RESUMO
BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.
Assuntos
Ensaios Clínicos como Assunto , Terapia de Reposição de Enzimas , Doença de Fabry/tratamento farmacológico , Rim/metabolismo , Adulto , Consenso , Técnica Delphi , Doença de Fabry/genética , Doença de Fabry/metabolismo , Doença de Fabry/patologia , Feminino , Globosídeos/uso terapêutico , Glicolipídeos/uso terapêutico , Humanos , Isoenzimas/genética , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Esfingolipídeos/uso terapêutico , Resultado do Tratamento , Triexosilceramidas/uso terapêutico , alfa-Galactosidase/genéticaRESUMO
BACKGROUND: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018. DESIGN: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here. RESULTS: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy. CONCLUSION: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.
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Oncologia/tendências , Neoplasias/epidemiologia , Neoplasias/terapia , Caracteres Sexuais , Composição Corporal , Tomada de Decisões , Feminino , Humanos , Masculino , Neoplasias/genética , Neoplasias/patologia , Médicos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate candidate biomarkers to predict future renal function decline (RFD) in children and adults with lupus nephritis (LN). METHODS: At the time of enrollment into prospective observational LN cohort studies liver-type fatty acid binding protein (LFABP), albumin, monocyte chemoattractant protein-1 (MCP-1), uromodulin, transferrin, and hepcidin were measured in urine samples of two cohorts of patients with LN, one followed at a pediatric (cohort-1; n = 28) and one at an adult institution (cohort-2; n = 69). The primary outcome was RFD, defined in cohort-1 as a decrease in estimated glomerular filtration rate (eGFR) of ≥20% and in cohort-2 as a sustained increase of ≥25% in serum creatinine concentration (SCr), both from baseline. RESULTS: All patients (n = 97) had normal eGFR or SCr at the time of urine collection at baseline. RFD occurred in 29% (8/28) of patients in cohort-1 during a mean follow-up of 6.1 months, and in 30% (21/69) of those in cohort-2 during a mean follow-up of 60 months. Individually, in cohort-1, levels of MCP-1, transferrin, LFABP, and albumin were higher in the RFD group than those who maintained renal function, with statistical significance for LFABP and albumin. In cohort-2 the RFD group also had higher levels of urine MCP-1 and albumin than others. The combination of LFABP, MCP-1, albumin, and transferrin had good predictive accuracy for RFD in both cohorts (area under the ROC curve = 0.77-0.82). CONCLUSION: The combinatorial urine biomarker LFABP, MCP-1, albumin, and transferrin shows promise as a predictor of renal functional decline in LN, and warrants further investigation.
Assuntos
Nefrite Lúpica/fisiopatologia , Nefrite Lúpica/urina , Adolescente , Adulto , Biomarcadores/urina , Quimiocina CCL2/urina , Criança , Creatinina/urina , Feminino , Taxa de Filtração Glomerular , Hepcidinas/urina , Humanos , Testes de Função Renal , Nefrite Lúpica/diagnóstico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transferrina/urina , Uromodulina/urina , Adulto JovemRESUMO
The application of multiple imputation (MI) techniques as a preliminary step to handle missing values in data analysis is well established. The MI method can be classified into two broad classes, the joint modeling and the fully conditional specification approaches. Their relative performance for the longitudinal ordinal data setting under the missing at random (MAR) assumption is not well documented. This article intends to fill this gap by conducting a large simulation study on the estimation of the parameters of a longitudinal proportional odds model. The two MI methods are also illustrated in quality of life data from a cancer clinical trial.
