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Human liver pyruvate kinase (hlPYK) catalyzes the final step in glycolysis, the formation of pyruvate (PYR) and ATP from phosphoenolpyruvate (PEP) and ADP. Fructose 1,6-bisphosphate (FBP), a pathway intermediate of glycolysis, serves as an allosteric activator of hlPYK. Zymomonas mobilis pyruvate kinase (ZmPYK) performs the final step of the Entner-Doudoroff pathway, which is similar to glycolysis in that energy is harvested from glucose and pyruvate is generated. The Entner-Doudoroff pathway does not have FBP as a pathway intermediate, and ZmPYK is not allosterically activated. In this work, we solved the 2.4 Å X-ray crystallographic structure of ZmPYK. The protein is dimeric in solution as determined by gel filtration chromatography, but crystallizes as a tetramer. The buried surface area of the ZmPYK tetramerization interface is significantly smaller than that of hlPYK, and yet tetramerization using the standard interfaces from higher organisms provides an accessible low energy crystallization pathway. Interestingly, the ZmPYK structure showed a phosphate ion in the analogous location to the 6-phosphate binding site of FBP in hlPYK. Circular Dichroism (CD) was used to measure melting temperatures of hlPYK and ZmPYK in the absence and presence of substrates and effectors. The only significant difference was an additional phase of small amplitude for the ZmPYK melting curves. We conclude that the phosphate ion plays neither a structural or allosteric role in ZmPYK under the conditions tested. We hypothesize that ZmPYK does not have sufficient protein stability for activity to be tuned by allosteric effectors as described for rheostat positions in the allosteric homologues.
Assuntos
Piruvato Quinase , Zymomonas , Humanos , Piruvato Quinase/metabolismo , Zymomonas/metabolismo , Sítios de Ligação , Metabolismo dos Carboidratos , Piruvatos , Regulação AlostéricaRESUMO
Various protein properties are often illuminated using sequence comparisons of protein homologs. For example, in analyses of the pyruvate kinase multiple sequence alignment, the set of positions that changed during speciation ("phylogenetic" positions) were enriched for "rheostat" positions in human liver pyruvate kinase (hLPYK). (Rheostat positions are those which, when substituted with various amino acids, yield a range of functional outcomes). However, the correlation was moderate, which could result from multiple biophysical constraints acting on the same position during evolution and/or various sources of noise. To further examine this correlation, we here tested Zymomonas mobilis PYK (ZmPYK), which has <65% sequence identity to any other PYK sequence. Twenty-six ZmPYK positions were selected based on their phylogenetic scores, substituted with multiple amino acids, and assessed for changes in Kapp-PEP . Although we expected to identify multiple, strong rheostat positions, only one moderate rheostat position was detected. Instead, nearly half of the 271 ZmPYK variants were inactive and most others showed near wild-type function. Indeed, for the active ZmPYK variants, the total range of Kapp,PEP values ("tunability") was 40-fold less than that observed for hLPYK variants. The combined functional studies and sequence comparisons suggest that ZmPYK has evolved functional and/or structural attributes that differ from the rest of the family. We hypothesize that including such "orphan" sequences in MSA analyses obscures the correlations used to predict rheostat positions. Finally, results raise the intriguing biophysical question as to how the same protein fold can support rheostat positions in one homolog but not another.
