RESUMEN
Pembrolizumab has received approval in the UK as first-line monotherapy for recurrent and/or metastatic HNSCC (R/M HNSCC) following the results of the KEYNOTE-048 trial, which demonstrated a longer overall survival (OS) in comparison to the EXTREME chemotherapy regimen in patients with a combined positive score (CPS) ≥1. In this article, we provide retrospective real-world data on the role of pembrolizumab monotherapy as first-line systemic therapy for HNSCC across 18 centers in the UK from March 20, 2020 to May 31, 2021. 211 patients were included, and in the efficacy analysis, the objective response rate (ORR) was 24.7%, the median progression-free survival (PFS) was 4.8 months (95% confidence interval [CI]: 3.6-6.1), and the median OS was 10.8 months (95% CI 9.0-12.5). Pembrolizumab monotherapy was well tolerated, with 18 patients having to stop treatment owing to immune-related adverse events (irAEs). 53 patients proceeded to second-line treatment with a median PFS2 of 10.2 months (95% CI: 8.8-11.5). Moreover, patients with documented irAEs had a statistically significant longer median PFS (11.3 vs. 3.3 months; log-rank p value = <.001) and median OS (18.8 vs. 8.9 months; log-rank p value <.001). The efficacy and safety of pembrolizumab first-line monotherapy for HNSCC has been validated using real-world data.
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Anticuerpos Monoclonales Humanizados , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Masculino , Femenino , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Reino Unido/epidemiología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/mortalidad , Adulto , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Supervivencia sin ProgresiónRESUMEN
Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.
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Diabetes Mellitus , Neoplasias de la Próstata , Masculino , Humanos , PPAR gamma/agonistas , Neoplasias de la Próstata/patología , Transducción de SeñalRESUMEN
BACKGROUND: Prostate cancer is the most common cancer in men in the developed world, with most deaths caused by advanced and metastatic disease which has no curative options. Here, we identified Mbtps2 alteration to be associated with metastatic disease in an unbiased in vivo screen and demonstrated its regulation of fatty acid and cholesterol metabolism. METHODS: The Sleeping Beauty transposon system was used to randomly alter gene expression in the PtenNull murine prostate. MBTPS2 was knocked down by siRNA in LNCaP, DU145 and PC3 cell lines, which were then phenotypically investigated. RNA-Seq was performed on LNCaP cells lacking MBTPS2, and pathways validated by qPCR. Cholesterol metabolism was investigated by Filipin III staining. RESULTS: Mbtps2 was identified in our transposon-mediated in vivo screen to be associated with metastatic prostate cancer. Silencing of MBTPS2 expression in LNCaP, DU145 and PC3 human prostate cancer cells reduced proliferation and colony forming growth in vitro. Knockdown of MBTPS2 expression in LNCaP cells impaired cholesterol synthesis and uptake along with reduced expression of key regulators of fatty acid synthesis, namely FASN and ACACA. CONCLUSION: MBTPS2 is implicated in progressive prostate cancer and may mechanistically involve its effects on fatty acid and cholesterol metabolism.
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Lipogénesis , Neoplasias de la Próstata , Masculino , Humanos , Animales , Ratones , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Línea Celular Tumoral , Neoplasias de la Próstata/patología , Colesterol , Ácidos Grasos , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metaloendopeptidasas/genética , Metaloendopeptidasas/metabolismoRESUMEN
The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In Saccharomyces cerevisiae, cytochrome c oxidase (CIV) forms SCs of varying stoichiometry with cytochrome bc1 (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels. Here we present the cryo-EM structures of the III2-IV1 and III2-IV2 SCs containing the hypoxic isoform Cox5B solved at 3.4 and 2.8 Å, respectively. We show that the change of isoform does not affect SC formation or activity, and that SC stoichiometry is dictated by the level of CIII/CIV biosynthesis. Comparison of the CIV5B- and CIV5A-containing SC structures highlighted few differences, found mainly in the region of Cox5. Additional density was revealed in all SCs, independent of the CIV isoform, in a pocket formed by Cox1, Cox3, Cox12, and Cox13, away from the CIII-CIV interface. In the CIV5B-containing hypoxic SCs, this could be confidently assigned to the hypoxia-induced gene 1 (Hig1) type 2 protein Rcf2. With conserved residues in mammalian Hig1 proteins and Cox3/Cox12/Cox13 orthologs, we propose that Hig1 type 2 proteins are stoichiometric subunits of CIV, at least when within a III-IV SC.
