Association Between Push-up Exercise Capacity and Future Cardiovascular Events Among Active Adult Men.

Importance: Cardiovascular disease (CVD) remains the leading cause of mortality worldwide. Robust evidence indicates an association of increased physical fitness with a lower risk of CVD events and improved longevity; however, few have studied simple, low-cost measures of functional status. Objective: To evaluate the association between push-up capacity and subsequent CVD event incidence in a cohort of active adult men. Design, Setting, and Participants: Retrospective longitudinal cohort study conducted between January 1, 2000, and December 31, 2010, in 1 outpatient clinics in Indiana of male firefighters aged 18 years or older. Baseline and periodic physical examinations, including tests of push-up capacity and exercise tolerance, were performed between February 2, 2000, and November 12, 2007. Participants were stratified into 5 groups based on number of push-ups completed and were followed up for 10 years. Final statistical analyses were completed on August 11, 2018. Main Outcomes and Measures: Cardiovascular disease-related outcomes through 2010 included incident diagnoses of coronary artery disease and other major CVD events. Incidence rate ratios (IRRs) were computed, and logistic regression models were used to model the time to each outcome from baseline, adjusting for age and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared). Kaplan-Meier estimates for cumulative risk were computed for the push-up categories. Results: A total of 1562 participants underwent baseline examination, and 1104 with available push-up data were included in the final analyses. Mean (SD) age of the cohort at baseline was 39.6 (9.2) years, and mean (SD) BMI was 28.7 (4.3). During the 10-year follow up, 37 CVD-related outcomes (8601 person-years) were reported in participants with available push-up data. Significant negative associations were found between increasing push-up capacity and CVD events. Participants able to complete more than 40 push-ups were associated with a significantly lower risk of incident CVD event risk compared with those completing fewer than 10 push-ups (IRR, 0.04; 95% CI, 0.01-0.36). Conclusions and Relevance: The findings suggest that higher baseline push-up capacity is associated with a lower incidence of CVD events. Although larger studies in more diverse cohorts are needed, push-up capacity may be a simple, no-cost measure to estimate functional status.

Prediction of therapy response in acromegalic patients under pegvisomant therapy within the German ACROSTUDY cohort.

PURPOSE: This study aimed at investigating predicting factors for therapy response under growth hormone receptor antagonist therapy with a focus on subjective and patient-oriented measures. METHODS: Observational, multicenter nested-cohort study including 271 selected patients with the diagnosis of acromegaly and a minimum of one-year follow-up period within the German ACROSTUDY cohort (total cohort: n = 514). Outcome measures were the change of the biomarker IGF-1 (IGF-1 change and IGF-1 normalisation) between baseline and after 1 year of pegvisomant therapy (12 ± 6 months). Main predictors were patient-assessed subjective measures according to the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) in conjugation with age, gender, BMI, max. dosage of pegvisomant at follow-up and IGF-1 before the start of pegvisomant therapy. RESULTS: The mean age of the study population was 51.2 (13.9) years and the mean BMI was 29.5 (5.1) kg/m(2). In adjusted analyses, none of the individual perceived health (PASQ) scores, but age, BMI and IGF-1 at baseline were predictive for an IGF-1 decrease after 1 year of pegvisomant therapy and BMI and IGF-1, but equally none of the PASQ items, were predicting IGF-1 normalisation. CONCLUSIONS: Age, BMI and baseline IGF-1 but not subjective perceived health measures predict therapy response under second line medical therapy with pegvisomant.

Association of sleep habits with accidents and near misses in United States transportation operators.