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Piruvato Quinase , Zymomonas , Aminoácidos , Humanos , Proteínas/química , Piruvato Quinase/química , Zymomonas/genética , Zymomonas/metabolismoRESUMO
PURPOSE: To externally validate previously published Normal Tissue Complication Probability (NTCP) models developed by separate teams for grade 3 oral mucositis (g3OM). MATERIALS AND METHODS: Two models were validated: a logistic model, based on 144 head and neck cancer (HNC) patients receiving induction chemotherapy followed by chemo-IMRT; a multivariable logistic model for prediction of g3OM for 253 patients receiving radical treatment for the head and neck squamous cell carcinoma (HNSCC). The EORTC HNCG-ROG 1219 DAHANCA trial dataset, consisting of 169 patients was used as the validation cohort. This cohort was treated with accelerated fractionated chemo-IMRT, with/without the hypoxic radiosensitizer Nimorazole for HNSCC. External validity was assessed using the scaled Brier score. Calibration was assessed in terms of calibration curves as well as measures of mean and weak calibration. Hosmer-Lemeshow was used for goodness-of-fit test. Discrimination was calculated using the area under the receiver operating curve (AUC-ROC). RESULTS: The prevalence of g3OM in the validation cohort (35.5%) was similar to that of two development cohorts, i.e. 38.7% and 31.9% for Bhide logistic and Otter multivariable logistic models respectively. The scaled Brier scores showed good overall model performance. Perfect calibration was observed in the prevalence range of 20% to 40%. AUC-ROC was acceptable in external validation (0.67). The Hosmer-Lemeshow test showed good agreement between predicted and observed outcomes for two models. CONCLUSION: The NTCP models were validated and lead to valid predictions in a wide range of diverse treatment techniques and patient characteristics, also when Nimorazole is added as hypoxic radiosensitizer.
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Neoplasias de Cabeça e Pescoço , Estomatite , Estudos de Coortes , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Probabilidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapiaRESUMO
Zeolites are porous aluminosilicate materials utilized in a variety of sorption, separation, and catalytic applications. The oil refining industry in particular has seen a number of significant advances due to the introduction of new technologies enabled by new zeolites. Of particular importance are zeolites with 10- or 12-membered ring pores, resulting in pore shapes and sizes appropriate for the interaction with small hydrocarbon molecules. Here, the synthesis of a new zeolite UZM-55 is reported and the idealized structure thereof is presented. The most complex structure solved to date, UZM-55 possesses a large triclinic unit cell containing 52 T-sites. The material uniquely contains both 10- and 12-membered ring pores in a single, undulating one-dimensional channel, the first example in a zeolitic material of multiple delimiting rings in a single channel. This discovery opens new opportunities in shape-selective adsorption and catalysis. Demonstrated here is the unique adsorption behavior of UZM-55, shown both experimentally and computationally to adsorb one nonane molecule per unit cell in a linear conformation.
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BACKGROUND: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). MATERIALS AND METHODS: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. RESULTS: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. CONCLUSIONS: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Hormônio Foliculoestimulante/metabolismo , Hormônio Liberador de Gonadotropina/agonistas , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Leuprolida/uso terapêutico , Oligopeptídeos/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Idoso , Substituição de Medicamentos , Humanos , Calicreínas/metabolismo , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismoRESUMO
BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.
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Proteínas Proto-Oncogênicas c-met/genética , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Piridinas/efeitos adversos , Piridinas/uso terapêutico , Sarcoma de Células Claras/tratamento farmacológico , Sarcoma de Células Claras/enzimologia , Adolescente , Adulto , Estudos de Coortes , Crizotinibe , Feminino , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteína EWS de Ligação a RNA/genética , Sarcoma de Células Claras/genética , Adulto JovemRESUMO