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Complejo III de Transporte de Electrones/metabolismo , Complejo IV de Transporte de Electrones/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Microscopía por Crioelectrón/métodos , Complejo III de Transporte de Electrones/química , Complejo IV de Transporte de Electrones/química , Complejo IV de Transporte de Electrones/fisiología , Hipoxia/metabolismo , Mitocondrias/química , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Isoformas de Proteínas , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/fisiologíaRESUMEN
Mitochondria metabolize almost all the oxygen that we consume, reducing it to water by cytochrome c oxidase (CcO). CcO maximizes energy capture into the protonmotive force by pumping protons across the mitochondrial inner membrane. Forty years after the H+/e- stoichiometry was established, a consensus has yet to be reached on the route taken by pumped protons to traverse CcO's hydrophobic core and on whether bacterial and mitochondrial CcOs operate via the same coupling mechanism. To resolve this, we exploited the unique amenability to mitochondrial DNA mutagenesis of the yeast Saccharomyces cerevisiae to introduce single point mutations in the hydrophilic pathways of CcO to test function. From adenosine diphosphate to oxygen ratio measurements on preparations of intact mitochondria, we definitely established that the D-channel, and not the H-channel, is the proton pump of the yeast mitochondrial enzyme, supporting an identical coupling mechanism in all forms of the enzyme.
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Complejo IV de Transporte de Electrones/química , Hemo/química , Oxidorreductasas/química , Bacterias/metabolismo , Cobre/química , Cobre/metabolismo , Complejo IV de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/metabolismo , Transporte Iónico , Mitocondrias/metabolismo , Membranas Mitocondriales/metabolismo , Oxidación-Reducción , Oxidorreductasas/metabolismo , Oxígeno/metabolismo , Bombas de Protones/metabolismo , Protones , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMEN
BACKGROUND: Quality of life (QoL) assessment forms an integral part of modern cancer care and research. The aim of this study is to determine patients' preferences and willingness to complete commonly used head-and-neck cancer (HNC) QoL questionnaires (QLQs) in routine follow-up clinics. METHODS: This is a randomised control trial of 583 subjects from 17 centres during follow-up after treatment for oral, oropharyngeal or laryngeal cancer. Subjects completed three structured validated questionnaires: EORTC QLQ-HN35; FACT-HN and UW-QOL, and an unstructured patient-generated list. The order of questionnaire presentation was randomised, and subjects were stratified by disease site and stage. Patients self-rated the questionnaires they found most helpful to communicate their health concerns to their clinicians. RESULTS: Of the 558 respondents, 82% (457) found QLQs useful to communicate their health concerns to their clinician (OR = 15.76; 95% CI 10.83-22.94). Patients preferred the structured disease-specific instruments (OR 8.79; 95% CI 5.99-12.91), while the open list was the most disliked (OR = 4.25; 95% CI 3.04-5.94). There was no difference in preference by treatment modality. More women preferred the FACT-HN (OR = 3.01, 95% CI 1.05-8.62), and patients under 70 preferred EORTC QLQ-HN35 (OR = 3.14, 95% CI 1.3-7.59). However, only 55% of patients expressed preference to complete questionnaires routinely at the clinic. CONCLUSIONS: Most patients found QLQs helpful during their follow-up and 55% supported routine questionnaires in follow-up clinics. Males and people over 70 years old were the least willing to complete the routine questionnaires and preferred shorter questionnaires (e.g., UW-QOL). Women preferred FACT-HN, and younger patients preferred EORTC QLQ-HN35. Reasons for the reluctance to complete questionnaires require elucidation.
