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PubMed2002

Dynamic load at baseline can predict radiographic disease progression in medial compartment knee osteoarthritis.

OBJECTIVE: To test the hypothesis that dynamic load at baseline can predict radiographic disease progression in patients with medial compartment knee osteoarthritis (OA). METHODS: During 1991-93 baseline data were collected by assessment of pain, radiography, and gait analysis in 106 patients referred to hospital with medial compartment knee OA. At the six year follow up, 74 patients were again examined to assess radiographic changes. Radiographic disease progression was defined as more than one grade narrowing of minimum joint space of the medial compartment. RESULTS: In the 32 patients showing disease progression, pain was more severe and adduction moment was higher at baseline than in those without disease progression (n=42). Joint space narrowing of the medial compartment during the six year period correlated significantly with the adduction moment at entry. Adduction moment correlated significantly with mechanical axis (varus alignment) and negatively with joint space width and pain score. Logistic regression analysis showed that the risk of progression of knee OA increased 6.46 times with a 1% increase in adduction moment. CONCLUSIONS: The results suggest that the baseline adduction moment of the knee, which reflects the dynamic load on the medial compartment, can predict radiographic OA progression at the six year follow up in patients with medial compartment knee OA.

Aged↗

PubMed1997

Early detection of visual field progression in glaucoma: a comparison of PROGRESSOR and STATPAC 2.

AIM: To compare the performance of PROGRESSOR (pointwise linear regression) and STATPAC 2 (comparison with baseline values) in detecting early deterioration in the visual fields of glaucoma patients. METHODS: Visual field series from 19 untreated normal tension glaucoma eyes which were deteriorating on clinical grounds were analysed by PROGRESSOR and STATPAC 2. Progression criteria for PROGRESSOR were (1) inner points: slope < -1 dB/year, p < 0.05 and (2) edge points: slope < -2 dB/year, p < 0.05. Criteria for STATPAC 2 were p < 0.05 change probability for any point on three consecutive fields. Detection time was defined as the time interval between the initial field and the first field in which at least one progressing point was identified. Detection times produced by the two techniques were compared. RESULTS: PROGRESSOR and STATPAC 2 agreed on progression in all 19 eyes. Mean detection time for PROGRESSOR was 1.077 (SD 0.985) years and for STATPAC 2 was 2.161 (1.357) years. PROGRESSOR detected progression sooner than STATPAC 2 in 18 eyes (p < 0.01), Wilcoxon matched pairs signed rank test). PROGRESSOR detected progression earlier by a mean of 1.085 (0.936) years. CONCLUSIONS: PROGRESSOR consistently detected progression earlier than STATPAC 2. The PROGRESSOR software is a useful tool for the early detection of visual field deterioration in glaucoma.

Algorithms↗

PubMed2003

Five year risk of progression of primary angle closure suspects to primary angle closure: a population based study.

AIM: To report progression of primary angle closure suspects (PACS) to primary angle closure (PAC) at the 5 year follow up of a population based sample. METHODS: 82 of 118 PACS who could be contacted and 110 randomly selected normals from a population based survey in 1995 were invited for a follow up examination in 2000. Progression to PAC was based on the development of raised IOP or synechiae in a PACS. RESULTS: 50 of the 82 PACS contacted were examined. 11 (22%; 95% CI 9.8 to 34.2) developed PAC (seven synechial and four appositional); all were bilateral PACS. Two of 50 people previously diagnosed as PACS were reclassified as normal. One person among the 110 normals progressed to PAC. The relative risk of progression among PACS was 24 (95% CI 3.2 to 182.4). There was no significant difference in axial length, anterior chamber depth, or lens thickness between those who progressed and those who did not. None of the patients developed optic disc or field damage attributable to angle closure. One angle closure suspect was diagnosed to have normotensive glaucoma. CONCLUSION: In this population based study of PACS the 5 year incidence of PAC was 22%; none developed functional damage. Bilateral PACS was a clinical risk factor for progression.