BACKGROUND: The absence of a survival benefit for whole brain radiotherapy (WBRT) among randomized trials has been attributed to a competing risk of death from extracranial disease. We re-analyzed EORTC 22952 to assess the impact of WBRT on survival for patients with controlled extracranial disease or favorable prognoses. PATIENTS AND METHODS: We utilized Cox regression, landmark analysis, and the Kaplan-Meier method to evaluate the impact of WBRT on survival accounting for (i) extracranial progression as a time-dependent covariate in all patients and (ii) diagnosis-specific graded prognostic assessment (GPA) score in patients with primary non-small-cell lung cancer (NSCLC). RESULTS: A total of 329 patients treated per-protocol were included for analysis with a median follow up of 26 months. One hundred and fifteen (35%) patients had no extracranial progression; 70 (21%) patients had progression <90 days, 65 (20%) between 90 and 180 days, and 79 (24%) patients >180 days from randomization. There was no difference in the model-based risk of death in the WBRT group before [hazard ratio (HR) (95% CI)=0.70 (0.45-1.11), P = 0.133), or after [HR (95% CI)=1.20 (0.89-1.61), P = 0.214] extracranial progression. Among 177 patients with NSCLC, 175 had data available for GPA calculation. There was no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores [HR (95% CI)=1.10 (0.68-1.79)] or unfavorable GPA scores [HR (95% CI)=1.11 (0.71-1.76)]. CONCLUSIONS: Among patients with limited extracranial disease and one to three brain metastases at enrollment, we found no significant survival benefit to WBRT among NSCLC patients with favorable GPA scores or patients with any histology and controlled extracranial disease status. This exploratory analysis of phase III data supports the practice of omitting WBRT for patients with limited brain metastases undergoing SRS and close surveillance. CLINICAL TRIALS NUMBER: NCT00002899.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/radioterapia , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiocirurgia , Irradiação Corporal TotalRESUMO
AIMS: Quality assurance (QA) in a surgical trial must be planned and implemented from study development to completion. Elements of quality must be consistently described in a protocols, case report forms (CRFs) and reported in publications. The purpose of this review was to evaluate the most common surgical parameters and how consistently they were described in EORTC study documents where surgery was included. This was the preliminary step in mapping out the challenges of developing a surgical QA strategy in EORTC. METHODS: A systematic review of EORTC surgical protocols from 1980 to 2013 was performed. Two independent reviewers selected and reviewed the protocols. Data extraction was done using a questionnaire developed by EORTC QA committee. The results were compared across the time period. RESULTS: The most common quality parameters described in protocols were surgical technique, definition of resectability, surgical margins and methods of assessing adverse events using the Common Terminology Criteria for Adverse Event (CTCAE). However, these were not consistently reported in publications. A general improvement in the method of protocol development was observed since year 2000 after standardization measures by EORTC. A new surgical chapter template has been proposed. CONCLUSION: There is a need to consistently define and report surgical parameters from protocol development to publication as a first step to QA. A standard surgical chapter in the EORTC protocol template can help address this need. A framework to consistently implement QA for future surgical trials is needed and the rationale for this is described in this review.
Assuntos
Pesquisa Biomédica/normas , Protocolos Clínicos , Neoplasias/cirurgia , Garantia da Qualidade dos Cuidados de Saúde , Oncologia Cirúrgica/normas , Europa (Continente) , HumanosRESUMO
Synaesthesia is a condition that gives rise to unusual secondary sensations (e.g., colours are perceived when listening to music). These unusual sensations tend to be reported as being stable throughout adulthood (e.g., Simner & Logie, 2007, Neurocase, 13, 358) and the consistency of these experiences over time is taken as the behavioural hallmark of genuineness. Our study looked at the influence of mood states on synaesthetic colours. In Experiment 1, we recruited grapheme-colour synaesthetes (who experience colours from letters/digits) and elicited their synaesthetic colours, as well as their mood and depression states, in two different testing sessions. In each session, participants completed the PANAS-X (Watson & Clark, 1999) and the BDI-II (Beck, Steer, & Brown, 1996, Manual for Beck Depression Inventory-II), and chose their synaesthetic colours for letters A-Z from an interactive colour palette. We found that negative mood significantly decreased the luminance of synaesthetic colours. In Experiment 2, we showed that synaesthetic colours were also less luminant for synaesthetes with anxiety disorder, versus those without. Additional evidence suggests that colour saturation, too, may inversely correlate with depressive symptoms. These results show that fluctuations in mood within both a normal and clinical range influence synaesthetic colours over time. This has implications for our understanding about the longitudinal stability of synaesthetic experiences, and of how mood may interact with the visual (imagery) systems.