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Neoplasias de Cabeza y Cuello , Calidad de Vida , Masculino , Humanos , Femenino , Anciano , Prioridad del Paciente , Estudios de Seguimiento , Encuestas y CuestionariosRESUMEN
BACKGROUND AND AIMS: In February 2020, the Organ Procurement and Transplantation Network replaced donor service area-based allocation of livers with acuity circles, a system based on three homogeneous circles around each donor hospital. This system has been criticized for neglecting to consider varying population density and proximity to coast and national borders. APPROACH AND RESULTS: Using Scientific Registry of Transplant Recipients data from July 2013 to June 2017, we designed heterogeneous circles to reduce both circle size and variation in liver supply/demand ratios across transplant centers. We weighted liver demand by Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) because higher MELD/PELD candidates are more likely to be transplanted. Transplant centers in the West had the largest circles; transplant centers in the Midwest and South had the smallest circles. Supply/demand ratios ranged from 0.471 to 0.655 livers per MELD-weighted incident candidate. Our heterogeneous circles had lower variation in supply/demand ratios than homogeneous circles of any radius between 150 and 1,000 nautical miles (nm). Homogeneous circles of 500 nm, the largest circle used in the acuity circles allocation system, had a variance in supply/demand ratios 16 times higher than our heterogeneous circles (0.0156 vs. 0.0009) and a range of supply/demand ratios 2.3 times higher than our heterogeneous circles (0.421 vs. 0.184). Our heterogeneous circles had a median (interquartile range) radius of only 326 (275-470) nm but reduced disparities in supply/demand ratios significantly by accounting for population density, national borders, and geographic variation of supply and demand. CONCLUSIONS: Large homogeneous circles create logistical burdens on transplant centers that do not need them, whereas small homogeneous circles increase geographic disparity. Using carefully designed heterogeneous circles can reduce geographic disparity in liver supply/demand ratios compared with homogeneous circles of radius ranging from 150 to 1,000 nm.
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Aloinjertos/provisión & distribución , Enfermedad Hepática en Estado Terminal/cirugía , Trasplante de Hígado/estadística & datos numéricos , Obtención de Tejidos y Órganos/organización & administración , Enfermedad Hepática en Estado Terminal/diagnóstico , Geografía , Disparidades en Atención de Salud/estadística & datos numéricos , Humanos , Sistema de Registros/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Donantes de Tejidos/estadística & datos numéricos , Obtención de Tejidos y Órganos/estadística & datos numéricos , Receptores de Trasplantes/estadística & datos numéricos , Estados UnidosRESUMEN
BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of <10 pack-years). Eligible patients were randomly assigned (1:1) to receive, in addition to radiotherapy (70 Gy in 35 fractions), either intravenous cisplatin (100 mg/m2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab (400 mg/m2 loading dose followed by seven weekly infusions of 250 mg/m2). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.
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Antineoplásicos/uso terapéutico , Cetuximab/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias Orofaríngeas/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Enfermedad Aguda , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cetuximab/administración & dosificación , Cetuximab/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Medición de Riesgo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Resultado del TratamientoRESUMEN
In this article, we report the number of cyclin B1 proteins tagged with enhanced green fluorescent protein (eGFP) in fixed U-2 OS cells across the cell cycle. We use a quantitative analysis of epifluorescence to determine the number of eGFP molecules in a nondestructive way, and integrated over the cell we find 104 to 105 molecules. Based on the measured number of eGFP tagged cyclin B1 proteins, knowledge of cyclin B1 dynamics through the cell cycle, and the cell morphology, we identify the stages of cells in the cell cycle. © 2020 The Authors. Cytometry Part A published by Wiley Periodicals LLC. on behalf of International Society for Advancement of Cytometry.
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Ciclinas , Ciclo Celular , División Celular , Ciclina B1/genética , Proteínas Fluorescentes Verdes/genéticaRESUMEN
BACKGROUND: The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS: In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS: From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS: Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).
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Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Disección del Cuello , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirugía , Quimioradioterapia , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Metástasis Linfática/diagnóstico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Estudios Prospectivos , Calidad de Vida , Tasa de SupervivenciaRESUMEN
Redox and CO photolysis FTIR spectra of yeast cytochrome c oxidase WT and mutants are compared to those from bovine and P. denitrificans CcOs in order to establish common functional features. All display changes that can be assigned to their E242 (bovine numbering) equivalent and to weakly H-bonded water molecules. The additional redox-sensitive band reported at 1736â¯cm-1 in bovine CcO and previously assigned to D51 is absent from yeast CcO and couldn't be restored by introduction of a D residue at the equivalent position of the yeast protein. Redox spectra of yeast CcO also show much smaller changes in the amide I region, which may relate to structural differences in the region around D51 and the subunit I/II interface.
