break until disease progression, when treatment was re-instated. Patients in the conventional continuation strategy group continued treatment. Patients, treating clinicians, and the study team were aware of treatment allocation. The co-primary endpoints were overall survival and quality-adjusted life-years (QALYs); non-inferiority was shown if the lower limit of the two-sided 95% CI for the overall survival hazard ratio (HR) was 0·812 or higher and if the lower limit of the two-sided 95% CI of the marginal difference in mean QALYs was -0·156 or higher. The co-primary endpoints were assessed in the intention-to-treat (ITT) population, which included all randomly assigned patients, and the per-protocol population, which excluded patients in the ITT population with major protocol violations and who did not begin their randomisation allocation as per the protocol. Non-inferiority was to be concluded if it was met for both endpoints in both analysis populations. Safety was assessed in all participants who received a tyrosine kinase inhibitor. The trial was registered with ISRCTN, 06473203, and EudraCT, 2011-001098-16. FINDINGS: Between Jan 13, 2012, and Sept 12, 2017, 2197 patients were screened for eligibility, of whom 920 were randomly assigned to the conventional continuation strategy (n=461) or the drug-free interval strategy (n=459; 668 [73%] male and 251 [27%] female; 885 [96%] White and 23 [3%] non-White). The median follow-up time was 58 months (IQR 46-73 months) in the ITT population and 58 months (46-72) in the per-protocol population. 488 patients continued on the trial after week 24. For overall survival, non-inferiority was demonstrated in the ITT population only (adjusted HR 0·97 [95% CI 0·83 to 1·12] in the ITT population; 0·94 [0·80 to 1·09] in the per-protocol population). Non-inferiority was demonstrated for QALYs in the ITT population (n=919) and per-protocol (n=871) population (marginal effect difference 0·06 [95% CI -0·11 to 0·23] for the ITT population; 0·04 [-0·14 to 0·21] for the per-protocol population). The most common grade 3 or worse adverse events were hypertension (124 [26%] of 485 patients in the conventional continuation strategy group vs 127 [29%] of 431 patients in the drug-free interval strategy group); hepatotoxicity (55 [11%] vs 48 [11%]); and fatigue (39 [8%] vs 63 [15%]). 192 (21%) of 920 participants had a serious adverse reaction. 12 treatment-related deaths were reported (three patients in the conventional continuation strategy group; nine patients in the drug-free interval strategy group) due to vascular (n=3), cardiac (n=3), hepatobiliary (n=3), gastrointestinal (n=1), or nervous system (n=1) disorders, and from infections and infestations (n=1). INTERPRETATION: Overall, non-inferiority between groups could not be concluded. However, there seemed to be no clinically meaningful reduction in life expectancy between the drug-free interval strategy and conventional continuation strategy groups and treatment breaks might be a feasible and cost-effective option with lifestyle benefits for patients during tyrosine kinase inhibitor therapy in patients with renal cell carcinoma. FUNDING: UK National Institute for Health and Care Research.
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Carcinoma de Células Renales , Adolescente , Adulto , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
OBJECTIVE: Epidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785). DESIGN: EGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients. RESULTS: EGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA. CONCLUSION: EGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials.
