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PubMed2002

Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study.

OBJECTIVE: The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. METHODS: This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). RESULTS: In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.

Arthritis, Rheumatoid↗

PubMed1996

Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis?

OBJECTIVE: Cumulative damage to tissues, mediated by reactive oxygen species, has been implicated as a pathway that leads to many of the degenerative changes associated with aging. We hypothesized that increased intake of antioxidant micronutrients might be associated with decreased rates of osteoarthritis (OA) in the knees, a common age-related disorder. METHODS: Participants in the Framingham Osteoarthritis Cohort Study underwent knee evaluations by radiography at examinations 18 (1983-1985) and 22 (1992-1993). Usual dietary intake was assessed using the Food Frequency Questionnaire, administered at examination 20 (1988-1989). Knees without OA at baseline (Kellgren and Lawrence [K&L] grade < or = 1) were classified as having incident OA if they had a K&L grade > or = 2 at followup. Knees with OA at baseline were classified as having progressive OA if their score increased by > or = 1 at followup. Knees were also classified as having cartilage loss or osteophyte growth if their maximal joint space narrowing or osteophyte growth score increased by > or = 1 (range 0-3). The association of vitamin C, beta carotene, and vitamin E intake, ranked in sex-specific tertiles, with incidence and progression of OA was compared with that of a panel of nonantioxidant vitamins, Bl, B6, niacin, and folate, using logistic regression and generalized estimation equations to adjust for correlation between fellow knees. The lowest tertile for each dietary exposure was used as the referent category. Odds ratios (OR) were adjusted for age, sex, body mass index, weight change, knee injury, physical activity, energy intake, and health status. RESULTS: Six hundred forty participants received complete assessments. Incident and progressive OA occurred in 81 and 68 knees, respectively. We found no significant association of incident OA with any nutrient. A 3-fold reduction in risk of OA progression was found for both the middle tertile (adjusted OR = 0.3, 95% confidence interval [95% CI] 0.1-0.8) and highest tertile (adjusted OR = 0.3, 95% CI 0.1-0.6) of vitamin C intake. This related predominantly to a reduced risk of cartilage loss (adjusted OR = 0.3, 95% CI 0.1-0.8). Those with high vitamin C intake also had a reduced risk of developing knee pain (adjusted OR = 0.3, 95% CI 0.1-0.8). A reduction in risk of OA progression was seen for beta carotene (adjusted OR = 0.4, 95% CI 0.2-0.9) and vitamin E intake (adjusted OR = 0.7, 95% CI 0.3-1.6), but was less consistent. No significant associations were observed for the nonantioxidant nutrients. CONCLUSION: High intake of antioxidant micronutrients, especially vitamin C, may reduce the risk of cartilage loss and disease progression in people with OA. We found no effect of antioxidant nutrients on incident OA. These preliminary findings warrant confirmation.

Aged↗

PubMed2006

The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study.

OBJECTIVE: To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population-based cohort. The 3 strategies were infliximab with concomitant disease-modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone. METHODS: We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders. RESULTS: A total of 372 patients treated with anti-tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination-treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti-TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045). CONCLUSION: When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone.

Adult↗

PubMed2006

Synovial membrane cytokine expression is predictive of joint damage progression in rheumatoid arthritis: a two-year prospective study (the DAMAGE study cohort).