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Monóxido de Carbono/metabolismo , Complejo IV de Transporte de Electrones/química , Complejo IV de Transporte de Electrones/metabolismo , Mutación , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/enzimología , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Animales , Dominio Catalítico , Bovinos , Complejo IV de Transporte de Electrones/genética , Cinética , Luz , Oxidación-Reducción , Fotólisis , Conformación Proteica , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genéticaRESUMEN
Climate data created from historic climate observations are integral to most assessments of potential climate change impacts, and frequently comprise the baseline period used to infer species-climate relationships. They are often also central to downscaling coarse resolution climate simulations from General Circulation Models (GCMs) to project future climate scenarios at ecologically relevant spatial scales. Uncertainty in these baseline data can be large, particularly where weather observations are sparse and climate dynamics are complex (e.g. over mountainous or coastal regions). Yet, importantly, this uncertainty is almost universally overlooked when assessing potential responses of species to climate change. Here, we assessed the importance of historic baseline climate uncertainty for projections of species' responses to future climate change. We built species distribution models (SDMs) for 895 African bird species of conservation concern, using six different climate baselines. We projected these models to two future periods (2040-2069, 2070-2099), using downscaled climate projections, and calculated species turnover and changes in species-specific climate suitability. We found that the choice of baseline climate data constituted an important source of uncertainty in projections of both species turnover and species-specific climate suitability, often comparable with, or more important than, uncertainty arising from the choice of GCM. Importantly, the relative contribution of these factors to projection uncertainty varied spatially. Moreover, when projecting SDMs to sites of biodiversity importance (Important Bird and Biodiversity Areas), these uncertainties altered site-level impacts, which could affect conservation prioritization. Our results highlight that projections of species' responses to climate change are sensitive to uncertainty in the baseline climatology. We recommend that this should be considered routinely in such analyses.
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Biodiversidad , Cambio Climático , Animales , Clima , Predicción , Modelos Teóricos , IncertidumbreRESUMEN
Adaptive sample size adjustment (SSA) for clinical trials consists of examining early subsets of on trial data to adjust estimates of sample size requirements. Blinded SSA is often preferred over unblinded SSA because it obviates many logistical complications of the latter and generally introduces less bias. On the other hand, current blinded SSA methods for binary data offer little to no new information about the treatment effect, ignore uncertainties associated with the population treatment proportions, and/or depend on enhanced randomization schemes that risk partial unblinding. I propose an innovative blinded SSA method for use when the primary analysis is a non-inferiority or superiority test regarding a risk difference. The method incorporates evidence about the treatment effect via the likelihood function of a mixture distribution. I compare the new method with an established one and with the fixed sample size study design, in terms of maximization of an expected utility function. The new method maximizes the expected utility better than do the comparators, under a range of assumptions. I illustrate the use of the proposed method with an example that incorporates a Bayesian hierarchical model. Lastly, I suggest topics for future study regarding the proposed methods.
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Teorema de Bayes , Modelos Estadísticos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Sesgo , Humanos , Funciones de Verosimilitud , Proyectos de Investigación , Riesgo , Tamaño de la MuestraRESUMEN
Three models defining mucosal tolerance when radiotherapy alone is delivered have been published. Modelling studies have converted the contribution of synchronous chemotherapy to the rate of grade 3 mucositis to biologically effective dose (BED). The purpose of this study was to apply radiotherapy mucosal tolerance models to studies of synchronous chemoradiation. Trials of synchronous cisplatin and radiotherapy were identified. The BED for cell kill for each regime was calculated. Initially, this was done using the protocol parameters and a global value for the contribution of chemotherapy of 5.1 Gy10. These values were then compared with the BED cell kill ceiling values from each of the models calculated using the intended overall treatment time. These steps were then repeated using the delivered radiotherapy parameters and a value for the contribution from chemotherapy calculated to take into account dose intensity. Eight eligible treatment arms were identified. When using the intended radiotherapy parameters, six of these appeared to be tolerable when compared with the ceiling values for two of the models. All were found intolerable by one model. When using the actual delivered radiotherapy doses and overall treatment times and correcting for chemotherapy dose intensity, one treatment arm remained intolerable by all three models, a further treatment arm by two models and four treatment arms by one model. Two current models of mucosal tolerance derived from radiotherapy data predict a majority of previously reported chemoradiation study arms to be tolerable particularly when the delivered parameters are used for calculation.