Adult↗

PubMed2003

Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.

BACKGROUND AND AIMS: Steatosis, a frequent histological finding in patients with chronic hepatitis C (CHC), has been suggested to influence liver fibrosis progression. The aim of the present study was to evaluate in patients with CHC and paired liver biopsies the relationship between the evolution of steatosis and that of fibrosis between the two biopsies. METHODS: Ninety six patients were selected according to the following criteria: absence of treatment; absence of cirrhosis at initial biopsy; and serum hepatitis B surface antigen and human immunodeficiency virus antibody negativity. Degrees of necroinflammatory activity, fibrosis, and steatosis grades were assessed in the two biopsies. In addition to histological lesions, parameters studied included the source of infection, duration of infection, body mass index, alcohol intake, alanine aminotransferase levels, hepatitis C virus genotype, and viral load. RESULTS: The mean interval between the two biopsies was 48 (32) months. Steatosis was found in 54% of patients at first biopsy, and was severe in 9%. Worsening of steatosis was observed in 34% of patients, stability in 50%, and improvement in 16%. Worsening of steatosis was significantly associated with hepatic fibrosis progression in patients with (p=0.03) or without (p<0.03) steatosis at diagnosis. Overall, fibrosis progression was observed in 31% of patients and stability in 69%. In a univariate analysis, fibrosis progression was associated with male sex (p=0.05), worsening of histological activity (p=0.04), and worsening of steatosis (p=0.0003). In a multivariate analysis, the only factor independently associated with fibrosis progression was worsening of steatosis (worsening v improvement/stability: odds ratio 4.7 (95% confidence interval 1.3-10.8); p=0.0001). CONCLUSIONS: Our results suggest that in untreated patients with CHC and serial liver biopsies, fibrosis progression is strongly associated with worsening of steatosis.

Adult↗

PubMed2003

Association of the CD14 gene -159C polymorphism with progression of IgA nephropathy.

The risk factors associated with the progression of IgA nephropathy (IgAN), the most common form of glomerulonephritis, are unclear. It has been suggested that CD14 signalling in response to various microbes affects the natural history of chronic inflammatory conditions. It has been hypothesised that variants in the promoter region of the CD14 gene might alter the expression of CD14, and this in turn could influence the progressive nature of IgAN. PCR-RFLP was used to determine the polymorphism at the -159 site (T to C). The distribution of the CD14/-159 polymorphism was no different in patients with IgAN (n=216) compared to 171 healthy controls. After follow up for 86 months, it was found that an excess of the C genotype occurred in patients with progressive disease (p=0.03) and the risk of disease progression increased as the number of C alleles increased (p for trend = 0.002). The hazard ratio for progression in the patients with the CC genotype was 3.2 (p=0.025) compared with the patients possessing the TT genotype. After LPS stimulation, sCD14 was released more abundantly from the PBMCs of the TT subjects than from that of the CC subjects (p=0.006), even though mCD14 expression level was no different. In addition, the TT subjects released less IL-6 than the CC subjects after stimulation (p=0.0003). These results suggest that the CD14/-159 polymorphism is an important marker for the progression of IgAN and may modulate the level of the inflammatory responses.

Adult↗

PubMed2005

Progression of structural neuropathology in preclinical Huntington's disease: a tensor based morphometry study.

