Digital rectal examination and the diagnosis of prostate cancer--a study based on 8 years and three screenings within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam

Background

Evidence indicates that an abnormal digital rectal examination (DRE) is a risk factor for high-grade prostate cancer (PC).

Objective

To determine whether men with an initially suspicious DRE, a prostate-specific antigen (PSA) level ≥3.0 ng/ml, and a benign prostate biopsy are at higher risk for significant PC at rescreening than men with an initially normal DRE, and whether an adaptation of the rescreening interval is warranted for this group.

Design, Setting, and Participants

Within the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rotterdam, 2218 men underwent biopsy of the prostate (from 1993 to 2000) with a benign result at initial screening. The serum PSA was determined every 4 yr. A PSA level of ≥3.0 ng/ml prompted a DRE and a lateralised sextant biopsy.

Measurements

Number and characteristics of PCs found at repeat screenings and as interval cancers (ICs) were compared between men with or without a suspicious DRE result at initial screening. Multivariate logistic regression analyses were performed to evaluate if an initially suspicious DRE was a significant predictor for detecting cancer at consecutive screenings.

Results and Limitations

After 4 yr, the total number of PCs detected in men with and without an initially suspicious DRE was, respectively, 27 (6%) versus 103 (6%) (p = 0.99). After 8 yr these numbers increased, respectively, to,45 (10%) versus 167 (10%) (p = 0.88). The proportion of clinically significant PCs was 2% and 3%, respectively, for the group with initially normal and abnormal DRE after 8 yr. Having a suspicious DRE result at initial screening was not a significant predictor for detecting PC after 4 yr [odds ratio (OR) = 1.15, p = 0.59) or 8 yr (OR = 1.41, p = 0.43)]. A limitation of this study is the relatively short follow-up of 8 yr.

Conclusions

During a follow-up of 8 yr after initial cancer-negative biopsy, an initially suspicious DRE did not influence the chance for detection of cancer or significant cancer at later screens. An adaptation of the rescreening interval on the basis of the initial DRE-outcome is not warranted in future population-based screening for prostate cancer.     

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11��-Hydroxysteroid Dehydrogenase Type 1

OBJECTIVE

Recent studies in humans and animal models of obesity have shown increased adipose tissue activity of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which amplifies local tissue glucocorticoid concentrations. The reasons for this 11β-HSD1 dysregulation are unknown. Here, we tested whether 11β-HSD1 expression, like the metabolic syndrome, is “programmed” by prenatal environmental events in a nonhuman primate model, the common marmoset monkey.

RESEARCH DESIGN AND METHODS

We used a “fetal programming” paradigm where brief antenatal exposure to glucocorticoids leads to the metabolic syndrome in the offspring. Pregnant marmosets were given the synthetic glucocorticoid dexamethasone orally for 1 week in either early or late gestation, or they were given vehicle. Tissue 11β-HSD1 and glucocorticoid receptor mRNA expression were examined in the offspring at 4 and 24 months of age.

RESULTS

Prenatal dexamethasone administration, selectively during late gestation, resulted in early and persistent elevations in 11β-HSD1 mRNA expression and activity in the liver, pancreas, and subcutaneous—but not visceral—fat. The increase in 11β-HSD1 occurred before animals developed obesity or overt features of the metabolic syndrome. In contrast to rodents, in utero dexamethasone exposure did not alter glucocorticoid receptor expression in metabolic tissues in marmosets.