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Quimioradioterapia/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Modelos Biológicos , Mucosa Bucal/efectos de los fármacos , Mucosa Bucal/efectos de la radiación , Estomatitis/inducido químicamente , Quimioradioterapia/métodos , Humanos , Radiometría , Dosificación RadioterapéuticaRESUMEN
BACKGROUND: Patients with intermediate and high-risk oropharyngeal cancer (OPC) have poorer response to standard treatment and poorer overall survival compared to low-risk OPC. CompARE is designed to test alternative approaches to intensified treatment for these patients to improve survival. METHODS: CompARE is a pragmatic phase III, open-label, multicenter randomised controlled trial with an adaptive multi-arm, multi-stage design and an integrated QuinteT Recruitment Intervention. Eligible OPC patients include those with human papillomavirus (HPV) negative, T1-T4, N1-N3 or T3-4, N0, or HPV positive N3, T4, or current smokers (or ≥ 10 pack years previous smoking history) with T1-T4, N2b-N3. CompARE was originally designed with four arms (one control [arm 1] and three experimental: arm 2-induction chemotherapy followed by arm 1; arm 3-dose-escalated radiotherapy plus concomitant cisplatin; and arm 4-resection of primary followed by arm 1). The three original experimental arms have been closed to recruitment and a further experimental arm opened (arm 5-induction durvalumab followed by arm 1 and then adjuvant durvalumab). Currently recruiting are arm 1 (control): standard treatment of 3-weekly cisplatin 100 mg/m2 or weekly 40 mg/m2 with intensity-modulated radiotherapy using 70 Gy in 35 fractions ± neck dissection determined by clinical and radiological assessment 3 months post-treatment, and arm 5 (intervention): one cycle of induction durvalumab 1500 mg followed by standard treatment then durvalumab 1500 mg every 4 weeks for a total of 6 months. The definitive and interim primary outcome measures are overall survival time and event-free survival (EFS) time, respectively. Secondary outcome measures include quality of life, toxicity, swallowing outcomes, feeding tube incidence, surgical complication rates, and cost-effectiveness. The design anticipates that after approximately 7 years, 84 required events will have occurred to enable analysis of the definitive primary outcome measure for this comparison. Planned interim futility analyses using EFS will also be performed. DISCUSSION: CompARE is designed to be efficient and cost-effective in response to new data, emerging new treatments or difficulties, with the aim of bringing new treatment options for these patients. TRIAL REGISTRATION: ISRCTN ISRCTN41478539 . Registered on 29 April 2015.
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Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Cisplatino/efectos adversos , Calidad de Vida , Resultado del Tratamiento , Neoplasias Orofaríngeas/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase III como AsuntoRESUMEN
PURPOSE: While there are several prognostic classifiers, to date, there are no validated predictive models that inform treatment selection for oropharyngeal squamous cell carcinoma (OPSCC).Our aim was to develop clinical and/or biomarker predictive models for patient outcome and treatment escalation for OPSCC. EXPERIMENTAL DESIGN: We retrospectively collated clinical data and samples from a consecutive cohort of OPSCC cases treated with curative intent at ten secondary care centers in United Kingdom and Poland between 1999 and 2012. We constructed tissue microarrays, which were stained and scored for 10 biomarkers. We then undertook multivariable regression of eight clinical parameters and 10 biomarkers on a development cohort of 600 patients. Models were validated on an independent, retrospectively collected, 385-patient cohort. RESULTS: A total of 985 subjects (median follow-up 5.03 years, range: 4.73-5.21 years) were included. The final biomarker classifier, comprising p16 and survivin immunohistochemistry, high-risk human papillomavirus (HPV) DNA in situ hybridization, and tumor-infiltrating lymphocytes, predicted benefit from combined surgery + adjuvant chemo/radiotherapy over primary chemoradiotherapy in the high-risk group [3-year overall survival (OS) 63.1% vs. 41.1%, respectively, HR = 0.32; 95% confidence interval (CI), 0.16-0.65; P = 0.002], but not in the low-risk group (HR = 0.4; 95% CI, 0.14-1.24; P = 0.114). On further adjustment by propensity scores, the adjusted HR in the high-risk group was 0.34, 95% CI = 0.17-0.67, P = 0.002, and in the low-risk group HR was 0.5, 95% CI = 0.1-2.38, P = 0.384. The concordance index was 0.73. CONCLUSIONS: We have developed a prognostic classifier, which also appears to demonstrate moderate predictive ability. External validation in a prospective setting is now underway to confirm this and prepare for clinical adoption.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias Orofaríngeas , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello , Pronóstico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/genética , Estudios Retrospectivos , Estudios Prospectivos , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/patología , BiomarcadoresRESUMEN
College students regularly report increased sleep disturbances as well as concomitant reductions in performance (e.g., academic grades) upon entering college. Sleep hygiene refers to healthy sleep practices that are commonly used as first interventions in sleep disturbances. One widely used practice of this sort involves arranging the sleep environment to minimize disturbances from excessive noise and light at bedtime. Communal sleep situations such as those in college residence halls do not easily support this intervention. Following several focus groups, a questionnaire was designed to gather self-reported information on sleep disturbances in a college population. The present study used The Young Adult Sleep Environment Inventory (YASEI) and sleep logs to investigate the sleep environment of college students living in residential halls. A summary of responses indicated that noise and light are significant sleep disturbances in these environments. Recommendations are presented related to these findings.