BACKGROUND AND OBJECTIVES: Regional cerebral atrophy occurs in carriers of the Huntington's disease (HD) gene mutation before clinical diagnosis is possible. The current inability to reliably measure progression of pathology in this preclinical phase impedes development of therapies to delay clinical onset. We hypothesised that longitudinal statistical imaging would detect progression of structural pathology in preclinical carriers of the HD gene mutation, in the absence of measurable clinical change. METHODS: Thirty subjects (17 preclinical mutation positive, 13 mutation negative) underwent serial clinical and magnetic resonance imaging (MRI) assessments over an interval of 2 years. Statistically significant changes in regional grey and white matter volume on MRI were analysed using tensor based morphometry (TBM). This technique derives a voxel-wise estimation of regional tissue volume change from the deformation field required to warp a subject's early to late T1 images. RESULTS: Over 2 years, there was progressive regional grey matter atrophy in mutation-positive relative to negative subjects, without significant clinical progression of disease. Significant grey matter volume loss was limited to bilateral putamen and globus pallidus externa (GPe), left caudate nucleus, and left ventral midbrain in the region of the substantia nigra. CONCLUSIONS: While these results are consistent with previous cross sectional pathologic and morphometric studies, significant progression of atrophy in HD before the onset of significant clinical decline is now demonstrable with longitudinal statistical imaging. Such measures could be used to assess the efficacy of potential disease modifying drugs in slowing the progression of pathology before confirmed clinical onset of HD.

Adult↗

PubMed1998

Measuring the rate of progression and estimating the preclinical period of Parkinson's disease with [18F]dopa PET.

OBJECTIVES: To measure the rate of progression in striatal [18F]dopa metabolism in a large group (n=32) of patients with Parkinson's disease, to estimate the average duration of preclinical period, and to examine the influence of the PET method on the assessment of rate of progression and preclinical period. METHODS: Thirty two patients with Parkinson's disease (mean age 58 (SD 13) years, mean duration 39 (SD 33) months) were assessed with [18F]dopa PET and UPDRS scoring on two occasions a mean of 18 (SD 6) months apart. PET data were sampled with separate caudate and putamen and total striatal regions of interest, and both graphical (Ki) and ratio methods of analysis. RESULTS: The mean annual rate of deterioration in [18F]dopa uptake varied according to structure and method of analysis, with putamen Ki showing the most rapid mean rate of progression (4.7% of normal mean per year). The group showed a significant deterioration (p<0.0004, paired two tailed t test) in UPDRS and in the putamen (p=0.008) and total striatal (p=0.012) [18F]dopa uptake measured using a graphical analysis, but no significant change in caudate or putamen uptake measured by a ratio approach. A study of sensitivity confirmed that putamen Ki was the most sensitive measure of disease progression, caudate ratio the least. Symptom onset in Parkinson's disease was estimated at a mean putamen [18F]dopa uptake (Ki) of 75% of normal and a mean caudate [18F]dopa uptake (Ki) of 91% of normal. CONCLUSIONS: Estimation of mean rate of progression varies according to the sensitivity of a functional imaging method to clinical severity. Sensitivity and reproducibility of method must be considered when designing studies of disease progression and neuroprotection. The mean preclinical period in Parkinson's disease is unlikely to be longer than seven years.

Aged↗

PubMed1999

The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases.

Progressive supranuclear palsy is characterised pathologically by the deposition of neurofibrillary tangles consisting of tau protein. Patients with the disease have been reported to have a more frequent occurrence of one allele of an intronic polymorphism of the tau gene. Other diseases which may involve tau deposition include frontotemporal dementia and corticobasal degeneration. This polymorphism has been studied in a series of subjects with progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, idiopathic Parkinson's disease, and normal controls to (1) confirm this association in a large series and (2) to investigate a possible role for this association in other disorders which involve tau deposition. The results confirm the finding of an overrepresentation of the A0 allele and the A0/A0 genotype in patients with progressive supranuclear palsy, in the largest series reported to date. The A0 allele was found in 91% of patients with progressive supranuclear palsy as opposed to 73% of controls (p<0.001) and the A0/A0 genotype was seen in 84% of patients as compared with 53% of controls (p<0.01). There was no significant difference between patients with Parkinson's disease, frontotemporal dementia, or corticobasal degeneration, and controls. The A0 allele may have a direct effect on tau isoform expression in progressive supranuclear palsy or it may be in linkage disequilibrium with an adjacent determinant of tau gene expression. The explanation for this difference between a predisposition factor to progressive supranuclear palsy and the other conditions may lie in the molecular pathology of these diseases.