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Adenocarcinoma/tratamiento farmacológico , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Epirrubicina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Esofágicas/tratamiento farmacológico , Panitumumab/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/química , Anciano , Antibióticos Antineoplásicos/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores de Tumor/análisis , Epirrubicina/administración & dosificación , Receptores ErbB/análisis , Neoplasias Esofágicas/química , Humanos , Masculino , Persona de Mediana Edad , Panitumumab/administración & dosificación , Neoplasias Gástricas/químicaRESUMEN
BACKGROUND: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma. METHODS: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331. FINDINGS: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis. INTERPRETATION: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Axitinib/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Sunitinib/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Axitinib/efectos adversos , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Sunitinib/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) is an important tool for noninvasive imaging of biliary disease, however, its assessment is currently subjective, resulting in the need for objective biomarkers. PURPOSE: To investigate the accuracy, scan/rescan repeatability, and cross-scanner reproducibility of a novel quantitative MRCP tool on phantoms and in vivo. Additionally, to report normative ranges derived from the healthy cohort for duct measurements and tree-level summary metrics. STUDY TYPE: Prospective. PHANTOMS/SUBJECTS: Phantoms: two bespoke designs, one with varying tube-width, curvature, and orientation, and one exhibiting a complex structure based on a real biliary tree. Subjects Twenty healthy volunteers, 10 patients with biliary disease, and 10 with nonbiliary liver disease. SEQUENCE/FIELD STRENGTH: MRCP data were acquired using heavily T2 -weighted 3D multishot fast/turbo spin echo acquisitions at 1.5T and 3T. ASSESSMENT: Digital instances of the phantoms were synthesized with varying resolution and signal-to-noise ratio. Physical 3D-printed phantoms were scanned across six scanners (two field strengths for each of three manufacturers). Human subjects were imaged on four scanners (two fieldstrengths for each of two manufacturers). STATISTICAL TESTS: Bland-Altman analysis and repeatability coefficient (RC). RESULTS: Accuracy of the diameter measurement approximated the scanning resolution, with 95% limits of agreement (LoA) from -1.1 to 1.0 mm. Excellent phantom repeatability was observed, with LoA from -0.4 to 0.4 mm. Good reproducibility was observed across the six scanners for both phantoms, with a range of LoA from -1.1 to 0.5 mm. Inter- and intraobserver agreement was high. Quantitative MRCP detected strictures and dilatations in the phantom with 76.6% and 85.9% sensitivity and 100% specificity in both. Patients and healthy volunteers exhibited significant differences in metrics including common bile duct (CBD) maximum diameter (7.6 mm vs. 5.2 mm P = 0.002), and overall biliary tree volume 12.36 mL vs. 4.61 mL, P = 0.0026). DATA CONCLUSION: The results indicate that quantitative MRCP provides accurate, repeatable, and reproducible measurements capable of objectively assessing cholangiopathic change. Evidence Level: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:807-820.
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Pancreatocolangiografía por Resonancia Magnética , Procesamiento de Imagen Asistido por Computador , Humanos , Imagen por Resonancia Magnética , Fantasmas de Imagen , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. METHODS: The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. DISCUSSION: The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. TRIAL REGISTRATION: PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). TRIAL STATUS: At the time of submission, PRISM is open to recruitment and data collection is ongoing.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Ipilimumab/administración & dosificación , Nivolumab/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Nivolumab/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Calidad de Vida , Resultado del TratamientoRESUMEN
INTRODUCTION: Lung retransplantation is an important therapy for a growing population of lung transplant recipients with graft failure, but detailed outcome data are lacking. METHODS: We conducted a retrospective cohort study of adult lung retransplant in the Toronto Lung Transplant Program from 2001 to 2013 (n = 38). We analyzed the postoperative course, graft function, renal function, microbiology, donor-specific antibodies (DSA), quality of life, and survival compared to a control cohort of primary transplant recipients matched for age and era. RESULTS: Indication for retransplant was chronic lung allograft dysfunction in most retransplant recipients (35/38, 92%). The postoperative course was more complex after retransplant than primary (ventilation time, 8 vs 2 days, P < .01; ICU stay 14 vs 4 days, P < 0.01), and peak lung function was lower (FEV1 2.2L vs 3L, P < .01). Quality of life scores were comparable, as were renal function, microbiology, and donor-specific antibody formation. Median survival was 1988 days after primary and 1475 days after retransplant (P = .39). CONCLUSIONS: Lung retransplantation is associated with a more complex postoperative course and lower peak lung function, but the long-term medical profile is similar to primary transplant. Lung retransplantation can be beneficial for carefully selected candidates with allograft failure.