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Afeto/fisiologia , Transtornos de Ansiedade/fisiopatologia , Percepção de Cores/fisiologia , Transtorno Depressivo/fisiopatologia , Transtornos da Percepção/fisiopatologia , Adolescente , Adulto , Associação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Inquéritos e Questionários , Sinestesia , Adulto JovemRESUMO
OBJECTIVE: The European Organisation for the Research and Treatment of Cancer (EORTC) Radiation Oncology Group (ROG) has performed radiotherapy quality assurance (QA) in clinical trials, including dummy runs (DR) and individual case reviews (ICR), since 1991. We investigated the influence of DR results on subsequent QA and patient outcomes. METHODS: EORTC ROG studies were reviewed for DR inclusion, QA and mature clinical outcomes. A DR was classified as a failure if corrections necessitated re-submission. ICR were graded as acceptable, minor or major deviation overall. Fisher's exact test characterised potential correlations and the Mantel-Haenszel statistic quantified pooled odds ratios (OR). RESULTS: DR and ICR data were available from 12 and 3 protocols, respectively. The proportion of institutions successful at first DR attempt varied per trial from 5.6% to 68.8%. Participants were 3.2 times more likely to pass at first attempt after previous DR participation (p=0.0002). Pooled OR for an acceptable ICR was 1.69 (p=0.06) for institutions successful at DR first attempt. The effect of DR participation was not significantly correlated with patient outcome in the trial available for analysis. CONCLUSIONS: Implementing QA measures in ROG clinical trials should ensure optimal radiotherapy delivery. Centres which previously participated in a DR were significantly more likely to be successful at subsequent QA procedures.
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Neoplasias/radioterapia , Garantia da Qualidade dos Cuidados de Saúde , Radioterapia/normas , Humanos , Estudos Multicêntricos como AssuntoRESUMO
BACKGROUND: We report the 10-year results of the EORTC trial 24891 comparing a larynx-preservation approach to immediate surgery in hypopharynx and lateral epilarynx squamous cell carcinoma. MATERIAL AND METHODS: Two hundred and two patients were randomized to either the surgical approach (total laryngectomy with partial pharyngectomy and neck dissection, followed by irradiation) or to the chemotherapy arm up to three cycles of induction chemotherapy (cisplatin 100 mg/m(2) day 1 + 5-FU 1000 mg/m(2) day 1-5) followed for complete responders by irradiation and otherwise by conventional treatment. The end points were overall survival [OS, noninferiority: hazard ratio (preservation/surgery) ≤ 1.428, one-sided α = 0.05], progression-free survival (PFS) and survival with a functional larynx (SFL). RESULTS: At a median follow-up of 10.5 years on 194 eligible patients, disease evolution was seen in 54 and 49 patients in the surgery and chemotherapy arm, respectively, and 81 and 83 patients had died. The 10-year OS rate was 13.8% in the surgery arm and 13.1% in the chemotherapy arm. The 10-year PFS rates were 8.5% and 10.8%, respectively. In the chemotherapy arm, the 10-year SFL rate was 8.7%. CONCLUSION: This strategy did not compromise disease control or survival (that remained poor) and allowed more than half of the survivors to retain their larynx.
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Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Hipofaríngeas/tratamento farmacológico , Laringe/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Neoplasias Hipofaríngeas/patologia , Laringe/fisiopatologia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
BACKGROUND: Two phase III trials of neoadjuvant treatment in T3-4 rectal cancer established that adding chemotherapy (CRT) to radiotherapy (RT) improves pathological complete response (pCR) and local control (LC). We combined trials to assess the clinical benefit of CRT on overall (OS) and progression free survival (PFS) and to explore the surrogacy of pCR and LC. PATIENTS AND METHODS: Individual patient data from European Organisation for Research and Treatment of Cancer (EORTC) 22921 (1011 patients) and FFCD 9203 (756 patients) were pooled. Meta-analysis methodology was used to compare neoadjuvant CRT to RT for OS, PFS LC and distant progression (DP). Weighted linear regression was used to estimate trial-level association (surrogacy R(2)) between treatment effects on candidate surrogate (pCR, LC, DP) and OS. RESULTS: The median follow-up was 5.6 years. Compared to RT (881 pts), CRT (886 pts) did not prolong OS, DP or PFS. The 5-y OS-rate was 66.3% with CRT versus 65.9% in RT (hazard ratios (HR) = 1.04 {0.88-1.21}). CRT significantly improved LC (HR = 0.54, 95%confidence interval (CI): 0.41-0.72). PFS was validated as surrogate for OS with R(2) = 0.88. Neoadjuvant treatment effects on LC (R(2) = 0.17) or DP (R(2) = 0.31) did not predict effects on OS. CONCLUSION: Preoperative CRT does not prolong OS or PFS. pCR or LC do not qualify as surrogate for PFS or OS while PFS is surrogate. Phase III trials should use OS or PFS as primary endpoint.