Alleles↗

PubMed2001

Drug treatment effects on disease progression.

Degenerative diseases are characterized by a worsening of disease status over time. The rate of deterioration is determined by the natural rate of progression of the disease and by the effect of drug treatments. A goal of drug treatment is to slow disease progression. Drug treatments can be categorized as symptomatic or protective. Symptomatic treatments do not affect the rate of disease progression whereas protective treatments have the ability to slow disease progression down. Many current methods for describing disease progression have two common drawbacks: a linear relationship between time and disease status is assumed, and within- and between-subject variability is ignored. Disease progress models combined with pharmacokinetic pharmacodynamic models and hierarchical random effects statistical models provide insights into understanding the time course and management of degenerative disease.

Alzheimer Disease↗

PubMed2003

Severe acute respiratory syndrome: radiographic appearances and pattern of progression in 138 patients.

PURPOSE: To retrospectively evaluate the radiographic appearances and pattern of progression of severe acute respiratory syndrome (SARS). MATERIALS AND METHODS: Chest radiographs obtained at clinical presentation and during treatment in 138 patients with confirmed SARS (66 men, 72 women; mean age, 39 years; age range, 20-83 years) were assessed. Radiographic appearances of pulmonary parenchymal abnormality, distribution, and extent of involvement on initial chest radiographs were documented. Recognizable patterns of radiographic progression were determined by comparing the overall mean percentage of lung involvement for each patient on serial radiographs. RESULTS: Initial chest radiographs were abnormal in 108 of 138 (78.3%) patients and showed air-space opacity. Lower lung zone (70 of 108, 64.8%) and right lung (82 of 108, 75.9%) were more commonly involved. In most patients, peripheral lung involvement was more common (81 of 108, 75.0%). Unifocal involvement (59 of 108, 54.6%) was more common than multifocal or bilateral involvement. No cavitation, lymphadenopathy, or pleural effusion was demonstrated. Four patterns of radiographic progression were recognized: type 1 (initial radiographic deterioration to peak level followed by radiographic improvement) in 97 of 138 patients (70.3%), type 2 (fluctuating radiographic changes) in 24 patients (17.4%), type 3 (static radiographic appearance) in 10 patients (7.3%), and type 4 (progressive radiographic deterioration) in seven patients (5.1%). Initial focal air-space opacity in 44 of 59 patients (74.6%) progressed to unilateral multifocal or bilateral involvement during treatment. CONCLUSION: Predominant peripheral location; common progression pattern from unilateral focal air-space opacity to unilateral multifocal or bilateral involvement during treatment; and lack of cavitation, lymphadenopathy, and pleural effusion are the more distinctive radiographic findings of SARS.

Adult↗

PubMed1999

Differences between relapsing-remitting and chronic progressive multiple sclerosis as determined with quantitative MR imaging.

PURPOSE: To investigate the cross-sectional relationships among multiple quantitative brain magnetic resonance (MR) imaging measurements in patients with relapsing-remitting versus chronic progressive multiple sclerosis (MS). MATERIALS AND METHODS: Thirty-eight patients with MS (relapsing-remitting, 26, chronic progressive, 12) were examined. Lesion volume on T2-weighted MR images, contrast material-enhancing lesion volume, percentage of brain parenchymal volume (brain volume/[brain volume + cerebrospinal fluid volume), and magnetization transfer ratio histogram peak height for the whole brain were calculated. RESULTS: Significant negative correlation was noted between volume on T2-weighted images and magnetization transfer ratio histogram peak height for both the relapsing-remitting and chronic progressive groups (P < .001 for both). A positive correlation was demonstrated for lesion volume on T2-weighted images and enhancing lesion volume in the relapsing-remitting group (P < .01) but not in the chronic progressive group. Negative correlations were demonstrated for enhancing lesion volume and magnetization transfer ratio histogram peak height (P = .02), for Expanded Disability Status Scale score and magnetization transfer histogram peak height (P = .02), and for Expanded Disability Status Scale score and percentage of brain parenchymal volume in the relapsing-remitting group (P = .004) but not in the chronic progressive group. CONCLUSION: The cross-sectional relationships among multiple quantitative brain MR imaging measurements are different between relapsing-remitting and chronic progressive MS.