Assuntos
Estudos Longitudinais , Modelos Estatísticos , Pacientes Desistentes do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Simulação por Computador , Glioblastoma/tratamento farmacológico , Glioblastoma/radioterapia , Humanos , Modelos Logísticos , Análise Multivariada , Pacientes Desistentes do Tratamento/estatística & dados numéricos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Distribuições Estatísticas , Inquéritos e QuestionáriosRESUMO
Several phase I/II studies of chemoradiotherapy for gastric cancer have reported promising results, but the significance of preoperative radiotherapy in addition to chemotherapy has not been proven. In this study, a systematic literature search was performed to capture survival and postoperative morbidity and mortality data in randomised clinical studies comparing preoperative (chemo)radiotherapy or chemotherapy versus surgery alone, or preoperative chemoradiotherapy versus chemotherapy for gastric and/or gastro-oesophageal junction (GOJ) cancer. Hazard ratios (HRs) for overall mortality were extracted from the original studies, individual patient data provided from the principal investigators of eligible studies or the earlier published meta-analysis. The incidences of postoperative morbidities and mortalities were also analysed. In total 18 studies were eligible and data were available from 14 of these. The meta-analysis on overall survival yielded HRs of 0.75 (95% CI 0.65-0.86, P < 0.001) for preoperative (chemo)radiotherapy and 0.83 (95% CI 0.67-1.01, P = 0.065) for preoperative chemotherapy when compared to surgery alone. Direct comparison between preoperative chemoradiotherapy and chemotherapy resulted in an HR of 0.71 (95% CI 0.45-1.12, P = 0.146). Combination of direct and adjusted indirect comparisons yielded an HR of 0.86 (95% CI 0.69-1.07, P = 0.171). No statistically significant differences were seen in the risk for postoperative morbidity or mortality between preoperative treatments and surgery alone, or preoperative (chemo)radiotherapy and chemotherapy. Preoperative (chemo)radiotherapy for gastric and GOJ cancer showed significant survival benefit over surgery alone. In comparisons between preoperative chemotherapy and (chemo)radiotherapy, there is a trend towards improved survival when adding radiotherapy, without increased postoperative morbidity or mortality.
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Adenocarcinoma/terapia , Quimiorradioterapia Adjuvante , Esofagectomia , Junção Esofagogástrica/cirurgia , Gastrectomia , Neoplasias Gástricas/terapia , Adenocarcinoma/mortalidade , Quimioterapia Adjuvante , Intervalo Livre de Doença , Humanos , Terapia Neoadjuvante/métodos , Radioterapia Adjuvante , Neoplasias Gástricas/mortalidade , Resultado do TratamentoRESUMO
PURPOSE: In cancer clinical trials, health-related quality of life (HRQoL) is a major outcome measure. It is generally assessed at specified time intervals by filling out a questionnaire with ordered response categories. Despite recent advances in the statistical methodology for handling ordinal longitudinal outcome data, most users keep treating HRQoL scales as continuous rather than ordinal variables regardless of the number of categories. The purpose of this study was to compare the results of analyzing HRQoL longitudinal data under both approaches, continuous and ordinal. METHODS: The EORTC QLQ-C30 scores of two EORTC randomized brain cancer clinical trials (26951 and 26981) were analyzed using the two approaches. In the 26951 trial, a total of 368 patients were randomly assigned to receive either radiotherapy (RT) or the same RT plus procarbazine, CCNU, and vincristine. In the 26981 trial, 573 patients were randomly allocated to RT or RT plus temozolomide. Comparison of the two treatment arms was done using methods for longitudinal quantitative and longitudinal ordinal data. Both statistical methods were adapted to account for missing data and compared in terms of statistical significance of the results (p values) but also with respect to data interpretation. RESULTS: Three scales, i.e., appetite loss, insomnia, and drowsiness, presenting four response categories ("Not at all", "A little", "Quite a bite", and "Very much") were analyzed in each trial. Both statistical methods (continuous and ordinal) showed statistically significant differences between the two treatments, not only globally but also at the same assessment time points. The magnitude of the p values, however, varied at some time points and was less pronounced in the ordinal approach. CONCLUSIONS: The analysis of the two clinical trials showed that treating the HRQoL scales by a quantitative or an ordinal method did not make much difference as far as statistical significance was concerned. The interpretation of results, however, was easier under the ordinal approach. Treatment effects may be more meaningful when expressed in terms of odds ratios than as mean values, particularly when the number categories is small.