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Rechazo de Injerto , Supervivencia de Injerto , Enfermedades Pulmonares/cirugía , Trasplante de Pulmón/mortalidad , Complicaciones Posoperatorias , Calidad de Vida , Adulto , Femenino , Estudios de Seguimiento , Rechazo de Injerto/etiología , Humanos , Trasplante de Pulmón/efectos adversos , Masculino , Persona de Mediana Edad , Pronóstico , Reoperación , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Although many studies have assessed the diagnostic utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the context of a specific disease, few studies have assessed the overall diagnostic yield, sensitivity, and negative predictive value in patients with isolated mediastinal and hilar lymphadenopathy (IMHL). OBJECTIVE: We evaluated the performance of EBUS-TBNA for diagnosing IMHL in a population with a high prevalence of concurrent or preexisting non-pulmonary malignancy. METHODS: A retrospective chart review of patients who underwent EBUS-TBNA from October 2008 to April 2014 was performed to identify patients with IMHL. Patients with known or suspected primary pulmonary malignancy were excluded. When available, EBUS-TBNA results were cross-referenced with further diagnostic investigation or clinical diagnosis based on follow-up. RESULTS: EBUS-TBNA was used to sample 765 lymph nodes from 350 patients. One hundred and fourteen (33.3%) patients had a concurrent or preexisting non-pulmonary malignancy. The overall yield of EBUS-TBNA for specific diagnosis was 300/350 (86%). The diagnostic yield for sarcoidosis, lymphoproliferative disease, metastatic lymphadenopathy from extrathoracic malignancy, and necrotizing granuloma was 123/149 (83%), 27/33 (82%), 20/25 (80%), and 13/19 (68%), respectively. Amongst 50 patients with non-diagnostic EBUS-TBNA, 25 yielded an insufficient sample and another 25 yielded only benign lymphoid material which was not representative of the underlying pathology. Overall, EBUS-TBNA had a sensitivity of 89%, a diagnostic yield of 86%, and a negative predictive value of 79%. CONCLUSION: For patients with isolated hilar or mediastinal lymphadenopathy and a high background prevalence of concurrent and preexisting non-pulmonary malignancy, EBUS-TBNA is a reliable first-line diagnostic investigation.
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Broncoscopía/estadística & datos numéricos , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico/estadística & datos numéricos , Linfadenopatía/diagnóstico , Enfermedades del Mediastino/diagnóstico , Neoplasias/diagnóstico , Adulto , Anciano , Femenino , Humanos , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Oesophagogastric adenocarcinoma (OGA) has a poor prognosis, even for patients with operable disease. However, the optimal surveillance strategy following surgery is unknown. METHODS: We performed a retrospective review of all patients with OGA who had undergone surgery with radical intent at the Royal Marsden between January 2001 and December 2010. RESULTS: Of the 360 patients with OGA who underwent potentially curative surgery, 100/214 patients (47%) with oesophageal/gastro-oesophageal junction (GOJ) adenocarcinoma and 47/146 patients (32%) with gastric adenocarcinoma developed recurrent disease. 51, 79 and 92% of relapses occurred within 1, 2 and 3 years respectively and the majority of patients relapsed at distant sites. Of the patients who relapsed, 67% (67/100) with oesophageal/GOJ adenocarcinoma and 72% of patients with gastric cancer (34/47) were symptomatic at the time of relapse. The majority of asymptomatic relapses were first detected by a rise in tumour markers. There was no difference in disease-free survival between asymptomatic and symptomatic patients, but asymptomatic patients were more likely to receive further treatment and had a longer survival beyond relapse. CONCLUSION: The majority of relapses occur within the first 3 years and at distant sites. Monitoring of tumour markers should be considered as part of a surveillance program.
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Adenocarcinoma/epidemiología , Adenocarcinoma/cirugía , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/cirugía , Recurrencia Local de Neoplasia/epidemiología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Oesophageal and gastric adenocarcinoma (OGA) treatment remains challenging. Improvements in early diagnosis, staging and management might have contributed to survival prolongation. To examine this hypothesis, we assessed outcomes of resected OGA patients in our institution over 10 years, comparing two time periods, 2001-2005 and 2006-2010. METHODS: Records from patients who had undergone surgery with radical intent and follow-up for OGA were retrospectively reviewed. Patients followed up at hospitals other than the Royal Marsden Hospital were excluded. Two different cohorts were identified: patients with oesophageal and type I or type II oesophagogastric junction (OGJ) tumours, and patients with gastric and type III OGJ tumours. RESULTS: We identified 360 patients: 147 from 2001-2005 and 213 from 2006-2010. The characteristics were comparable across the two time periods. Between 2001-2005 and 2006-2010, the percentage of R0 resections increased (from 67.1 to 81.1 % for proximal tumours and from 76.3 to 95.9 % for gastric and type III OGJ tumours). The mean number of lymph nodes retrieved increased over time. The 5-year overall survival rate increased significantly from 42.3 to 56.6 % for proximal tumours and from 38.8 to 55.3 % for gastric and type III OGJ tumours. Similarly, the disease-free survival rate significantly increased from 34.6 to 53.5 % for proximal tumours and from 35.9 to 51.1 % for gastric and type III OGJ tumours. CONCLUSION: This study comprehensively describes the improvement in survival outcomes in a major UK referral centre over a 10-year period, identifying potentially relevant factors such as increased number of R0 resections and higher lymph node yield.