Adult↗

PubMed2005

Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis but is not additive to a high dose of enalapril.

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2007

Bin1 ablation in mammary gland delays tissue remodeling and drives cancer progression.

Genes that modify oncogenesis may influence dormancy versus progression in cancer, thereby affecting clinical outcomes. The Bin1 gene encodes a nucleocytosolic adapter protein that interacts with and suppresses the cell transforming activity of Myc. Bin1 is often attenuated in breast cancer but its ability to negatively modify oncogenesis or progression in this context has not been gauged directly. In this study, we investigated the effects of mammary gland-specific deletion of Bin1 on initiation and progression of breast cancer in mice. Bin1 loss delayed the outgrowth and involution of the glandular ductal network during pregnancy but had no effect on tumor susceptibility. In contrast, in mice where tumors were initiated by the ras-activating carcinogen 7,12-dimethylbenz(a)anthracene, Bin1 loss strongly accentuated the formation of poorly differentiated tumors characterized by increased proliferation, survival, and motility. This effect was specific as Bin1 loss did not accentuate progression of tumors initiated by an overexpressed mouse mammary tumor virus-c-myc transgene, which on its own produced poorly differentiated and aggressive tumors. These findings suggest that Bin1 loss cooperates with ras activation to drive progression, establishing a role for Bin1 as a negative modifier of oncogenicity and progression in breast cancer.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Dedifferentiation precedes invasion in the progression from Barrett's metaplasia to esophageal adenocarcinoma.

PURPOSE: Adenocarcinoma arises in Barrett's esophagus by progression from metaplasia to cancer through grades of dysplasia. Our aim in this exploratory study was to characterize the broad changes in gene expression that underlie this histologic progression to cancer and assess the potential for using these gene expression changes as a marker predictive of malignant progression in Barrett's epithelium. EXPERIMENTAL DESIGN: Microarray analysis was used to obtain individual gene expression profiles from endoscopic biopsies of nine esophageal adenocarcinomas and the Barrett's epithelia from which three of the cancers had arisen. Pooled samples from the Barrett's epithelia of six patients without cancer or dysplasia served as a reference. RESULTS: Barrett's epithelia from which cancer had arisen differed from the reference Barrett's epithelia primarily by underexpression of genes, many of which function in governing cell differentiation. These changes in gene expression were found even in those specimens of Barrett's epithelia from which cancer had arisen that lacked dysplasia. Each cancer differed from the Barrett's epithelium from which it had arisen primarily by an overexpression of genes, many of which were associated with tissue remodeling and invasiveness. Cancers without identifiable Barrett's epithelium differed from cancers that had arisen from a Barrett's epithelium by having an even greater number of these overexpressed genes. CONCLUSIONS: Histologic progression from Barrett's epithelium to cancer is associated with a gradient of increasing changes in gene expression characterized by an early loss of gene function governing differentiation that begins before histologic change; gain in function of genes related to remodeling and invasiveness follows later. This correlation of histologic progression with increasing changes in gene expression suggests that gene expression changes in biopsies taken from Barrett's epithelium potentially could serve as a marker for neoplastic progression that could be used to predict risk for developing cancer.

Adenocarcinoma↗

PubMed2006

Metastasis tumor antigen family proteins during breast cancer progression and metastasis in a reliable mouse model for human breast cancer.