Assuntos
Neoplasias Encefálicas/psicologia , Nível de Saúde , Qualidade de Vida , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Apetite , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Feminino , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Procarbazina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Fases do Sono , Inquéritos e Questionários , Temozolomida , Vincristina/uso terapêuticoRESUMO
AIM: The aim of this study is to describe local tumour control after radiofrequency ablation (RFA) and surgical resection (RES) of colorectal liver metastases (CLM) in two independent European Organisations for Research and Treatment of Cancer (EORTC) studies. BACKGROUND: Only 10-20% of patients with newly diagnosed CLM are eligible for curative RES. RFA has found a place in daily practice for unresectable CLM. There are no prospective trials comparing RFA to RES for resectable CLM. METHODS: The CLOCC trial randomised 119 patients with unresectable CLM between RFA (±RES)+adjuvant FOLFOX (±bevacizumab) versus FOLFOX (±bevacizumab) alone. The EPOC trial randomised 364 patients with resectable CLM between RES±perioperative FOLFOX. We describe the local control of resected patients with lesions ≤4 cm in the perioperative chemotherapy arm of the EPOC trial (N=81) and the RFA arm of the CLOCC trial (N=55). RESULTS: Local recurrence (LR) rate for RES was 7.4% per patient and 5.5% per lesion. LR rate for RFA was 14.5% per patient and 6.0% per lesion. When lesion size was limited to 30 mm, LR rate for RFA lesions was 2.9% per lesion. Non-local hepatic recurrences were more often observed in RFA patients than in RES patients, 30.9% and 22.3% respectively. Patients receiving RFA had a more advanced disease. CONCLUSIONS: LR rate after RFA for lesions with a limited size is low. The local control per lesion does not appear to differ greatly between RFA and surgical resection. This study supports the local control of RFA in patients with limited liver metastases. Future studies should evaluate in which patients RFA could be an equal alternative to liver resection.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ablação por Cateter , Neoplasias Colorretais/terapia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Bevacizumab , Quimioterapia Adjuvante , Neoplasias Colorretais/patologia , Terapia Combinada , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Compostos Organoplatínicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: This study investigates the possible benefits of radiofrequency ablation (RFA) in patients with non-resectable colorectal liver metastases. METHODS: This phase II study, originally started as a phase III design, randomly assigned 119 patients with non-resectable colorectal liver metastases between systemic treatment (n = 59) or systemic treatment plus RFA ( ± resection) (n = 60). Primary objective was a 30-month overall survival (OS) rate >38% for the combined treatment group. RESULTS: The primary end point was met, 30-month OS rate was 61.7% [95% confidence interval (CI) 48.2-73.9] for combined treatment. However, 30-month OS for systemic treatment was 57.6% (95% CI 44.1-70.4), higher than anticipated. Median OS was 45.3 for combined treatment and 40.5 months for systemic treatment (P = 0.22). PFS rate at 3 years for combined treatment was 27.6% compared with 10.6% for systemic treatment only (hazard ratio = 0.63, 95% CI 0.42-0.95, P = 0.025). Median progression-free survival (PFS) was 16.8 months (95% CI 11.7-22.1) and 9.9 months (95% CI 9.3-13.7), respectively. CONCLUSIONS: This is the first randomized study on the efficacy of RFA. The study met the primary end point on 30-month OS; however, the results in the control arm were in the same range. RFA plus systemic treatment resulted in significant longer PFS. At present, the ultimate effect of RFA on OS remains uncertain.
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Neoplasias Colorretais/patologia , Neoplasias Hepáticas/secundário , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/radioterapia , Masculino , Pessoa de Meia-Idade , Taxa de SobrevidaRESUMO
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.
Assuntos
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
Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.
