ABSTRACT
BACKGROUND: A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. METHODS: In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. FINDINGS: Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4-48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6-25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. INTERPRETATION: A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. FUNDING: None.
Subject(s)
Carcinoma, Renal Cell/secondary , Kidney Neoplasms/pathology , Tomography, X-Ray Computed/methods , Aged , Carcinoma, Renal Cell/diagnostic imaging , Carcinoma, Renal Cell/epidemiology , Carcinoma, Renal Cell/surgery , Female , Follow-Up Studies , Humans , Kidney Neoplasms/diagnostic imaging , Kidney Neoplasms/epidemiology , Kidney Neoplasms/surgery , Male , Middle Aged , Neoplasm Staging , Nephrectomy , Population Surveillance , Prognosis , Prospective Studies , Spain/epidemiology , Survival Rate , United Kingdom/epidemiology , United States/epidemiologyABSTRACT
Urothelial carcinoma is one of the leading causes of death in Europe and the United States. Despite its chemosensitivity, median overall survival for advanced disease is still nearly 1 year. Most second-line chemotherapeutic agents tested have been disappointing. Thus, new treatment strategies are clearly needed. This review focuses on emerging therapies in urothelial carcinoma. Results from recent clinical trials, investigating the activity of new generation cytostatic agents, as well as results from studies assessing the toxicity and efficacy of novel targeted therapies, are discussed. In this setting, anti-epidermal growth factor receptor, angiogenesis, and phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitors account for the majority of phase I and II trials.
Subject(s)
Urinary Bladder Neoplasms/drug therapy , Humans , Molecular Targeted Therapy , Urologic Neoplasms/drug therapyABSTRACT
Alpha-synuclein, parkin, and synphilin-1 are proteins mainly involved in the pathogenesis of Lewy body (LB) diseases. mRNAs of all three undergo alternative splicing, so that the existence of various isoforms has been described. Since increasing evidence supports the importance of differential isoform-expression changes in disease development, we have established isoform-expression profiles in frontal cortices of LB disease brains in comparison with those of Alzheimer disease (AD) and control frontal cortices. The differential expression of four alpha-synuclein, seven parkin, and four synphilin-1 isoforms was ascertained by the use of isoform-specific primers and relative expression analysis with SybrGreen and beta-actin as an internal standard. The establishment of isoform-expression profiles revealed that these are disease specific. Moreover, isoform-expression deregulation of mainly one gene in each disease could be observed. All four alpha-synuclein isoforms were affected in the case of the pure form of dementia with LB, most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. Only minor involvement was detected in AD. Finally, the existence of a proprietary isoform-expression profile in common LB disease indicates that this disease develops as a result of its own molecular mechanisms, and so, at the molecular level, it does not exactly share changes found in pure dementia with LB and AD. In conclusion, isoform-expression profiles in LB diseases represent additional evidence for the direct involvement of isoform-expression deregulation in the development of neurodegenerative disorders.
Subject(s)
Carrier Proteins/genetics , Lewy Body Disease/genetics , Nerve Tissue Proteins/genetics , Ubiquitin-Protein Ligases/genetics , alpha-Synuclein/genetics , Aged , Aged, 80 and over , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Base Sequence , Carrier Proteins/metabolism , Case-Control Studies , DNA Primers/genetics , Female , Frontal Lobe/metabolism , Gene Expression , Gene Expression Profiling , Humans , Lewy Body Disease/etiology , Lewy Body Disease/metabolism , Male , Middle Aged , Multiple System Atrophy/genetics , Multiple System Atrophy/metabolism , Nerve Tissue Proteins/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , Polymerase Chain Reaction , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ubiquitin-Protein Ligases/metabolism , alpha-Synuclein/metabolismABSTRACT
Alternative splicing gives rise to at least seven parkin and eight synphilin-1 isoforms. Since both parkin and synphilin-1 have been involved in Lewy body (LB) formation, we decided to explore whether their isoforms are differentially expressed in LB diseases. With this aim, we studied relative mRNA expression levels of parkin and synphilin-1 isoforms in the frontal cortices of patients with dementia with LBs, the LB variant of Alzheimer's disease and Parkinson's disease and compared the findings with those obtained from Alzheimer's disease patients and control individuals. Duplex real-time PCR reactions, with beta-actin as internal standard, were carried out in a LightCycler. mRNA expression levels of parkin and synphilin-1 isoforms were seen to be specifically altered in each of the LB diseases studied. These findings suggest that parkin and synphilin-1 isoform expression changes play a significant role in the pathogenesis of LB diseases.