OBJECTIVE: To explore sleep risk factors and their association with adverse events in transportation operators. METHODS: Self-reported sleep-related behaviors were analyzed in transportation operators (drivers, pilots, and rail operators) aged 26 to 78 years who completed the National Sleep Foundation's 2012 "Planes, Trains, Automobiles, and Sleep" survey. Regression analyses were used to assess the associations of various sleep-related variables with the combined outcome of self-reported accidents and near misses. RESULTS: Age- and body mass-adjusted predictors of accidents/near misses included an accident while commuting (odds ratio [OR] = 4.6; confidence interval [CI], 2.1 to 9.8), driving drowsy (OR = 4.1; CI, 2.5 to 6.7), and Sheehan Disability Scale score greater than 15 (OR = 3.5; CI, 2.2 to 5.5). Sleeping more than 7 hours nightly was protective for accident/near misses (OR = 0.6; CI, 0.4 to 0.9). CONCLUSION: Recognized risk factors for poor sleep or excessive daytime sleepiness were significantly associated with self-reported near misses and/or accidents in transportation operators.

High hsCRP is associated with reduced lung function in structural firefighters.

BACKGROUND: To assess the association between markers of systemic inflammation and pulmonary function in a population of structural firefighters. METHODS: We studied male career members of a large Midwestern fire department with questionnaires, spirometry, and high-sensitivity C-reactive protein (hsCRP) as a biomarker of systemic inflammation. We examined percent predicted forced expiratory volume in 1 s (FEV1 %-predicted) and forced vital capacity (FVC%-predicted). RESULTS: Complete data were available for 401 firefighters. Higher hsCRP levels were associated with lower lung function values, after adjusting for confounding variables. Specifically, for every twofold increase in log10-hsCRP, FEV1 %-predicted decreased by a mean 1.5% (95% CI: 0.4, 2.6%) and FVC%-predicted decreased by a mean 1.4% (95% CI: 0.4, 2.3%). CONCLUSION: hsCRP as a biomarker of systemic inflammation may indicate reduced lung function in structural firefighters.

Long-term follow-up after endoscopic stent therapy for benign biliary strictures.

BACKGROUND AND AIMS: Endoscopic therapy holds an important role in the management of benign biliary strictures. This study compares the long-term outcome of stenting therapy depending on the underlying cause of the stricture. METHODS: In a retrospective cohort study, 228 patients with benign biliary strictures were identified using an endoscopic database, hospital charts, and cholangiograms between January 1992 and December 2008. Long-term follow-up was evaluated with cholangiograms, transabdominal ultrasound, laboratory parameters, and physical examination. The median follow-up period was 44.7 months. RESULTS: Endoscopic management showed best long-term results in patients with stone-associated biliary stricture. In this subgroup, endoscopic therapy could be successfully completed in 92% (71/77) of the patients. Patients with postoperative biliary stricture had good outcome in 83% (53/64) of cases. Idiopathic strictures presented a successful outcome in 58% (15/26). Biliary strictures caused by chronic pancreatitis had a significantly poorer outcome compared with strictures of other origin. Therapeutic success of endoscopic therapy could only be observed in 31% of patients (19/61). CONCLUSIONS: Long-term outcome of endoscopic therapy for benign strictures was significantly dependent on the underlying cause of the stricture. In particular, patients with biliary strictures due to chronic pancreatitis benefit least from endoscopic therapy, whereas patients with stone-associated strictures had the highest therapeutic success rate.

Sudden cardiac death among firefighters ≤45 years of age in the United States.