Asunto(s)
Ambiente , Trastornos del Sueño-Vigilia/etiología , Sueño/fisiología , Estudiantes/psicología , Encuestas y Cuestionarios/normas , Adulto , Femenino , Humanos , Masculino , Universidades , Adulto JovenRESUMEN
OBJECTIVE AND BACKGROUND: We assessed current understandings in interpretation of Bayesian and traditional statistical results within the clinical researcher (non-statistician) community. METHODS: Within a 22-question survey, including demographics and experience and comfort levels with Bayesian analyses, we included questions on how to interpret both Bayesian and traditional statistical outputs. We also assessed whether Bayesian or traditional interpretations are considered more useful. RESULTS: Among the 323 respondent clinicians, 42.4% and 36.5% chose the correct interpretations of the posterior probability and 95% credible interval, respectively. Only 11.5% of respondents interpreted the p-value correctly and 23.5% interpreted the 95% confidence interval correctly. CONCLUSIONS: Based on these survey results, we conclude that most of these clinicians face uncertainty when attempting to interpret results from both Bayesian and traditional statistical outputs. When presented with accurate interpretations, clinicians generally conclude that Bayesian results are more useful than conventional ones. We believe there is a need for education of clinicians in statistical interpretation in ways that are customized to this audience.
Asunto(s)
Personal de Salud , Humanos , Teorema de Bayes , Probabilidad , IncertidumbreRESUMEN
OBJECTIVE AND BACKGROUND: The clinical trials community has been hesitant to adopt Bayesian statistical methods, which are often more flexible and efficient with more naturally interpretable results than frequentist methods. We aimed to identify self-reported barriers to implementing Bayesian methods and preferences for becoming comfortable with them. METHODS: We developed a 22-question survey submitted to medical researchers (non-statisticians) from industry, academia, and regulatory agencies. Question areas included demographics, experience, comfort levels with Bayesian analyses, perceived barriers to these analyses, and preferences for increasing familiarity with Bayesian methods. RESULTS: Of the 323 respondents, most were affiliated with pharmaceutical companies (33.4%), clinical research organizations (29.7%), and regulatory agencies (18.6%). The rest represented academia, medical practice, or other. Over 56% of respondents expressed little to no comfort in interpreting Bayesian analyses. "Insufficient knowledge of Bayesian approaches" was ranked the most important perceived barrier to implementing Bayesian methods by a plurality (48%). Of the approaches listed, in-person training was the most preferred for gaining comfort with Bayesian methods. CONCLUSIONS: Based on these survey results, we recommend that introductory level training on Bayesian statistics be presented in an in-person workshop that could also be broadcast online with live Q&A. Other approaches such as online training or collaborative projects may be better suited for higher-level trainings where instructors may assume a baseline understanding of Bayesian statistics. Increased coverage of Bayesian methods at medical conferences and medical school trainings would help improve comfort and overcome the substantial knowledge barriers medical researchers face when implementing these methods.
Asunto(s)
Desarrollo de Medicamentos , Personal de Salud , Humanos , Teorema de Bayes , Encuestas y Cuestionarios , EscolaridadRESUMEN
Adaptive sample size redetermination (SSR) for clinical trials consists of examining early subsets of on-trial data to adjust prior estimates of statistical parameters and sample size requirements. Blinded SSR, in particular, while in use already, seems poised to proliferate even further because it obviates many logistical complications of unblinded methods and it generally introduces little or no statistical or operational bias. On the other hand, current blinded SSR methods offer little to no new information about the treatment effect (TE); the obvious resulting problem is that the TE estimate scientists might simply 'plug in' to the sample size formulae could be severely wrong. This paper proposes a blinded SSR method that formally synthesizes sample data with prior knowledge about the TE and the within-treatment variance. It evaluates the method in terms of the type 1 error rate, the bias of the estimated TE, and the average deviation from the targeted power. The method is shown to reduce this average deviation, in comparison with another established method, over a range of situations. The paper illustrates the use of the proposed method with an example.