Subject(s)
Alzheimer Disease/genetics , Carrier Proteins/genetics , Genetic Predisposition to Disease/genetics , Lewy Body Disease/genetics , Nerve Tissue Proteins/genetics , Parkinson Disease/genetics , Ubiquitin-Protein Ligases/genetics , Aged , Aged, 80 and over , Alternative Splicing/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Brain/metabolism , Brain/physiopathology , Brain Chemistry/genetics , Carrier Proteins/metabolism , Disease Progression , Female , Gene Expression Regulation/genetics , Genetic Markers/genetics , Humans , Lewy Body Disease/metabolism , Lewy Body Disease/physiopathology , Male , Middle Aged , Nerve Tissue Proteins/metabolism , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Messenger/analysis , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Ubiquitin-Protein Ligases/metabolismABSTRACT
alpha-Synuclein, the main component of proteinaceous inclusions in synucleinopathies, is centrally involved in aggregation processes preceding Lewy body formation. Here we describe a new alpha-synuclein gene poly-T polymorphism that is situated upstream to exon 3 and consists of three different alleles. A correlation between poly-T length and expression of alpha-synuclein 126 mRNA, an isoform lacking exon 3, was detected in the human cerebral cortex. Specifically, when compared with the most frequent 7T/7T genotype, the shortest poly-T stretch (5T) was associated with the lowest alpha-synuclein 126 expression levels, whereas the longest poly-T stretch (12T) was accompanied by the highest alpha-synuclein 126 expression levels. Thus, three different expression-level-specific genotypes, with 5T+ genotypes as low alpha-synuclein 126 expression genotypes and 12T+ genotypes as high alpha-synuclein 126 expression genotypes, could be established. Poly-T genotype distributions were also analyzed in a healthy control population. Age-dependent variations in this distribution were observed and showed accumulation of low alpha-synuclein 126 expression genotypes at ages under 60 years and high alpha-synuclein 126 expression genotypes at ages over 80 years. To determine human specificity of the variable poly-T strech, the mouse alpha-synuclein gene sequence was analyzed. Although alpha-synuclein is very well conserved in vertebrates, the poly-T sequence was found to be absent in mice, and an alpha-synuclein 126 mouse homologue could not be detected. In conclusion, this newly identified poly-T polymorphism is a human-specific sequence; its length influences alpha-synuclein 126 expression levels; and, finally, it seems to exert a specific influence on normal aging.
Subject(s)
Aging/metabolism , Alzheimer Disease/genetics , Frontal Lobe/metabolism , alpha-Synuclein/genetics , Aged , Aged, 80 and over , Alzheimer Disease/metabolism , Animals , Base Sequence , Case-Control Studies , Female , Gene Expression Regulation/physiology , Gene Frequency , Genotype , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Molecular Sequence Data , Protein Isoforms , Reference Values , Sequence Homology , Species Specificity , alpha-Synuclein/metabolismABSTRACT
Alpha-synuclein, a main component of Lewy bodies in synucleinopathies and senile plaques in Alzheimer disease, is centrally involved in neurodegeneration. Three different isoforms (alpha-synuclein 112, 126, and 140) resulting from alternative splicing have been described so far. The present study explores alpha-synuclein 126 mRNA expression levels in the prefrontal cortex of six patients with dementia with Lewy bodies, eight patients with Lewy body variant of Alzheimer disease, eight patients with Alzheimer disease, and 10 controls. Relative alpha-synuclein 126 expression levels were determined by real-time polymerase chain reaction with competimer technology. Alpha-synuclein 126 mRNA expression was markedly decreased in the three dementias in comparison with controls, suggesting an important role of this alpha-synuclein isoform in the normal brain.