Sudden cardiac death (SCD) is the leading cause of death in firefighters. Although on-duty SCD usually occurs in older victims almost exclusively because of coronary heart disease, no studies have examined causation across the career span. In the present retrospective case-control study, cases of SCD in young (aged ≤45 years) firefighters from the National Institute for Occupational Safety and Health fatality investigations (n = 87) were compared with 2 age- and gender-matched control groups: occupationally active firefighters (n = 915) and noncardiac traumatic firefighter fatalities (n = 56). Of the SCD cases, 63% were obese and 67% had a coronary heart disease-related cause of death. The SCD victims had much heavier hearts (522 ± 102 g) than noncardiac fatality controls (400 ± 91 g, p <0.001). Cardiomegaly (heart weight >450 g) was found in 66% of the SCD victims and conveyed a fivefold increase (95% confidence interval [CI] 1.93 to 12.4) in SCD risk. Furthermore, hypertension, including cases with left ventricular hypertrophy, increased SCD risk by 12-fold (95% CI 6.23 to 22.3) after multivariate adjustment. A history of cardiovascular disease and smoking were also independently associated with elevated SCD risk (odds ratio 6.89, 95% CI 2.87 to 16.5; and odds ratio 3.53, 95% CI 1.87 to 6.65, respectively). In conclusion, SCD in young firefighters is primarily related to preventable lifestyle factors. Obesity entry standards, smoking bans, and improved screening and/or wellness program are potential strategies to reduce SCD in younger firefighters.

Spectrum of pathogens in acute cholangitis in patients with and without biliary endoprosthesis.

BACKGROUND: Knowledge of bacterial spectrum for acute cholangitis is essential for adequate empiric antibiotic treatment. Main focus of the study was to analyse the spectrum of pathogens in acute cholangitis with and without biliary endoprosthesis. METHODS: Retrospective cohort study of 1024 patients with acute cholangitis treated at a German tertiary center. RESULTS: 447 cholangitis episodes with positive bile and/or blood cultures obtained from 388 patients were studied. In total, 1088 pathogen were isolated. The predominant strains were Enterococcus species (25%), followed by Escherichia coli (18%) and Klebsiella species (14%). Bacteraemia was mainly caused by E. coli (91/282; 32%) and Enterococcus species (550/282; 18%). The incidences of Enterococcus species [121(74%) vs. 89(60%); p = 0.011] and non-fermenters [41(25%) vs. 16(11%); p = 0.001] were significantly higher in cholangitis episodes with biliary endoprosthesis compared to cholangitis episodes without biliary endoprosthesis. In particular, more Pseudomonas aeruginosa [27(16%) vs. 12(8%); p = 0.027] and Enterococcus faecium [59(36%) vs. 34(23%); p = 0.013] were isolated from patients with a biliary endoprosthesis. CONCLUSIONS: Unlike cholangitis without stent, the presence of biliary endoprosthesis in patients with cholangitis can serve as a surrogate indicator of nosocomial pathogens and therefore should be considered, when selecting empiric antimicrobial therapy.

Exercise-induced hypertension among healthy firefighters-a comparison between two different definitions.

Different studies have yielded conflicting results regarding the association of hypertensive response to exercise and cardiovascular morbidity. We compared two different definitions of exaggerated hypertensive response to exercise and their association with cardio-respiratory fitness in a population of healthy firefighters. We examined blood pressure response to exercise in 720 normotensive male career firefighters. Fitness was measured as peak metabolic equivalent tasks (METs) achieved during maximal exercise treadmill tests. Abnormal hypertensive response was defined either as systolic blood pressure ≥ 200 mm Hg; or alternatively, as responses falling in the upper tertile of blood pressure change from rest to exertion, divided by the maximal workload achieved. Using the simple definition of a 200 mm Hg cutoff at peak exercise less fit individuals (METs ≤ 12) were protected from an exaggerated hypertensive response (OR 0.45, 95%CI 0.30-0.67). However, using the definition of exercise-induced hypertension that corrects for maximal workload, less fit firefighters had almost twice the risk (OR 1.8, 95%CI 1.3-2.47). Blood pressure change corrected for maximal workload is better correlated with cardiorespiratory fitness. Systolic blood pressure elevation during peak exercise likely represents an adaptive response, whereas elevation out of proportion to the maximal workload may indicate insufficient vasodilation and a maladaptive response. Prospective studies are needed to best define exaggerated blood pressure response to exercise.

Age-Related Decline in Cardiorespiratory Fitness among Career Firefighters: Modification by Physical Activity and Adiposity.