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Adenocarcinoma/mortalidad , Neoplasias Esofágicas/mortalidad , Esofagectomía/mortalidad , Unión Esofagogástrica/cirugía , Gastrectomía/mortalidad , Neoplasias Gástricas/mortalidad , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/cirugía , Unión Esofagogástrica/patología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Anciano , Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Capecitabina , Distribución de Chi-Cuadrado , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Terminación Anticipada de los Ensayos Clínicos , Epirrubicina/administración & dosificación , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Análisis Multivariante , Oportunidad Relativa , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Panitumumab , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Factores de Tiempo , Resultado del Tratamiento , Reino UnidoRESUMEN
Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.
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Inmunomodulación , Interleucina-10 , Trasplante de Pulmón , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Trasplante de Pulmón/métodos , Animales , Interleucina-10/metabolismo , Células Madre Mesenquimatosas/metabolismo , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/citología , Porcinos , Trasplante de Células Madre Mesenquimatosas/métodos , Humanos , Ingeniería Genética , Pulmón/metabolismo , Pulmón/patología , Pulmón/inmunologíaRESUMEN
PURPOSE: Ipilimumab (IPI), in combination with nivolumab (NIVO), is an approved frontline treatment option for patients with intermediate- or poor-risk advanced renal cell carcinoma (aRCC). We conducted a randomized phase II trial to evaluate whether administering IPI once every 12 weeks (modified), instead of once every 3 weeks (standard), in combination with NIVO, is associated with a favorable toxicity profile. METHODS: Treatment-naïve patients with clear-cell aRCC were randomly assigned 2:1 to receive four doses of modified or standard IPI, 1 mg/kg, in combination with NIVO (3 mg/kg). The primary end point was the proportion of patients with a grade 3-5 treatment-related adverse event (trAE) among those who received at least one dose of therapy. The key secondary end point was 12-month progression-free survival (PFS) in the modified arm compared with historical sunitinib control. The study was not designed to formally compare arms for efficacy. RESULTS: Between March 2018 and January 2020, 192 patients (69.8% intermediate/poor-risk) were randomly assigned and received at least one dose of study drug. The incidence of grade 3-5 trAEs was significantly lower among participants receiving modified versus standard IPI (32.8% v 53.1%; odds ratio, 0.43 [90% CI, 0.25 to 0.72]; P = .0075). The 12-month PFS (90% CI) using modified IPI was 46.1% (38.6 to 53.2). At a median follow-up of 21 months, the overall response rate was 45.3% versus 35.9% and the median PFS was 10.8 months versus 9.8 months in the modified and standard IPI groups, respectively. CONCLUSION: Rates of grade 3-5 trAEs were significantly lower in patients receiving modified versus standard IPI. Although 12-month PFS did not meet the prespecified efficacy threshold compared with historical control, informal comparison of treatment groups did not suggest any reduction in efficacy with the modified schedule.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Nivolumab/uso terapéutico , Ipilimumab , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patologíaRESUMEN
BACKGROUND: Bacteriophages (phages) have been used extensively as analytical tools to type bacterial cultures and recently for control of zoonotic foodborne pathogens in foods and in animal reservoirs. METHODS: We examined the host range, morphology, genome and proteome of the lytic E. coli O157 phage rV5, derived from phage V5, which is a member of an Escherichia coli O157:H7 phage typing set. RESULTS: Phage rV5 is a member of the Myoviridae family possessing an icosahedral head of 91 nm between opposite apices. The extended tail measures 121 x 17 nm and has a sheath of 44 x 20 nm and a 7 nm-wide core in the contracted state. It possesses a 137,947 bp genome (43.6 mol%GC) which encodes 233 ORFs and six tRNAs. Until recently this virus appeared to be phylogenetically isolated with almost 70% of its gene products ORFans. rV5 is closely related to coliphages Delta and vB-EcoM-FY3, and more distantly related to Salmonella phages PVP-SE1 and SSE-121, Cronobacter sakazakii phage vB_CsaM_GAP31, and coliphages phAPEC8 and phi92. A complete shotgun proteomic analysis was carried out on rV5, extending what had been gleaned from the genomic analyses. Host range studies revealed that rV5 is active against several other E. coli.