PURPOSE: Chromatin remodeling pathways are critical in the regulation of cancer-related genes and are currently being explored as potential targets for therapeutic intervention. The metastasis tumor antigen (MTA) family of proteins, MTA1, MTA2, and MTA3, are components of chromatin remodeling pathways with potential roles in breast cancer. Although all three MTA family proteins have been shown to be associated with metastatic progression of breast cancers, the expression characteristic of MTA1-3 proteins in a multistep breast cancer progression model remains unknown. Structural and functional studies have suggested that they are heterogeneous in the Mi-2/NuRD complex, exhibit tissue-specific patterns of expression, and impart unique properties to estrogen receptor-alpha (ERalpha) action. This led us to hypothesize that each member of the MTA family possesses a unique role and interacts with different pathways in the stepwise process of breast cancer development and progression. EXPERIMENTAL DESIGN: MTA family proteins were examined by immunohistochemistry in breast cancer processes ranging from normal duct, to premalignant lesions, to invasive carcinoma, and to metastasized tumors in PyV-mT transgenic mice, which represents a reliable model for multistage tumorigenesis of human breast cancer. We also determined the association of MTA proteins with the status of cell proliferation, ER, E-cadherin and cytoplasmic beta-catenin, and cancer-related coactivators, AIB1 and PELP1. RESULTS: The expression of all three MTA proteins was altered in primary breast tumors. Each MTA protein had a unique expression pattern during the primary breast tumor progression. Altered expression of MTA1 was observed in both premalignant lesion and malignant carcinoma, but an elevated nuclear expression was observed in ER-negative carcinomas. MTA3 was exclusively expressed in a subset of cells of ER-positive premalignant lesions but not in carcinomas. MTA2 expression seems to be unrelated to ER status. Loss of MTA3 expression and more nuclear localization of MTA1 occurred with loss of E-cadherin and decreased cytoplasmic beta-catenin, two molecules essential for epithelial cell adhesion and important tumor cell invasion. At the late stage of tumor formation, MTA1 is usually expressed in the center of tumors. Coincidentally, the distribution of MTA1-positive cells at this stage was complementary to that of AIB1 and PELP1, which were localized to the tumor periphery with relatively active cell proliferation, scattered ER-positive cells and a limited differentiation. In metastasized lung tumors, the expression pattern of MTA-protein expression was distinct from that in primary counterparts. CONCLUSIONS: The findings presented here support the notion that each member of the MTA family might potentially play a stepwise role in a cell type-specific manner during breast cancer progression to metastasis. On the basis of the noted temporal expression patterns of MTA proteins with ER status, cell adhesion-essential regulators (E-cadherin and cytoplasmic beta-catenin), and coactivators, we propose that MTA protein-related chromatin remodeling pathways interact with steroid receptors, growth factor receptors, and other transcriptional signaling pathways to orchestrate the governing of events in breast cancer progression and metastasis.

Animals↗

PubMed1999

Late recurrence and progression after a long tumor-free period in primary Ta and T1 bladder cancer.

OBJECTIVE: To determine the probability and risk factors of recurrence and progression (to T2 or worse) after a long tumor-free period in patients with superficial (stage Ta and T1) bladder cancer. PATIENTS AND METHODS: A consecutive series of 100 patients with superficial bladder cancer who remained tumor-free for longer than 4 years after initial treatment were reviewed. The rates of recurrence and progression were statistically assessed and the significance of risk factors was determined. RESULTS: Of the 100 patients, 24 (24. 0%) recurred within 15 years after the initial treatment. The 10- and 15-year recurrence-free rates were 76.0 and 59.6%, respectively. Among the clinicopathological variables examined, intravesical chemotherapy was determined by a log-rank test to be a significant unfavorable risk factor for late recurrence (p < 0.001). Progression of the tumor occurred in 5 patients. Four variables including presence of multiple tumors, involvement of the bladder neck, positive urine cytology, and intravesical chemotherapy were found by a univariate analysis to be significant risk factors for late progression (p < 0.05). Among these factors, initial presence of multiple tumors (3 or more) was determined by a multivariate analysis to be an independent risk factor for late progression. CONCLUSION: Recurrence and progression continue to occur in patients with superficial bladder cancer even after long periods of dormancy. Regular follow-up urological assessments should be continued until at least 15 years of tumor-free existence, especially in patients treated by intravesical chemotherapy or those initially having multiple tumors.