Firefighting is a very hazardous occupation, and strenuous fire duties require high levels of physical fitness. In the general adult population, cardiorespiratory fitness (CRF) declines with aging. We sought to investigate the effect of increasing age on CRF in male career firefighters as well as the modifying effects of physical activity and adiposity. We cross-sectionally examined 804 male career firefighters from two Midwestern states. CRF was determined from symptom-limited maximal treadmill exercise testing in metabolic equivalents (METS) following the Bruce protocol. Physical activity self-reports were extracted from responses to a health and lifestyle questionnaire. We found as expected that CRF declines with advancing age; however, the decline is greatly attenuated among leaner firefighters who report more physical activity. Furthermore, in a linear regression model including age, BMI, and variables describing physical activity behaviors, we could predict CRF (R(2) = 0.6286). The total weekly duration of aerobic exercise as well as the duration of weight lifting sessions both had significant impacts on age-related decline. We conclude that firefighters are more likely to maintain the high levels of CRF needed to safely perform their duties if they engage in frequent exercise and maintain healthy weights.

Weight- perception in male career firefighters and its association with cardiovascular risk factors.

BACKGROUND: The prevalence of obesity has reached epidemic proportions worldwide, and is also increasing among public safety professionals like firefighters who are expected to be fit and more active. The present study evaluates the associations among Body Mass Index (BMI), weight perception and cardiovascular risk factors in 768 male career firefighters from two Midwestern states in the United States. METHODS: A physical examination was performed and fasting blood samples were taken. Cardio-respiratory fitness (CRF) was determined from symptom- limited maximal treadmill exercise testing with electrocardiogram (ECG) monitoring and estimation of oxygen consumption (metabolic equivalents, METS) using the Bruce protocol. A health and lifestyle questionnaire was administered with standardized written instructions for completion. Self-reports of weight perception were extracted from responses to the completed multiple choice questionnaire. Baseline characteristics were described using the mean (standard deviation) for continuous variables and frequency for categorical variables. Group comparisons were calculated using analysis of variance (ANOVA). Linear models and logistic regression models were used to adjust for possible confounders. Logistic regression analyses were used to calculate the odds ratios of underestimating one's weight category. RESULTS: A high proportion of overweight and obese male career firefighters underestimate their weight categories (68%). The risk of underestimating one's weight category increased by 24% with each additional unit of increasing BMI after adjustment for age and CRF. When divided into six groups based on combinations of measured BMI category and weight perception, there were significant differences among the groups for most cardiovascular risk factors. After adjustment for age and BMI, these differences remained statistically significant for CRF, amount of weekly exercise, prevalence of Metabolic Syndrome (MetSyn), body fat percentage and cholesterol measurements. CONCLUSION: A high proportion of overweight and obese male career firefighters underestimate their measured BMI categories. As a result, they are unlikely to fully appreciate the negative health consequences of their excess weight. The results of this study emphasize the importance of objectively measuring BMI and then informing patients of their actual weight status and the associated disease risks.

Metabolic syndrome is inversely related to cardiorespiratory fitness in male career firefighters.

Cardiovascular disease (CVD) accounts for 45% of on-duty fatalities among firefighters, occurring primarily in firefighters with excess CVD risk factors in patterns resembling the metabolic syndrome (MetSyn). Additionally, firefighters have a high prevalence of obesity and sedentary behavior suggesting that MetSyn is also common. Therefore, we assessed the prevalence of MetSyn in firefighters and its association with cardiorespiratory fitness (CRF) in a cross-sectional study of 957 male career firefighters. The CRF was measured by maximal exercise tolerance testing (standard metabolic equivalent [METS]). The MetSyn was defined according to modified criteria from the Joint Scientific Statement. Group differences were compared using χ-test and logistic regression. The prevalence of MetSyn was 28.3%. Firefighters in the lowest fitness category (METS ≤ 10) had a nearly 10-fold higher prevalence of MetSyn (51.2%) compared with colleagues in the highest fitness category (METS > 14) (MetSyn prevalence 5.2%) (p value < 0.0001, adjusted for age). In multivariate regression models, every 1-unit increase in METS decreased the odds of having the MetSyn by 31% (odds ratio 0.69 [95% confidence interval 0.63-0.76] [age adjusted]), whereas age had no significant effect after adjusting for CRF. We found a high prevalence of the MetSyn in this group of career emergency responders expected to be more active, fit, and relatively younger than the general population. Moreover, there is a highly significant inverse, dose-response association with CRF. Firefighters should be given strong incentives to improve their fitness, which would decrease prevalent MetSyn, a likely precursor of on-duty CVD events and contributor to CVD burden in this population.