Assuntos
Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Projetos de Pesquisa , Antineoplásicos/farmacologia , Europa (Continente) , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa/normas , Projetos de Pesquisa/tendênciasRESUMO
Is knowledge structured and acquired as independent facts and concepts, as parcels of independent domains, or as domains that share conceptual abilities? For an answer, we looked at the development of two concepts, belief and identity. These concepts are not part of the same domain, but the application of both depends on the common ability to separate sense from reference. We show that both capacities become functional between the ages of 3 and 5 years, which provides empirical support for the contention that deep conceptual structures play an important role in cognitive development.
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Cognição , Compreensão , Formação de Conceito , Teoria da Mente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , MemóriaRESUMO
BACKGROUND: The EORTC 24971/TAX 323, a phase III study of 358 patients with unresectable locoregionally advanced squamous cell carcinoma of the head and neck, showed an improved progression-free and overall survival (OS) with less toxicity when docetaxel (T) was added to cisplatin and 5-fluorouracil (PF) for induction and given before radiotherapy (RT). The impact of the addition of docetaxel on patients' health-related quality of life (HRQOL) and symptoms was investigated. METHODS: HRQOL was assessed at baseline, at end of cycle 2, and 4, 6, and 9 months after completion of RT using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC QLQ Head and Neck Cancer-Specific Module (EORTC QLQ-H&N35). The primary HRQOL scale was global HRQOL per protocol. RESULTS: Compliance to HRQOL assessments was 97% at baseline, but dropped to 54% by 6 months. Data were analysed up to 6 months. There was a trend towards improved global HRQOL during the treatment period. At 6 months after the end of RT, global HRQOL was higher in the TPF arm than in the PF arm, but the low compliance does not allow to draw definitive conclusions. Swallowing and coughing problems decreased more in the TPF arm than in the PF arm at the end of cycle 2, but to a limited extent. CONCLUSION: Induction chemotherapy with TPF before RT not only improves survival and reduces toxicity compared with PF but also seems to improve global HRQOL in a more sustainable manner.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Qualidade de Vida , Taxoides/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/fisiopatologia , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Progressão da Doença , Docetaxel , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/fisiopatologia , Nível de Saúde , Humanos , Taxoides/efeitos adversos , Taxoides/uso terapêutico , Fatores de Tempo , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: We examined whether retinal vessel diameter in persons with type 1 diabetes mellitus is associated with changes in subclinical anatomical and functional indicators of diabetic nephropathy. METHODS: Persons with type 1 diabetes mellitus had gradable fundus photographs and renal biopsy data at baseline and 5-year follow-up (n = 234). Retinal arteriolar and venular diameters were measured at baseline and follow-up. Central retinal arteriole equivalent (CRAE) and central retinal venule equivalent (CRVE) were computed. Baseline and 5-year follow-up renal structural variables were assessed by masked electron microscopic morphometric analyses from percutaneous renal biopsy specimens. Variables assessed included: mesangial fractional volume, glomerular basement membrane width, mesangial matrix fractional volume and glomerular basement membrane width composite glomerulopathy index. RESULTS: While controlling for other covariates, baseline CRAE was positively associated with change in the glomerulopathy index over the 5-year period. Change in CRAE was inversely related to a change in mesangial matrix fractional volume and abnormal mesangial matrix fractional volume, while change in CRVE was directly related to change in the volume fraction of cortex that was interstitium [Vv((Int/cortex))] over the 5-year period. Baseline CRAE or CRVE or changes in these diameters were not related to changes in other anatomical or functional renal endpoints. CONCLUSIONS/INTERPRETATION: Independently of other factors, baseline CRAE correlated with changes in glomerulopathy index, a composite measure of extracellular matrix accumulation in the mesangium and glomerular basement membrane. A narrowing of the CRAE was related to mesangial matrix accumulation. Changes in CRVE were related to changes in Vv((Int/cortex),) a measure of interstitial expansion in persons with type 1 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/patologia , Vasos Retinianos/patologia , Adolescente , Adulto , Análise de Variância , Diabetes Mellitus Tipo 1/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Rim/patologia , Rim/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Vasos Retinianos/fisiopatologiaRESUMO
Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). The natural history of diabetic nephropathy has changed over the last decades, as a consequence of better metabolic and blood pressure management. Thus, it may now be possible to delay or halt the progression towards ESRD in patients with overt diabetic nephropathy, and the decline of renal function is not always inexorable and unavoidable. Also, the rate of progression from microalbuminuria to overt nephropathy is much lower than originally estimated in the early 80s. Furthermore, there is now evidence that it is possible, in humans, to obtain reversal of the established lesions of diabetic nephropathy. This review focuses on the contribution of kidney biopsy studies to the understanding of the pathogenesis and natural history of diabetic nephropathy and the identification of patients at high risk of progression to ESRD. The classic lesions of diabetic nephropathy and the well-established structural-functional relationships in type 1 diabetes will be briefly summarised and the renal lesions leading to renal dysfunction in type 2 diabetes will be described. The relevance of these biopsy studies to diabetic nephropathy pathogenesis will be outlined. Finally, the evidence and the possible significance of reversibility of diabetic renal lesions will be discussed, as well as future directions for research in this field.