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Quimiorradioterapia , Terapia Neoadjuvante , Neoplasias Retais/mortalidade , Neoplasias Retais/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/patologia , Neoplasias Retais/radioterapia , Adulto JovemRESUMO
The European Organisation for Research and Treatment of Cancer (EORTC) Master Protocol for phase III radiation therapy (RT) studies was published in 1995 to define in a consistent sequence the parameters which must be addressed when designing a phase III trial 'from the rationale to the references'. This was originally implemented to assist study investigators and writing committees, and to increase homogeneity within Radiation Oncology Group (ROG) study protocols. However, RT planning, delivery, treatment verification and quality assurance (QA) have evolved significantly over the last 15 years and clinical trial protocols must reflect these developments. The goal of this update is to describe the incorporation of these developments into the EORTC-ROG protocol template. Implementation of QA procedures for advanced RT trials is also briefly described as these essential elements must also be clearly articulated. This guide may assist both investigators participating in current ROG trials and others involved in writing an advanced RT trial protocol.
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Protocolos Clínicos/normas , Ensaios Clínicos Fase III como Assunto/normas , Radioterapia (Especialidade)/normas , Humanos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Radioterapia de Intensidade Modulada/normasRESUMO
AIM: We investigated the prognostic significance of intraductal carcinoma of the prostate (IDC-P) in biopsies and transurethral resections prior to external beam radiotherapy with or without androgen deprivation. METHODS: Cohort 1 consisted of 118 intermediate risk prostate cancer patients treated by radiotherapy, with biochemical relapse as primary end-point (median follow-up 6.5 years). Cohort 2 consisted of 132 high risk patients, enrolled in a phase III randomised trial (EORTC 22863) comparing radiotherapy alone to radiotherapy with long-term androgen deprivation (LTAD) with clinical progression free survival as primary end-point (median follow-up 9.1 years). Presence of IDC-P was identified after central review. Multivariable regression modelling and Kaplan-Meier analysis were performed with IDC-P as dichotomous variable. RESULTS: IDC-P was a strong prognosticator for early (<36 months) biochemical relapse (HR 7.3; p = 0.007) in cohort 1 and for clinical disease-free survival in both arms of cohort 2 (radiotherapy arm: HR 3.5; p < 0.0001; radiotherapy plus LTAD arm: HR 2.8, p = 0.018). IDC-P retained significance after stratification for reviewed Gleason score in the radiotherapy arm (HR 2.3; p = 0.03). IDC-P was a strong prognosticator for metastatic failure rate (radiotherapy arm: HR 5.3; p < 0.0001; radiotherapy plus LTAD arm: HR 3.6; p = 0.05). CONCLUSIONS: IDC-P in diagnostic samples of patients with intermediate or high risk prostate cancer is an independent prognosticator of early biochemical relapse and metastatic failure rate after radiotherapy. We suggest that the presence of IDC-P in prostate biopsies should routinely be reported.