OBJECTIVE: The primary aim of this prospective 2-year study was to explain the wide variability in joint damage progression in patients with rheumatoid arthritis (RA) from measures of pathologic changes in the synovial membrane. METHODS: Patients underwent clinical measurements and joint damage assessments by magnetic resonance imaging (MRI) and radiography at enrollment and at year 2. Synovial membrane was obtained by knee biopsy and assessed histologically by hematoxylin and eosin staining. Interleukin-1beta (IL-1beta), IL-10, IL-16, IL-17, RANKL, tumor necrosis factor alpha (TNFalpha), and interferon-gamma (IFNgamma) messenger RNA (mRNA) expression was determined by quantitative reverse transcription-polymerase chain reaction. The relationship of synovial measurements to joint damage progression was determined by multivariate analysis. RESULTS: Sixty patients were enrolled. Histologic features had no relationship to damage progression. Multivariate analysis by several different methods consistently demonstrated that synovial membrane mRNA levels of IL-1beta, TNFalpha, IL-17, and IL-10 were predictive of damage progression. IL-17 was synergistic with TNFalpha. TNFalpha and IL-17 effects were most pronounced with shorter disease duration, and IL-1beta effects were most pronounced with longer disease duration. IFNgamma was protective. These factors explained 57% of the MRI joint damage progression over 2 years. CONCLUSION: We have demonstrated for the first time in a prospective study that synovial membrane cytokine mRNA expression is predictive of joint damage progression in RA. The findings for IL-1beta and TNFalpha are consistent with results of previous clinical research, but the protective role of IFNgamma, the differing effects of disease duration, and IL-17-cytokine interactions had only been demonstrated previously by animal and in vitro research. These findings explain some of the variability of joint damage in RA and identify new targets for therapy.

Adult↗

PubMed2003

Impact of restenosis and disease progression on clinical outcome after multivessel stenting in diabetic patients.

Clinical outcome after percutaneous coronary intervention (PCI) is significantly worse in diabetic patients in comparison to nondiabetic patients. The subset of diabetic patients in the ARTS trial treated with multivessel stenting had the lowest 1-year event-free survival. We examined our experience of multivessel PCI in diabetics to assess clinical outcome outside clinical trials and to determine if repeat revascularizations are the result of restenosis or the progression of nontreated disease. Between January 2000 and December 2001, we performed multivessel PCI in 99 diabetic patients. Our group was well matched with those in the ARTS trial, with mean age of 69 +/- 8 years, male sex 70%, hypertension 68%, hypercholesterolemia 51%, and mean LV ejection fraction 60%. The mean number of diseased segments treated was 2.8 +/- 0.9 and 56% of the patients had three-vessel disease. There were 2.3 +/- 0.6 stents implanted per patient. Target vessels included the LAD in 90%, LCx in 77%, and the RCA in 87% of cases. The in-hospital MACE rate was 8%, which included eight nonfatal MI but no deaths or repeat revascularizations. After a mean follow-up of 14 +/- 8 months, there were 4 deaths (4%), no further MIs, and 21 (21%) repeat revascularizations (2 CABG; 19 PCI), giving a 1-year event-free survival of 67%. There were 18 repeat revascularizations (2 CABG; 16 PCI) for restenosis, but in 9 of the 18 (50%) patients treatment was also required for progression of disease. Three further patients had PCI for symptomatic disease progression without restenosis. Thus, disease progression contributed to 57% of repeat revascularization procedures. The medium- and longer-term success of multivessel PCI in diabetic patients is limited principally by the need for repeat revascularization. However, it is important to realize that these revascularizations are performed not only for restenosis but also for disease progression in more than 50% of patients. Consequently, even if drug-eluting stent technology can eliminate restenosis, disease progression will continue to impact the clinical outcome of diabetic patients after PCI.

Aged↗

PubMed2005

Body mass index is weakly associated with, and not a helpful predictor of, disease progression in men with clinically localized prostate carcinoma treated with radical prostatectomy.