Asunto(s)
Bacteriófagos/genética , Escherichia coli O157/virología , Genoma Viral , Especificidad del Huésped , Myoviridae/fisiología , Bacteriófagos/clasificación , Bacteriófagos/aislamiento & purificación , Bacteriófagos/fisiología , Genómica , Datos de Secuencia Molecular , Myoviridae/clasificación , Myoviridae/genética , Myoviridae/aislamiento & purificación , Sistemas de Lectura Abierta , Filogenia , Proteómica , Proteínas Virales/genéticaRESUMEN
BACKGROUND: Tivozanib is a licensed as first-line treatment for metastatic renal cell carcinoma (mRCC). OBJECTIVE: To evaluate the outcomes from tivozanib in a real-world mRCC population. PATIENTS AND METHODS: Patients with mRCC commencing first-line tivozanib between March 2017 and May 2019 were identified across four specialist cancer centres in the UK. Data relating to response, overall survival (OS), progression-free survival (PFS) and adverse events (AEs) were collected retrospectively with censoring on 31 December 2020. RESULTS: A total of 113 patients were identified: median age was 69 years; 78% had ECOG PS 0-1; 82% had clear cell histology; 66% had previous nephrectomy; International Metastatic RCC Database Consortium (IMDC) score was 22% favourable (F), 52% intermediate (I) and 26% poor (P). Twenty-six per cent were switched from another tyrosine kinase inhibitor (TKI) to tivozanib due to toxicity. Median follow-up was 26.6 months with 18% remaining on treatment at data censoring. Median PFS was 8.75 months. Median PFS by IMDC risk group was: F = 23.0 months; I = 10.0 months; P = 3.0 months, p value < 0.0001. Median OS was 25.0 months (F = not reached (NR) with 72% alive at data cut-off; I = 26.0 months; P = 7.0 months, p value < 0.0001). Seventy-seven per cent had an AE of any grade, and 13% had a grade ≥ 3 AE. Eighteen per cent of patients discontinued treatment due to toxicity. No patients who discontinued a prior TKI due to AEs stopped tivozanib due to AEs. CONCLUSIONS: These data suggest comparable activity of tivozanib with the pivotal trial data and other TKIs in a real-world population. Its tolerability positions tivozanib as an attractive first-line option for those unsuitable for combination therapies or unable to tolerate other TKIs.
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Carcinoma de Células Renales , Neoplasias Renales , Anciano , Humanos , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Reino UnidoRESUMEN
Noninvasive delivery of near-infrared light (IRL) to human tissues has been researched as a treatment for several acute and chronic disease conditions. We recently showed that use of specific IRL wavelengths, which inhibit the mitochondrial enzyme cytochrome c oxidase (COX), leads to robust neuroprotection in animal models of focal and global brain ischemia/reperfusion injury. These life-threatening conditions can be caused by an ischemic stroke or cardiac arrest, respectively, two leading causes of death. To translate IRL therapy into the clinic an effective technology must be developed that allows efficient delivery of IRL to the brain while addressing potential safety concerns. Here, we introduce IRL delivery waveguides (IDWs) which meet these demands. We employ a low-durometer silicone that comfortably conforms to the shape of the head, avoiding pressure points. Furthermore, instead of using focal IRL delivery points via fiberoptic cables, lasers, or light-emitting diodes, the distribution of the IRL across the entire area of the IDW allows uniform IRL delivery through the skin and into the brain, preventing "hot spots" and thus skin burns. The IRL delivery waveguides have unique design features, including optimized IRL extraction step numbers and angles and a protective housing. The design can be scaled to fit various treatment areas, providing a novel IRL delivery interface platform. Using fresh (unfixed) human cadavers and isolated cadaver tissues, we tested transmission of IRL via IDWs in comparison to laser beam application with fiberoptic cables. Using the same IRL output energies IDWs performed superior in comparison to the fiberoptic delivery, leading to an up to 95% and 81% increased IRL transmission for 750 and 940 nm IRL, respectively, analyzed at a depth of 4 cm into the human head. We discuss the unique safety features and potential further improvements of the IDWs for future clinical implementation.
RESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICI) have revolutionised treating advanced cancers. ICI are administered intravenously every 2-6 weeks for up to 2 years, until cancer progression/unacceptable toxicity. Physiological efficacy is observed at lower doses than those used as standard of care (SOC). Pharmacodynamic studies indicate sustained target occupancy, despite a pharmacological half-life of 2-3 weeks. Reducing frequency of administration may be possible without compromising outcomes. The REFINE trial aims to limit individual patient exposure to ICI whilst maintaining efficacy, with potential benefits in quality of life and reduced drug treatment/attendance costs. METHODS/DESIGN: REFINE is a randomised phase II, multi-arm, multi-stage (MAMS) adaptive basket trial investigating extended interval administration of ICIs. Eligible patients are those responding to conventionally dosed ICI at 12 weeks. In stage I, patients (n = 160 per tumour-specific cohort) will be randomly allocated (1:1) to receive maintenance ICI at SOC vs extended dose interval. REFINE is currently recruiting UK patients with locally advanced or metastatic renal cell carcinoma (RCC) who have tolerated and responded to initial nivolumab/ipilimumab, randomised to receive maintenance nivolumab SOC (480 mg 4 weekly) vs extended interval (480 mg 8 weekly). Additional tumour cohorts are planned. Subject to satisfactory outcomes (progression-free survival) stage II will investigate up to 5 different treatment intervals. Secondary outcome measures include overall survival, quality-of-life, treatment-related toxicity, mean incremental pathway costs and quality-adjusted life-years per patient. REFINE is funded by the Jon Moulton Charity Trust and Medical Research Council, sponsored by University College London (UCL), and coordinated by the MRC CTU at UCL. Trial Registration ISRCTN79455488. NCT04913025 EUDRACT #: 2021-002060-47. CTA 31330/0008/001-0001; MREC approval: 21/LO/0593. REFINE Protocol version 4.0.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Nivolumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Calidad de Vida , Neoplasias Renales/tratamiento farmacológico , InmunoterapiaRESUMEN
Previous analyses of KEYNOTE-426, an open-label, phase 3 randomized study, showed superior efficacy of first-line pembrolizumab plus axitinib to sunitinib in advanced clear cell renal cell carcinoma (ccRCC). We report results of the final protocol-prespecified analysis of KEYNOTE-426. Patients received pembrolizumab 200 mg intravenously every 3 wk plus axitinib 5 mg orally twice daily or sunitinib 50 mg orally once daily (4 wk per 6-wk cycle). The dual primary endpoints were overall survival (OS) and progression-free survival (PFS) as per RECIST v1.1 by a blinded independent central review. The secondary endpoints included objective response rate (ORR) and duration of response (DOR). The median study follow-up was 43 (range, 36-51) mo. Benefit with pembrolizumab plus axitinib versus sunitinib was maintained for OS (hazard ratio [HR], 0.73 [95% confidence interval {CI}, 0.60-0.88]), PFS (HR, 0.68 [95% CI, 0.58-0.80]), and ORR (60% vs 40%). The median DOR was 24 (range, 1.4+ to 43+) versus 15 (range, 2.3-43+) mo in the pembrolizumab plus axitinib versus the sunitinib arm. No new safety signals emerged. These results support pembrolizumab plus axitinib as a standard of care for patients with previously untreated advanced ccRCC. PATIENT SUMMARY: Extended results of KEYNOTE-426 support pembrolizumab plus axitinib as the standard of care for advanced clear cell renal cell carcinoma.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Axitinib/efectos adversos , Sunitinib/uso terapéutico , Estudios de Seguimiento , Neoplasias Renales/patología , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMEN
OBJECTIVE: Type 2 diabetes (T2D) is associated with significant end-organ damage and ectopic fat accumulation. Multiparametric magnetic resonance imaging (MRI) can provide a rapid, noninvasive assessment of multiorgan and body composition. The primary objective of this study was to investigate differences in visceral adiposity, ectopic fat accumulation, body composition, and relevant biomarkers between people with and without T2D. METHODS: Participant demographics, routine biochemistry, and multiparametric MRI scans of the liver, pancreas, visceral and subcutaneous adipose tissue, and skeletal muscle were analyzed from 266 participants (131 with T2D and 135 without T2D) who were matched for age, gender, and BMI. Wilcoxon and χ2 tests were performed to calculate differences between groups. RESULTS: Participants with T2D had significantly elevated liver fat (7.4% vs. 5.3%, p = 0.011) and fibroinflammation (as assessed by corrected T1 [cT1]; 730 milliseconds vs. 709 milliseconds, p = 0.019), despite there being no differences in liver biochemistry, serum aspartate aminotransferase (p = 0.35), or alanine transaminase concentration (p = 0.11). Significantly lower measures of skeletal muscle index (45.2 cm2 /m2 vs. 50.6 cm2 /m2 , p = 0.003) and high-density lipoprotein cholesterol (1.1 mmol/L vs. 1.3 mmol/L, p < 0.0001) were observed in participants with T2D. CONCLUSIONS: Multiparametric MRI revealed significantly elevated liver fat and fibroinflammation in participants with T2D, despite normal liver biochemistry. This study corroborates findings of significantly lower measures of skeletal muscle and high-density lipoprotein cholesterol in participants with T2D versus those without T2D.