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Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/patologia , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia/métodos , Carcinoma Intraductal não Infiltrante/radioterapia , Carcinoma Intraductal não Infiltrante/cirurgia , Estudos de Coortes , Intervalo Livre de Doença , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/cirurgia , Fatores de Risco , Resultado do TratamentoRESUMO
Given the high failure rates and the increased costs of Phase III trials in oncology and the recent explosion of targeted agents, researchers are looking for better design strategies to try and optimise the use of available patients and financial resources. In this context, adaptive designs are seen as promising tools. We reviewed the different possible adaptations in the design of a clinical trial on the basis of the FDA guidance and summarized these. The pro and cons of adaptive designs are highlighted with a focus on one of the more 'controversial' adaptive designs, the sample size reassessment based on interim-effect size as proposed by Mehta and Pocock. While group sequential designs are preferable to such adaptive designs, both are difficult to implement in the case of rapid accrual and long time to event. Adaptive designs may have some potential in less favourable situations. However, the increase in overall power should be carefully weighted as well as the risk of a large negative trial. Adaptive designs need good, sometimes extensive, logistics. Some adaptive designs (e.g. group sequential designs) proved to be very useful and are already a part of the standard repertoire of trial designs used at European Organisation for Research and Treatment of Cancer (EORTC). Adaptive designs need strong measures to prevent bias that could otherwise become uncontrollable, particularly if interim results are leaked. This includes a prospective planning of adaptations. Finally, these studies currently have the potential to induce a heavy workload and cost linked to their regulatory management.
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Ensaios Clínicos Fase II como Assunto/métodos , Ensaios Clínicos Fase III como Assunto/métodos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , Tamanho da Amostra , Europa (Continente) , Humanos , Organizações , Estudos ProspectivosRESUMO
BACKGROUND: To compare the efficacy of one cycle of standard dose cisplatin, etoposide, and ifosfamide (VIP) plus three cycles of high-dose VIP followed by stem-cell infusion [high-dose chemotherapy (HD-CT arm)] to four cycles of standard cisplatin, etoposide, and bleomycin (BEP) in patients with poor-prognosis germ-cell cancer (GCC). PATIENT AND METHODS: Patients with poor-prognosis GCC were assigned to receive either BEP or VIP followed by HD-CT. To show a 15% improvement in a 1-year failure-free survival (FFS), the study aimed to recruit 222 patients but closed with 137, due to slow accrual. RESULTS: One hundred thirty-one patients were included in this analysis. The complete response rates in the HD-CT and in the BEP arm did not differ: (intention to treat) 44.6% versus 33.3% (P = 0.18). There was no difference in FFS between the two treatment arms (P = 0.057, 66 events). At 2 years, the FFS rate was 44.8% [95% confidence interval (CI) 32.5-56.4] and 58.2%, respectively (95% CI 48.0-71.9); but this 16.3% (standard deviation 7.5%) difference was not statistically significant (P = 0.060). Overall survival did not differ between the two groups (log-rank P > 0.1, 47 deaths). CONCLUSION: This study could not demonstrate that high-dose chemotherapy given as part of first-line therapy improves outcome in patients with poor-prognosis GCC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias do Mediastino/terapia , Neoplasias Embrionárias de Células Germinativas/terapia , Neoplasias Retroperitoneais/terapia , Transplante de Células-Tronco , Neoplasias Testiculares/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Gonadotropina Coriônica/sangue , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Intervalo Livre de Doença , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Humanos , Ifosfamida/efeitos adversos , Ifosfamida/uso terapêutico , Estimativa de Kaplan-Meier , L-Lactato Desidrogenase/sangue , Masculino , Neoplasias do Mediastino/diagnóstico , Neoplasias do Mediastino/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/mortalidade , Prognóstico , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/mortalidade , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/mortalidade , Adulto Jovem , alfa-Fetoproteínas/metabolismoRESUMO
AIMS: After treatment, early breast cancer patients undergo follow-up according to standard regimens. After the first year, the main goal is particularly to detect locoregional recurrences (LRR). Our aim was to develop a simple prognostic index to predict LRR to tailor the follow-up programme. METHODS: We used data from four large international clinical randomised trials and constructed the prognostic index using Cox proportional hazards regression. The bootstrap (a resampling method) was used for internal validation. RESULTS: A total of 6516 patients treated according to current guidelines with complete covariable information were used for analysis. Covariables important for LRR in patients treated with breast conserving therapy were age, pathological tumour status, boost and surgical margins. The same variables were important for patients treated with a mastectomy, however, instead of the boost, the pathological nodal status was important. The index is composed to consist of three groups based on LRR risk after 10-years. CONCLUSIONS: We constructed a simple prognostic index that can be used to estimate risks of LRR in patients with early breast cancer. The prognostic index enables patients to be stratified into three subgroups with different outcomes with regard to LRR.