Cardiorespiratory fitness predicts cardiovascular risk profiles in career firefighters.

OBJECTIVE: Evaluate the association between cardiovascular disease (CVD) risk factors and cardiorespiratory fitness (CRF) in firefighters. METHODS: Cross-sectional study of 968 male career firefighters. Cardiorespiratory fitness was measured by maximal exercise tolerance tests. Cardiovascular disease risk parameters included body composition, resting vital signs, and metabolic profiles. Group comparisons were performed using χ test, analysis of variance, and general linear regression with/without adjustment for age and body mass index (BMI). RESULTS: Higher metabolic equivalents categories were significantly associated with lower diastolic blood pressure, body fat, triglycerides, low-density lipoprotein cholesterol and total/high-density cholesterol ratio, and higher high-density lipoprotein (P ≤ 0.0272, age and BMI adjusted). CONCLUSIONS: Increasing CRF has beneficial independent effects on CVD risk factor profiles among firefighters. Higher CRF was beneficial regardless of BMI; nevertheless, increasing BMI had strong independent unfavorable effects. Firefighters should be encouraged to increase their CRF to decrease their future risk of CVD.

Cardiovascular disease in US firefighters: a systematic review.

Cardiovascular disease (CVD) is the leading cause of on-duty death among firefighters (45% of on-duty fatalities) and a major cause of morbidity. CVD in the fire service also has adverse public safety implications as well as significant cost impacts on government agencies. Over the last decade, our understanding of CVD among firefighters has significantly improved and provides insight into potential preventive strategies. The physiology of cardiovascular arousal and other changes that occur in association with acute firefighting activities have been well-characterized. However, despite the strenuous nature of emergency duty, firefighters' prevalence of low fitness, obesity, and other CVD risk factors are high. Unique statistical approaches have documented that on-duty CVD events do not occur at random in the fire service. They are more frequent at certain times of day, certain periods of the year, and are overwhelmingly more frequent during strenuous duties compared with nonemergency situations. Moreover, as expected on-duty CVD events occur almost exclusively among susceptible firefighters with underlying CVD. These findings suggest that preventive measures with proven benefits be applied aggressively to firefighters. Furthermore, all fire departments should have entry-level medical evaluations, institute periodic medical and fitness evaluations, and require rigorous return to work evaluations after any significant illness. Finally, on the basis of the overwhelming evidence supporting markedly higher relative risks of on-duty death and disability among firefighters with established coronary heart disease, most firefighters with clinically significant coronary heart disease should be restricted from participating in strenuous emergency duties.

Firefighters' physical activity: relation to fitness and cardiovascular disease risk.