BACKGROUND: Several studies have recently suggested an association between body mass index (BMI) and disease progression after radical prostatectomy. In the current study, the authors examined this association and that between the reciprocal of BMI (INVBMI, 1/BMI) and progression-free probability in men treated with radical retropubic prostatectomy (RRP) for clinically localized prostate carcinoma. METHODS: The authors retrospectively studied 2210 patients who underwent RRP at Memorial Sloan-Kettering Cancer Center between September 1986 and May 2003. Clinicopathologic variables analyzed included BMI (kg/m2), preoperative serum prostate-specific antigen level (ng/mL), clinical T classification, year of surgery, race, biopsy-derived primary and secondary Gleason grades, and INVBMI, known to better correlate with percent body fat than BMI. Cox regression analysis was used to examine the possible association between BMI or its reciprocal with disease progression after controlling for the effects of common prognostic factors. The areas under the receiver operating curve (AUC) for models with and without INVBMI were calculated. RESULTS: Of the 2210 patients analyzed, 251 experienced disease progression in a median follow-up time of 25.9 months (range, 0-143 months). After adjusting for all clinical variables, both BMI (P = 0.071; hazards ratio [HR] = 1.027) and INVBMI (P = 0.041; HR < 0.001) were associated with disease progression. However, the areas under AUC for models with and without INVBMI were similar (range, 0.794-0.798). CONCLUSIONS: Although conflicting evidence has been reported regarding the link between obesity and an increased risk of developing prostate carcinoma, as well as an increased risk of developing aggressive disease and prostate carcinoma-related mortality, the authors found weak associations with disease progression for both BMI and INVBMI. These variables were of negligible prognostic value in men who received surgery. Studies with longer follow-up, that examine alternative end points, and that follow treatment(s) besides surgery are needed.

Area Under Curve↗

PubMed2006

Progressive low-grade oligodendrogliomas: response to temozolomide and correlation between genetic profile and O6-methylguanine DNA methyltransferase protein expression.

BACKGROUND: Loss of heterozygosity (LOH) on chromosomes 1p and 19q has been associated with chemosensitivity and improved prognosis in patients with oligodendrogliomas. The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) may induce resistance to DNA-alkylating agents. Recent studies demonstrated that temozolomide (TMZ), an oral alkylating agent, has efficacy in the treatment of patients with progressive, low-grade oligodendroglioma (LGO). However, to the authors' knowledge, limited data are available regarding the 1p/19q profile and its correlation with MGMT protein expression and response to treatment with DNA-alkylating drugs. METHODS: Adult patients with magnetic resonance imaging (MRI) findings and/or clinical deterioration compatible with progressive LGO were eligible for the study if they were radiotherapy-naive. TMZ cycles were repeated every 28 days at a dose of 200 mg/m2 daily for 5 consecutive days. Clinical and MRI data were used to evaluate outcomes, and Kaplan-Meier estimates were used to assess the median time to tumor progression (TTP). The 1p/19q status was analyzed from paired tumor-blood DNA samples using polymerase chain reaction-based microsatellite analysis. MGMT protein expression was estimated semiquantitatively by immunohistochemistry using paraffin embedded tumor sections. RESULTS: There were 28 patients who received treatment, and the median time from diagnosis to tumor progression was 33.5 months. The median number of TMZ cycles per patient was 12.5. Marked clinical improvements were recorded in 15 patients (54%), and objective responses were recorded in 17 patients (61%). The median TTP was 31 months, and the progression-free survival rate was 70% at 24 months. Loss of chromosome 1p and low MGMT protein expression were associated with objective response (P < .003 and P < .04, respectively). CONCLUSIONS: TMZ was active in patients with progressive LGO, and their response to treatment was associated with 1p deletion and low MGMT protein expression. The authors suggest the possible use of MGMT immunostaining as a surrogate marker for predicting tumor chemosensitivity.

Adolescent↗

PubMed2006

CpG island methylation of genes accumulates during the adenoma progression step of the multistep pathogenesis of colorectal cancer.