Assuntos
Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/diagnóstico , Adulto , Idoso , Análise de Variância , Neoplasias da Mama/cirurgia , Fatores de Confusão Epidemiológicos , Árvores de Decisões , Feminino , Seguimentos , Humanos , Mastectomia Radical Modificada , Mastectomia Segmentar , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de RiscoRESUMO
PURPOSE: To assess the feasibility and activity of radio-chemotherapy with mitomycin C (MMC) and cisplatin (CDDP) in locally advanced squamous cell anal carcinoma with reference to radiotherapy (RT) combined with MMC and fluorouracil (5-FU). PATIENTS AND METHODS: Patients with measurable disease >4 cmN0 or N+ received RT (36Gy+2 week gap+23.4Gy) with either MMC/CDDP or MMC/5-FU (MMC 10mg/m(2) d1 of each sequence; 5-FU 200mg/m(2)/day c.i.v. daily; CDDP 25mg/m(2) weekly). Forty patients/arm were needed to exclude a RECIST objective response rate (ORR), 8 weeks after treatment, of <75% (Fleming 1, alpha=10%, beta=10%). RESULTS: The ORR was 79.5% (31/39) (lower bound confidence interval [CI]: 68.8%) with MMC/5-FU versus 91.9% (34/ 37) (lower bound CI: 82.8%) with MMC/CDDP. In the MMC/5-FU group, two patients (5.1%) discontinued treatment due to toxicity versus 11 (29.7%) in the MMC/CDDP group. Nine grade 3 haematological events occurred with MMC/CDDP versus none with 5-FU/MMC. The rate of other toxicities did not differ. There was no toxic death. Thirty-one patients in the MMC/5-FU arm (79.5%) and 18 in the MMC/CDDP arm (48.6%) were fully compliant with the protocol treatment (p=0.005). CONCLUSIONS: Radio-chemotherapy with MMC/CDDP seems promising as only MMC/CDDP demonstrated enough activity (RECIST ORR >75%) to be tested further in phase III trials; MMC/5-FU did not. MMC/CDDP also had an overall acceptable toxicity profile.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/tratamento farmacológico , Neoplasias do Ânus/radioterapia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Ânus/cirurgia , Carcinoma de Células Escamosas/cirurgia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Terapia Combinada , Intervalo Livre de Doença , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Cooperação do Paciente , Resultado do TratamentoRESUMO
BACKGROUND: The association between diverting stomas and symptomatic anastomotic leakage after rectal cancer surgery was studied, as well as the impact of leakage on local recurrence, distant metastasis, and disease-free, overall and cancer-specific survival. METHODS: Data from the Swedish Rectal Cancer Trial, Dutch TME trial, CAO/ARO/AIO-94 trial, EORTC 22921 trial and Polish Rectal Cancer Trial were pooled (n = 5187). All eligible patients without distant metastases at the time of low anterior resection were selected (n = 2726); overall survival was studied in patients aged 75 years or less (n = 2480). Multivariable models were used to study the association between diverting stomas and anastomotic leakage, and between leakage and recurrence or survival. RESULTS: Some 9.7 per cent of patients were diagnosed with a symptomatic anastomotic leak; diverting stomas were negatively associated with leakage (11.6 per cent without and 7.8 per cent with a stoma; P = 0.002). Anastomotic leakage was negatively associated with overall survival in the multivariable analysis (hazard ratio (HR) 1.29 (95 per cent confidence interval 1.02 to 1.63); P = 0.034), but not with cancer-specific survival (HR 1.12 (0.83 to 1.52); P = 0.466). CONCLUSION: Diverting stomas were associated with less symptomatic anastomotic leakage. Oncological outcome was not significantly influenced by leakage, but overall survival was reduced.