PURPOSE: Cardiovascular disease (CVD) accounts for 44% of on-duty deaths among US firefighters with a markedly higher event risk during strenuous duties compared with nonemergencies. Sedentary persons are most susceptible to such CVD "event-triggering" due to irregular bouts of vigorous physical activity (PA). Conversely, regular PA and increased levels of cardiorespiratory fitness (CRF) protect against CVD triggering. Therefore, the present study evaluates PA measures in structural firefighters and their relationship to CRF and CVD risk factors. METHODS: Cross-sectional cohort study of 527 Midwestern career firefighters. PA frequency, duration, and intensity measures from a questionnaire along with total weekly aerobic exercise were analyzed. CRF was measured by maximal exercise tolerance testing. CVD risk parameters included body composition, blood pressure, and metabolic profiles. Group differences were compared using general linear models. RESULTS: Measures of increasing frequency, duration, intensity of PA, and total weekly exercise (min) were significantly associated with higher CRF (P < 0.001) after adjustment for age, body mass index (BMI), and smoking status. After multivariate adjustment, increasing PA frequency was significantly associated with reduced total cholesterol-HDL ratio, triglycerides, and glucose, as well as HDL increments. Increasing BMI category was associated with significant decrements in CRF and unfavorable dose-response trends in CVD risk factors (P < 0.001), even for those reporting very frequent, sustained, and intense PA. CONCLUSIONS: Increasing PA has beneficial independent effects on CRF, and PA frequency has similar favorable effects on CVD risk profiles. Whereas PA was beneficial regardless of BMI category, increasing BMI category had strong independent unfavorable effects. PA should be strongly encouraged for all firefighters with the highest priority given to PA frequency, followed by PA duration and intensity.

Type 2 diabetes mellitus and medications for type 2 diabetes mellitus are associated with risk for and mortality from cancer in a German primary care cohort.

There is growing evidence that patients with type 2 diabetes mellitus have increased cancer risk. We examined the association between diabetes, cancer, and cancer-related mortality and hypothesized that insulin sensitizers lower cancer-related mortality. Participants in the Diabetes Cardiovascular Risk and Evaluation: Targets and Essential Data for Commitment of Treatment study, a nationwide cross-sectional and prospective epidemiological study, were recruited from German primary care practices. In the cross-sectional study, subjects with type 2 diabetes mellitus had a higher prevalence of malignancies (66/1308, 5.1%) compared to nondiabetic subjects (185/6211, 3.0%) (odds ratio, 1.64; 95% confidence interval, 1.12-2.41) before and after adjustment for age, sex, hemoglobin A(1c), smoking status, and body mass index. Patients on metformin had a lower prevalence of malignancies, comparable with that among nondiabetic patients, whereas those on any other oral combination treatment had a 2-fold higher risk for malignancies even after adjusting for possible confounders; inclusion of metformin in these regimens decreased the prevalence of malignancies. In the prospective analyses, diabetic patients in general and diabetic patients treated with insulin (either as monotherapy or in combination with other treatments) had a 2- and 4-fold, respectively, higher mortality rate than nondiabetic patients, even after adjustment for potential confounders (incidence of cancer deaths in patients with type 2 diabetes mellitus [2.6%] vs the incidence of cancer deaths in patients without type 2 diabetes mellitus [1.2%]). Our results suggest that diabetes and medications for diabetes, with the exception of the insulin sensitizer metformin, increase cancer risk and mortality.

Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids.

BACKGROUND AND AIMS: Well-differentiated neuro-endocrine ileal carcinoids are composed of serotonin-producing enterochromaffin (EC) cells. Life expectancy is determined by metastatic spread to the liver because medical treatment options are still very limited. Selective inhibition of angiogenesis or lymphangiogenesis might prevent tumour growth and metastatic spread. We examined the role of the vascular endothelial growth factors (VEGFs) A, B, C, D, and their receptors (VEGFRs) 1, 2, 3 in angiogenesis and lymphangiogenesis of ileal EC cell carcinoids with and without liver metastases. METHODS: The expression of various VEGFs and VEGFRs was determined by quantitative real-time RT-PCR in healthy mucosa, primary tumour, lymph node metastases and liver metastases of 25 patients with ileal EC cell carcinoids. Microvessel density (MVD) was determined by CD-31 staining in primary tumours and lymphatic vessel density (LVD) by LYVE-1 staining. VEGF expression levels, MVD, LVD, and patients' survival time were correlated using logistic regression and Kaplan-Meier survival analysis. RESULTS: VEGF-A was highly expressed with no difference between normal mucosa and tumours. VEGF-B and -D as well as VEGFR-1 and -2 expression levels were significantly increased in the tumours when compared to normal mucosa. Patients with liver metastasis, however, had a significantly lower expression of the factors A, B, and C and the receptors 2 and 3. MVD in primary tumours positively correlated with the expression of VEGF ligands and their receptors, except for VEGF-D. LVD did not correlate with any VEGF ligand or receptor. Interestingly, low expression levels of VEGF-B were associated with poor survival. CONCLUSION: Patients with more aggressive metastatic spreading had relatively decreased expression levels of VEGF ligands and receptors. Thus, anti-angiogenic therapy may not be a suitable target in metastatic ileal EC cell carcinoids.