Genetic alterations occur during the adenoma-carcinoma sequence of colon cancer formation and drive the initiation and progression of colon cancer formation. The aberrant methylation of genes is an alternate, epigenetic mechanism for silencing tumor suppressor genes in colon cancer. The aim of this study was to determine on a global and gene-specific level the role of CpG island methylation in the initiation and progression of colon cancer. Consequently, we assessed the frequency of gene methylation in tumors representative of the commonly recognized histological steps of the adenoma-carcinoma progression sequence through the analysis of eight genes previously identified to be methylated in colon cancer, MGMT, HLTF, MLH1, p14(ARF), CDKN2A, TIMP3, THBS1, and CDH1. We observed that the proportion of tumors carrying methylated alleles increased from adenomas to adenocarcinomas but that the proportion of tumors with methylated alleles was not different between adenocarcinomas and metastases (69% versus 90%, P = 0.01 and 90% versus 81%, P > 0.05). The most substantial difference occurred between early and advanced adenomas (47% versus 84%, P = 0.018). Furthermore, we observed that the frequency of gene methylation at the different steps of the progression sequence varied between genes. Thus, the aberrant methylation of genes appears to increase most significantly during the progression of early adenomas to advanced adenomas, and the frequency of specific gene methylation at the different steps of the adenoma-carcinoma progression sequence varies in a gene-specific fashion.

Adenocarcinoma↗

PubMed2006

Microsatellite instability as an indicator of malignant progression in laryngeal premalignancy.

BACKGROUND: Microsatellite instability (MSI) is considered a novel marker of genetic instability, and preliminary studies have shown that it may provide useful information in assessing the risk of malignant progression in preinvasive lesions. METHODS: We analyzed MSI in serial biopsy specimens from 10 patients with preinvasive laryngeal lesions and corresponding metachronous laryngeal cancers compared with biopsy specimens of similar lesions without malignant transformation from 20 subjects in a match-paired analysis. MSI was determined by assessing the status of 14 microsatellite markers (chromosome loci: 2p16, 3q21-24, 4q12, 9p21, 13q14, 16q22.1, 17p12 and 21q21) in DNA biopsy specimens. RESULTS: MSI(+) (aberration at two or more loci) was detected in seven of 10 patients with premalignant lesions progressed to carcinoma, whereas only four of the 20 biopsy specimens from control subjects showed an unstable phenotype (p < .01). Interestingly, preinvasive laryngeal lesions with MSI at hMSH2/hMSH6 loci frequently had instability at one or more additional loci and were considered as MSI(+) (overall in eight of 12 cases: six premalignant lesions progressed to cancer and one without progression of the original laryngeal lesion, p < .01). The immunohistochemical analysis of the hMSH2 protein expression in our series, however, did not suggest its involvement in laryngeal carcinogenesis. CONCLUSIONS: Our study indicates that MSI is more common in preneoplastic laryngeal lesions progressing to cancer, thus suggesting that microsatellite status assessment may be useful in determining the risk of malignant progression in patients with preinvasive laryngeal lesions for whom chemopreventive and multiple endoscopic protocols can be attempted.

Adult↗

PubMedDate not supplied

Bulbar amyotrophic lateral sclerosis: patterns of progression and clinical management.

Patients with bulbar amyotrophic lateral sclerosis (ALS) are often referred to the otolaryngologist/head and neck surgeon and speech pathologist for evaluation and management of dysphagia and dysarthria. These patients comprise an unusual group because of the progressive and multi-system nature of their illness. The neuromuscular disabilities associated with bulbar ALS cause a myriad of related symptoms associated with swallowing, speech, and respiration. Although the rate of progression cannot be predicted, a general pattern of progression is noted. Bulbar disease accounts for the majority of the worst symptoms of ALS. The loss of the ability to swallow changes eating from a pleasurable task to a burden of survival. Loss of communication effectively imprisons the patient in a state of isolation. The progressive weakness of respiration, predominantly a spinal rather than bulbar manifestation, is the cause of death for nearly all ALS patients and is also discussed. The general patterns of progression of bulbar ALS are outlined in this paper. The development of symptoms are correlated with specific treatment recommendations to aid the clinician in devising an orderly plan of management for this progressive disease.