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Diabetes Mellitus Tipo 2 , Colesterol , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico por imagen , Diabetes Mellitus Tipo 2/patología , Humanos , Grasa Intraabdominal/diagnóstico por imagen , Grasa Intraabdominal/patología , Lipoproteínas HDL , Hígado/diagnóstico por imagen , Hígado/patología , Músculo Esquelético/diagnóstico por imagenRESUMEN
BACKGROUND: Our recent work has challenged 4°C as an optimal lung preservation temperature by showing storage at 10°C to allow for the extension of preservation periods. Despite these findings, the impact of 10°C storage has not been evaluated in the setting of injured donor lungs. METHODS: Aspiration injury was created through bronchoscopic delivery of gastric juice (pH: 1.8). Injured donor lungs (n = 5/group) were then procured and blindly randomized to storage at 4°C (on ice) or at 10°C (in a thermoelectric cooler) for 12 hours. A third group included immediate transplantation. A left lung transplant was performed thereafter followed by 4 hours of graft evaluation. RESULTS: After transplantation, lungs stored at 10°C showed significantly better oxygenation when compared to 4°C group (343 ± 43 mm Hg vs 128 ± 76 mm Hg, p = 0.03). Active metabolism occurred during the 12 hours storage period at 10°C, producing cytoprotective metabolites within the graft. When compared to lungs undergoing immediate transplant, lungs preserved at 10°C tended to have lower peak airway pressures (p = 0.15) and higher dynamic lung compliances (p = 0.09). Circulating cell-free mitochondrial DNA within the recipient plasma was significantly lower for lungs stored at 10°C in comparison to those underwent immediate transplant (p = 0.048), alongside a tendency of lower levels of tissue apoptotic cell death (p = 0.075). CONCLUSIONS: We demonstrate 10°C as a potentially superior storage temperature for injured donor lungs in a pig model when compared to the current clinical standard (4°C) and immediate transplantation. Continuing protective metabolism at 10°C for donor lungs may result in better transplant outcomes.
Asunto(s)
Trasplante de Pulmón , Daño por Reperfusión , Animales , Modelos Animales de Enfermedad , Pulmón/metabolismo , Preservación de Órganos , Daño por Reperfusión/metabolismo , Porcinos , TemperaturaRESUMEN
BACKGROUND: Cold static preservation (CSP) at higher temperatures (10°C) has been recently shown as an optimal strategy up to 24-36h of preservation. Here, we hypothesized that alternating 10°C static storage with cycles of normothermic ex vivo lung perfusion (EVLP) would provide conditions for cellular "recharge", allowing for multi-day lung preservation. METHODS: Donor lungs from male Yorkshire pigs were preserved using 10°C CSP with two cycles of 4h EVLP. After a total of 3 days of preservation, a left lung transplant was performed followed by 4h of graft evaluation. As controls, 2 lungs were preserved solely with continuous 10°C preservation for 3 days and transplanted. FINDINGS: For animals receiving lungs preserved using a cyclic EVLP protocol, lung function and histological structures were stable and the recipient systemic partial pressure of oxygen/fraction of inspired oxygen (P/F Ratio) after excluding the contralateral lung was 422 ± 61 mmHg. In contrast, lungs preserved solely in continuous cold static storage at 10°C for 72h developed massive lung failure, resulting in recipient death. Metabolomic analysis revealed that EVLP plays a critical role in the re-vitalization of key central carbon energy metabolites (Glucose, Succinate, N-Acetyl Aspartate) and reducing the expression of the inflammasome activation marker CASP1. INTERPRETATION: In conclusion, we demonstrate for the first time the feasibility of 3-day lung preservation leading to excellent early post-transplant outcomes. The thoughtful combination of cold storage (10°C) and intermittent EVLP can open new opportunities in organ transplantation. FUNDING: This work was supported by the UHN Foundation (Grant#1013612).