Correlation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase expression in ileal carcinoids, lymph nodes and liver metastasis with prognosis and survival.

PURPOSE: Ileal carcinoids are gut epithelial tumors originating from serotonin-containing enterochromaffin (EC) cells. Therapeutic options for effectively inhibiting the growth and spread of metastatic carcinoids are still limited. We aimed to identify the role of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) during tumor development and metastasis. PATIENTS AND METHODS: Tissue samples were obtained from surgically treated patients. Expression of the EC-cell marker, vesicular monoamine transporter-1 (VMAT-1), was used to verify ileal carcinoids. We investigated the differential expression of MMP-2, 7, 9, 11, and 13 and their endogenous inhibitors (TIMP-1, 2, and 3) by quantitative real-time RT-PCR in 25 primary tumors, their corresponding lymph node metastases and/or liver metastases and matched normal mucosa. RESULTS: Significantly increased expression of VMAT-1, MMP-2, MMP-11, TIMP-1 and TIMP-3 was determined by quantitative RT-PCR in EC-cell carcinoids compared to normal intestinal mucosa (p < 0.05). In contrast, MMP-2 and MMP-9 as well as TIMP-1, TIMP-2, and TIMP-3 expression in primary tumors of patients with liver metastases (M1) was significantly lower than in patients lacking liver metastases (M0). EC-cell tumors were significantly larger in the M1 group of tumors, while VMAT-1 expression was significantly decreased. We found an inverse correlation between tumor size and prognosis. Univariate analysis further revealed that decreased expression of VMAT-1, MMP-2 and TIMP-3 in primary tumors was significantly associated with a reduced survival time of the patients. CONCLUSION: Our data reveal that MMP-2 and TIMP-3 expression together with VMAT-1 expression are of potential prognostic and clinical value in ileal carcinoids.

Pattern of secondary genomic changes in pancreatic tumors of Tgf alpha/Trp53+/- transgenic mice.

Trp53(+/-) mice overexpressing Tgfalpha in a pancreas-specific manner represent a well-established animal model for pancreatic cancer. In this study we analyzed 38 pancreatic adenocarcinomas of these mice for secondary genomic changes by comparative genomic hybridization (CGH), loss of heterozygosity (LOH) analysis, real-time PCR, and methylation-specific analysis. CGH screening of the tumors revealed a recurrent pattern of genomic changes. In more than 50% of the tumors, chromosome 11 was affected. The gain of the proximal part spans about 16 cM, including the genes for Egfr, Rel, and Stk10. The distal part of chromosome 11, which contains the Trp53 locus, was deleted. LOH analysis proved that almost all tumors segregate the wild-type Trp53 allele. The Cdkn2a locus on chromosome 4 was inactivated by hypermethylation in 55% of all tumors. In addition, two other changes were detected in a mutually exclusive manner: overrepresentation of part of chromosome 15, or more rarely, loss of the distal part of chromosome 14. Together these data suggest the induction of a uniform pattern of secondary genomic changes in this transgenic tumor model for pancreatic cancer.