Aged↗

PubMed2006

Hepatitis C -- identifying patients with progressive liver injury.

Hepatitis C follows a variable course with some patients developing progressive liver fibrosis, cirrhosis and hepatocellular carcinoma, while others have minimal or no significant liver disease after decades of infection. Studies have identified both host and viral factors associated with disease progression. The importance of general factors such as age at infection, gender, immune status and alcohol consumption has long been recognized; however recently, polymorphisms in a wide array of genes have also been shown to be associated with progressive fibrosis. How specific viral proteins may contribute to disease progression has also been studied. This review highlights what is currently known about the factors associated with progressive liver injury in patients with hepatitis C. A greater understanding of the determinants of disease progression will hopefully lead to improved utilization of existing treatments and ultimately may aid in identification of new therapeutic targets.

Adult↗

PubMed2006

Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis.

Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL-40 and PIIINP and the cytokines, transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNuF-alpha). A 10-year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow-up), and true rates in the progression of fibrosis were calculated per year. Serum YKL-40, N-terminal propeptide of collagen III (PIIINP), TGF-beta, and TNF-alpha were measured, as well as the expression of TGF-beta, TNF-alpha, and YKL-40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 +/- 0.13) compared with the HCV monoinfection group (0.1 +/- 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL-40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL-40 showed a linear correlation with TGF-beta (r = 0.897, P < .001). Hepatic mRNA levels of YKL-40 and TGF-beta correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease.

Adipokines↗

PubMed1999

Long-term ursodeoxycholic acid delays histological progression in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease frequently leading to development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) is a beneficial medical therapy for patients with PBC. Improvement in some histological features, but not in histological stage, has been reported after 2 years of UDCA therapy. Thus, longer follow-up may be necessary to determine whether UDCA has a favorable effect on histological stage of disease and progression to cirrhosis. Our aim was to determine the long-term effects of UDCA therapy on histological stage and progression to cirrhosis in patients with PBC. Sixteen unselected patients with noncirrhotic PBC who had been on long-term UDCA therapy (13-15 mg/kg/d) for 6.6 +/- 0.4 years (range, 5-9 years) were identified and their histological finding during treatment compared with that of 51 noncirrhotic patients with PBC who had received ineffective therapy (D-penicillamine [DPCA] or placebo) for 5.6 +/- 0.07 years (range, 5-8 years). Histological stage was determined using the Ludwig classification. The rate of progression to cirrhosis (stage 4) was significantly less in the UDCA group than in the control group (13% vs. 49%; P =.009). Although the overall rate of progression of histological stage was less in the UDCA group than in the control group (50% vs. 71%), this difference was not significant (P =.1). A marked improvement in liver biochemistries and Mayo risk score was noted in all patients during UDCA therapy; however, this improvement was not significantly different between patients who progressed and those who did not. In conclusion, long-term UDCA therapy appeared to delay the development of cirrhosis in PBC.

Adult↗

PubMed2000

Progressive development of a Th1-type hepatic cytokine profile in rats with experimental cholangitis.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are presumed autoimmune chronic cholestatic liver diseases characterized by cholangitis and progressive loss of bile ducts. Cytokines have been postulated to be involved in the progression of these diseases, but their role is poorly defined. Our objectives were to characterize a rat model of cholangitis and to determine Type 1/Type 2 (Th1/Th2) cytokine profile shifts in this model. Cholangitis was induced in Sprague-Dawley rats (200 to 225 g) by low-dose oral administration of the biliary toxin alpha-naphthylisothiocyanate (ANIT) (1 g/kg powdered rat chow ad libitum) for 4, 7, and 14 days. Cholestasis was observed in ANIT-treated animals. Liver histology of ANIT-treated rats showed hepatic inflammation centered on damaged bile ducts, significant bile duct proliferation, and progressive fibrosis. Immunohistochemistry showed enhanced staining of hepatic major histocompatibility complex (MHC) II, CD4, and CD8 in portal areas of ANIT-treated animals. In addition, the hepatic cytokine profile became increasingly Th1 in nature with progressive ANIT treatment. In summary, experimental cholangitis biochemically and histologically mimics human chronic cholangitis and furthermore, is associated with a progressive shift to a more Th1-dominant hepatic cytokine profile. Therefore, this model may be useful for examining the role of cytokines in the progression of chronic cholangitic diseases.