Assuntos
Diabetes Mellitus/fisiopatologia , Nefropatias Diabéticas/fisiopatologia , Rim/fisiopatologia , Membrana Basal/patologia , Biópsia , Diabetes Mellitus/cirurgia , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/fisiopatologia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/reabilitação , Progressão da Doença , Membrana Basal Glomerular/patologia , Humanos , Rim/lesões , Rim/patologia , Falência Renal Crônica/etiologia , Falência Renal Crônica/fisiopatologia , Túbulos Renais/patologia , Transplante de PâncreasRESUMO
This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.
Assuntos
Neoplasias Encefálicas/fisiopatologia , Glioblastoma/fisiopatologia , Qualidade de Vida , Análise de Sobrevida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosAssuntos
Microcirculação/patologia , Microcirculação/fisiopatologia , Monitorização Fisiológica , Insuficiência de Múltiplos Órgãos/etiologia , Diagnóstico por Imagem , Humanos , Leucócitos/imunologia , Leucócitos/fisiologia , Microcirculação/diagnóstico por imagem , Insuficiência de Múltiplos Órgãos/mortalidade , Radiografia , Fluxo Sanguíneo Regional , Índice de Gravidade de Doença , Choque Séptico/fisiopatologiaRESUMO
Tubular atrophy and interstitial fibrosis, important in progression of renal diseases, including diabetic (D) and cyclosporine-induced (CSA) nephropathy, have been considered irreversible. Normoglycemia for 10 years following pancreas transplantation alone (PTA) reversed D glomerulopathy lesions. This study quantified tubular, interstitial, and arteriolar parameters in PTA recipients. Kidney function studies and biopsies were performed in eight non-uremic type I D patients (pts) at 5 and 10 years after PTA. Renal biopsies were analyzed by morphometric analysis. All pts were normoglycemic and insulin independent and received CSA during the study. Cortical interstitial volume fraction was increased at 5 years (0.31+/-0.07 vs normal 0.15+/-0.02, P<0.01) and decreased at 10 years post-PTA (0.23+/-0.03, P<0.02 vs 5 years). There was a reduction in the volume fraction of interstitial collagen and cells per cortical tissue, measured using electron microscopy, from 5 (0.126+/-0.061 and 0.103+/-0.026, respectively) to 10 years (0.079+/-0.031, P<0.05, and 0.074+/-0.018, P<0.05, respectively). The volume fraction of tubules which were atrophic (AT) was abnormal at 5 years (0.160+/-0.090) and decreased from 5 to 10 years (0.044+/-0.034, P<0.02), apparently due to AT reabsorption. The index of arteriolar hyalinosis did not change during the study (1.30+/-0.22 and 1.34+/-0.33 at 5 and 10 years, respectively, nonsignificant). This study demonstrates, for the first time in humans, that interstitial expansion is reversible and that atrophic tubules can be reabsorbed. In contrast, there was no improvement in the arteriolar lesions. Whether this is due to long-term normoglycemia, reduction of CSA dose or other mechanisms is unclear.