Administration, Intravesical↗

PubMed2000

Benidipine, a long-acting calcium-channel blocker, prevents the progression to end-stage renal failure in a rat mesangioproliferative glomerulonephritis.

BACKGROUND: Although the renoprotective effect of calcium-channel blockers (CCBs) has been examined in several models of hypertensive nephropathy, it remains unclear. It also remains to be clarified whether CCBs prevent the progression to end-stage renal failure in chronic progressive glomerulonephritis (GN). A new rat model of progressive mesangioproliferative GN was used to study the effect of benidipine hydrochloride, a long-acting dihydropyridine CCB, on the clinical features and morphological lesions. METHODS: This animal model of progressive GN was induced by a single intravenous injection of anti-Thy-1 monoclonal antibody (MoAb 1-22-3) two weeks after unilateral nephrectomy. After 10 weeks of treatment with benidipine (1, 3, and 5 mg/kg body weight, p.o.) or hydralazine (5 mg/kg body weight, p.o.), systolic blood pressure (SBP), urinary protein excretion, creatinine clearance, glomerulosclerosis index, tubulointerstitial lesion index, glomerular cross-sectional area, and glomerular expression of transforming growth factor-beta (TGF-beta) and alpha-smooth muscle actin (alpha-SMA) were measured. RESULTS: Untreated rats developed hypertension, massive proteinuria, renal dysfunction, severe glomerular and tubulointerstitial injury, higher glomerular size, and marked glomerular staining for TGF-beta and alpha-SMA, while uninephrectomized control rats did not. Each dose of benidipine and hydralazine equally reduced SBP to uninephrectomized control levels. Three and five mg/kg/day of benidipine increased creatinine clearance, ameliorated glomerular and tubulointerstitial injury, and reduced glomerular staining for TGF-beta and alpha-SMA, but 1 mg/kg/day of benidipine and hydralazine failed. Only a dose of 5 mg/kg/day of benidipine reduced glomerular size, although it did not reduce the size to control levels. CONCLUSION: These results indicate that in a rat model of progressive mesangioproliferative GN, benidipine prevents the progression to end-stage renal failure in a dose-dependent manner. This renoprotective action is associated with the suppression of glomerular expression of TGF-beta and alpha-SMA.

Actins↗

PubMed2001

Prospective evaluation of Ki-67 labeling in predicting the recurrence and progression of superficial bladder transitional cell carcinoma.

PURPOSE: We studied a series of superficial transitional cell carcinoma of the bladder to assess whether the Ki-67 labeling index predicts recurrence and progression in a cohort of patients treated by transurethral resection alone or receiving adjuvant intravesical bacillus Calmette-Guerin therapy (BCG). MATERIALS AND METHODS: From 1989 to 1990, we prospectively studied 70 consecutive cases of superficial transitional cell carcinoma of the bladder using Ki-67 immunostaining. The tumors were 43 pTa and 27 pTl. Thirteen were treated with transurethral resection only and 57 received adjuvant intravesical BCG. The median follow-up times was 64 months. The threshold index values of Ki-67 for recurrence and progression were determined using ROC curves. The relative predictive values of the Ki-67 labeling index and tumor characteristics for recurrence and progression were evaluated using Cox's proportional hazards model. RESULTS: A cutoff value of 13% was determined. The recurrence free survival rate at 5 years was 68% for cases with a Ki-67 labeling index of 13 or higher and 71% for those with an index of less than 13 (NS). The progression-free survival rate at 5 years was 43% in cases with an index of 13 or higher and 89% in those with an index of less than 13 (p<0.0001). Using multivariate analysis the Ki-67 labeling index is an independent risk factor for tumor progression with a relative risk of 4.61 (p<0.05). CONCLUSION: When BCG is used for high and intermediate risk superficial bladder cancers, the Ki-67 labeling index is an independent predictive factor of progression but not of recurrence.

Adult↗