Animals↗

PubMed2004

Progression to androgen-independent LNCaP human prostate tumors: cellular and molecular alterations.

Lethal phenotypes of human prostate cancer are characterized by progression to androgen-independence and metastasis. For want of a clinically relevant animal model, mechanisms behind this progression remain unclear. Our study used an in vivo model of androgen-sensitive LNCaP human prostate cancer cell xenografts in male SCID mice to study the cellular and molecular biology of tumor progression. Primary tumors were established orthotopically, and the mice were then surgically castrated to withdraw androgens. Five generations of androgen-independent tumors were developed using castrated host mice. Tumor samples were used to determine expressions of cellular and molecular markers. Androgen-independent tumors had increased proliferation and decreased apoptosis compared to androgen-sensitive tumors, outcomes associated with elevated expression of p53, p21/waf1, bcl-2, bax and the bcl-2/bax ratio. Blood vessel growth in androgen-independent tumor was associated with increased expression of vascular endothelial growth factor. Overexpression of androgen receptor mRNA and reduced expression of androgen receptor protein in androgen-independent tumors suggest that the androgen receptor signaling pathway may play an important role in the progression of human prostate cancer to androgen-independence. The in vivo orthotopic LNCaP tumor model described in our study mimics the clinical course of human prostate cancer progression. As such, it can be used as a model for defining the molecular mechanisms of prostate cancer progression to androgen-independence and for evaluating the effect of preventive or therapeutic regimens for androgen-independent human prostate cancer.

Androgens↗

PubMed2005

Progressive microvascular injury in liver and colorectal liver metastases following laser induced focal hyperthermia therapy.

BACKGROUND AND OBJECTIVES: Focal hyperthermia by laser or radiofrequency is currently the preferred method for local ablation of liver tumors. The underlying mechanism of action of focal hyperthermia, in particular the relationship between the microvascular and tissue effect is uncertain and was investigated in a murine model. STUDY DESIGN/MATERIALS AND METHODS: Focal hyperthermia produced by a Neodymium-Yttrium-Aluminium-Garnet laser (wavelength 1,064 nm) was applied to the normal liver and colorectal cancer liver metastases in inbred male CBA strain mice at 2 W for 50 seconds (100 J). Tissue injury was assessed at 0, 24, 48, 72, 120, and 168 hours following therapy by measurements of necrosis in tissue sections stained for nicotinamide adenine dinucleotide (NADH) diaphorase activity. Characteristics of microvascular injury were assessed at the various time points by scanning electron microscopy (SEM) of vascular resin casts, Laser Doppler flowmetry, and confocal in vivo microscopy. RESULTS: Focal hyperthermia produced progressive tissue and vascular injury. There was an initial reduction in blood flow and increased vascular permeability in the microcirculation of both tumor and liver tissue immediately following heat application as assessed by laser Doppler flowmetry and confocal in vivo microscopy, respectively. SEM of vascular casts showed heterogeneous regions of microvascular injury immediately following heat application. The extent of initial vascular disruption or occlusion on SEM of vascular resin casts (mean+/-SE) was significantly less than the tissue necrosis in liver (1.9+/-0.1 mm vs. 3.0 mm+/-0.2 mm P<0.001), but was equivalent to the tissue injury in tumor tissue (3.5 mm+/-0.2 mm vs. 3.6 mm+/-0.1 mm P = 0.907). This was followed by a progressive increase in both microvascular and tissue injury in liver and tumor that peaked by 72 hours following treatment. The peak microvascular injury and tissue damage in liver (6.6 mm+/-0.2 and 6.3 mm+/-0.2 mm, respectively) was significantly greater than the extent of microvascular and tissue damage in tumors (4.8 mm+/-0.2 mm and 4.5 mm+/-0.2 mm, respectively) (P<0.001). The progression of microvascular injury in liver and tumor at times preceded the tissue injury. CONCLUSION: Focal hyperthermia produces both progressive microvascular and tissue damage in liver and colorectal liver metastases. An increase in tissue injury following focal hyperthermia may be a direct result of progressive microvascular damage. Tumor vessels appear more susceptible to direct focal hyperthermia destruction than liver sinusoids. The liver sinusoids are however more susceptible to progressive damage or occlusion following the initial laser thermal stimulus.