Assuntos
Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/cirurgia , Transplante de Pâncreas , Adulto , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/cirurgia , Feminino , Humanos , Glomérulos Renais/patologia , Túbulos Renais/patologia , Masculino , Microscopia Eletrônica , Fatores de TempoRESUMO
AIMS/HYPOTHESIS: Altered glucose transporter expression has been implicated in the pathogenesis of diabetic nephropathy. There is increasing evidence that genetic factors convey risk of, or protection from, diabetic nephropathy and that the behaviour of cultured skin fibroblasts from type 1 diabetic patients may reflect these genetic influences. This study aimed to compare GLUT1 mRNA expression levels in skin fibroblasts from type 1 diabetic patients with either rapid ("fast-track", n=25) or slow ("slow-track", n=25) development of diabetic nephropathy and from non-diabetic normal control subjects (controls, n=25). METHODS: Skin fibroblasts were cultured in Dulbecco's Modified Eagle's Medium with 25 mmol/l glucose for 36 h. Total RNA was isolated, and GLUT1 mRNA levels were estimated by microarray analysis and RT-PCR. RESULTS: Levels of GLUT1 mRNA expression in skin fibroblasts from "slow-track" patients were greater than those from "fast-track" patients (p=0.02), as initially detected by microarray. GLUT1 mRNA expression levels were confirmed by RT-PCR to be higher in skin fibroblasts from "slow-track" patients (4.59+/-2.04) than in those from "fast-track" patients (3.34+/-1.2, p=0.02), and were also higher than in skin fibroblasts from control subjects (3.52+/-1.66, p=0.03). There was no statistically significant difference between levels of expression in the "fast-track" patients and the control subjects. CONCLUSIONS/INTERPRETATION: This finding is consistent with the presence of cellular protection factors against diabetic nephropathy in the "slow-track" patients. These factors could be associated with the regulation of the GLUT1 pathway and may be genetically determined.
Assuntos
Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Proteínas de Transporte de Monossacarídeos/genética , RNA Mensageiro/genética , Adulto , Pressão Sanguínea , Células Cultivadas , Diabetes Mellitus Tipo 1/complicações , Angiopatias Diabéticas/epidemiologia , Nefropatias Diabéticas/epidemiologia , Fibroblastos/metabolismo , Taxa de Filtração Glomerular , Transportador de Glucose Tipo 1 , Humanos , Hipertensão/epidemiologia , Valores de Referência , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Risco , Pele/metabolismoRESUMO
AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disorder associated with T-cell mediated injury to multiple endocrine tissues. T-cell infiltration of the juxtaglomerular apparatus could be associated with changes in local renin angiotensin system activity and, thus, with changes in the renal microenvironment. We examined the frequency of juxtaglomerular apparatus T-cell infiltration early in Type 1 diabetes and tested whether this is associated with renal structure and function. METHODS: We classified 89 Type 1 diabetic patients by immunohistochemical analysis as either juxtaglomerular apparatus T-cell positive ( n=37) or T-cell negative ( n=38). Borderline cases ( n=14) were not considered further. RESULTS: T-cell positive patients had a shorter duration of diabetes (6.7+/-2.5 years) than T-cell negative patients (9.2+/-5.0 years, p=0.011) and lower albumin excretion rate, but they had a similar glomerular filtration rate and blood pressure. Renal biopsy morphometric analysis showed similar glomerular basement membrane width and mesangial fractional volume in these two groups. However, glomerular capillary surface density ( p=0.0012) and filtration surface per glomerulus ( p=0.0155) were greater in the T-cell positive patients. CONCLUSION/INTERPRETATION: Increased filtration surface per glomerulus could be associated with glomerular filtration rate preservation in diabetes. Thus, juxtaglomerular apparatus immunologic injury in Type 1 diabetes patients could delay the clinical consequences of diabetic nephropathy.