Animals↗

PubMed2002

Disease progression in amyotrophic lateral sclerosis: predictors of survival.

Predicting the rate of disease progression has become important as trials of new medical treatments for amyotrophic lateral sclerosis (ALS) are planned. Bulbar onset, early impairment of forced vital capacity, and older age have all been associated with shorter survival. We performed a retrospective study to compare survival factors with disease progression in a German ALS population. We analyzed disease progression in 155 patients at intervals of 4 months over a period of 3 years. To evaluate disease progression, the ALS functional rating scale (ALS-FRS), forced vital capacity (FVC%), and a Medical Research Council (MRC) compound score based on a nine-step modified MRC scale were used. We compared age (< 55 years vs. > or =55 years), different sites of disease onset (bulbar vs. limb), and gender to the rate of disease progression and performed survival analyses. No overall significant difference could be detected when analyzing these subgroups with regard to disease progression. By contrast, significantly longer survival was observed in the younger age group (56 months vs. 38 months, P < 0.0001) and in patients with limb-onset disease (51 months vs. 37 months, P = 0.0002). Using Cox analyses values we found that the declines of ALS-FRS, FVC%, and MRC compound score were predictive of survival (P < 0.0001, P = 0.002, and P = 0.003, respectively). Future studies are needed to clarify whether nonspecific factors including muscle atrophy, dysphagia, and coexisting diseases influence prediction of survival in ALS patients. A more precise set of predictors may help to better stratify patient subgroups for future treatment trials.

Age of Onset↗

PubMed2001

Progression of heterogeneous breast tumors.

Two possible pathways of breast tumor progression were investigated by searching for values of transition rates that could reproduce the clinically observed co-occurrence frequencies of grades of ductal carcinoma in situ and grades of invasive ductal carcinoma in heterogeneous tumors. Two different pathways were analysed, a linear pathway with seven parameters, and a nonlinear pathway with three parameters. In each pathway ductal carcinoma in situ (DCIS) is a progenitor of invasive carcinoma (IDC). In the linear pathway breast tumor progression is along increasing grades: DCIS 1-DCIS 2-DCIS 3-IDC 1-IDC 2-IDC 3. In the nonlinear pathway progression of DCIS and progression of IDC can proceed in parallel steps, and in addition, with transitions from each grade of DCIS to a corresponding grade of IDC. The biological pathways were interpreted mathematically as compartment models with transition rates between stages in an explicit series of coupled differential equations. Two methods were used to search for transition rates that could reproduce the observed co-occurrence frequencies, a limited empirical search and an extensive genetic algorithmic search. Neither search method, with either pathway, could find a combination of transition rates that would reproduce the set of observed co-occurrence frequencies. We conclude that neither the linear pathway, nor the nonlinear pathway considered here, is an adequate description of progression in heterogeneous breast tumors. This quantitative investigation lends support to previous evidence from histopathology and molecular biology that the grades of DCIS and IDC seen together in heterogeneous breast tumors may not be obligate steps in tumor progression.

Breast Neoplasms↗