CONCLUSIONS

These data suggest that long-term upregulation of 11β-HSD1 in metabolically active tissues may follow prenatal “stress” hormone exposure and indicates a novel mechanism for fetal origins of adult obesity and the metabolic syndrome.The metabolic syndrome and its component features (central obesity, insulin resistance/type 2 diabetes, hypertension, dyslipidemia) have been causally linked to early life events as marked by low birth weight and other features of an adverse intrauterine environment (1,2). Two major etiological hypotheses of the “developmental origins” effects have been proposed: malnutrition and glucocorticoid overexposure (3,4). These mechanisms of “programming” may be linked because maternal undernutrition increases maternal glucocorticoid concentrations and reduces the placental enzymatic barrier to maternal glucocorticoids in rats, thus increasing fetal glucocorticoid exposure (5). Moreover, maternal glucocorticoid administration reduces food intake in rodents (6).The processes that link intrauterine insults and later risk of the metabolic syndrome are not yet understood. The metabolic syndrome resembles the rare Cushing''s syndrome of circulating glucocorticoid excess, but in uncomplicated metabolic syndrome, plasma cortisol levels are not raised, spawning the suggestion that increased tissue sensitivity to glucocorticoid action may be important in its pathogenesis (7). In the major metabolic organs, tissue sensitivity and exposure to glucocorticoids are determined by the density of intracellular glucocorticoid receptors and the activity of the microsomal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyzes the regeneration of active cortisol (corticosterone in rodents) from inert cortisone (11-dehydrocorticosterone) (7). 11β-HSD1 is highly expressed in liver and adipose tissue, where glucocorticoids reduce insulin sensitivity and action (7).In obese humans and in monogenic obesity in rodents, there is a selective increase in 11β-HSD1 mRNA and activity in adipose tissues (8–10). Increased 11β-HSD1 in liver is found in other causes of metabolic syndrome, such as myotonic dystrophy (11). Transgenic overexpression of 11β-HSD1 selectively in adipose tissue in mice recapitulates all the major features of metabolic syndrome without changes in circulating steroid levels (12), whereas overexpression of 11β-HSD1 in liver alone produces an attenuated syndrome with insulin resistance, dyslipidemia, and hypertension, but not hyperglycemia or obesity (13). Conversely, 11β-HSD1 knockout mice are insulin sensitized and resist metabolic syndrome with dietary obesity (14).However, genetic variation in the HSD1B1 gene does not associate with obesity (15), suggesting the cause of increased 11β-HSD1 in adipose tissue in obesity is environmentally determined. Although many factors may upregulate 11β-HSD1 in the short term, attempts to chronically induce 11β-HSD1 in adipose tissue by nongenetic approaches have been unsuccessful. In particular, high-fat diets in rodents downregulate 11β-HSD1 in adipose tissue (16), although this does not appear to occur in humans (17), underlining the importance of relevant models of the human situation.Here, we have explored the early life antecedents of metabolic syndrome and especially 11β-HSD1 expression in metabolic tissues in a nonhuman primate model (the common marmoset monkey) of fetal programming.     

Outcome and Survival of Patients Aged 65 Years and Younger after Abdominal Aortic Aneurysm Rupture

Advanced age (> 80 years) confers a survival disadvantage after operative repair of a ruptured abdominal aortic aneurysm (AAA). This study aimed to determine if young age (≤65 years) confers a survival benefit. Consecutive patients undergoing attempted repair of a ruptured AAA between 1995 and 2001 were included in the study. Demographic, clinical, and operative factors were analyzed together with in-hospital mortality, duration of postoperative hospital stay, and long-term survival. Of 378 patients admitted with a ruptured AAA, 52 (14%) were ≤ 65 years of age and 326 (86%) were > 65 years. There were 4 (8%) women in the younger cohort compared to 74 (23%) women in the older group (p = 0.015). Four (8%) patients in the younger group were thought to be unsuitable for surgical repair compared to 77 (24%) patients in the older cohort (p = 0.009). Of the 48 younger patients who underwent attempted operative repair, 22 (46%) died in hospital, compared to 108 (43%) of 249 patients > 65 years (p = 0.753). The median (range) postoperative hospital stay of survivors was 11 days (6–59 days) in the younger cohort and 15 days (6–121 days) in the older group (p = 0.005). Patients ≤ 65 years of age undergoing operative repair of ruptured AAA have no survival advantage over older patients. These data support AAA screening for the “at risk” and age-defined population. This work was presented to the 53^rd International Congress of the European Society for Cardiovascular Surgery, Ljubljana, 2004 and published in abstract form in Interactive Cardiovascular and Thoracic Surgery 2004;3(S1):81.     

Hidradenoma papilliferum with oxyphilic metaplasia: a clinicopathological study of 18 cases, including detection of human papillomavirus

Reported here are 18 cases of hidradenoma papilliferum with oxyphilic metaplasia. All patients were women ranging in age from 29 to 74 years. Each presented clinically with a small, solitary tumor in the anogenital region. Microscopically, in addition to classic histopathological features, in every case there was oxyphilic metaplasia of the constituent epithelial cells. This finding could be likened to apocrine metaplasia, a term used in breast pathology. Other histopathological findings observed in this series, analogous to benign breast disease, included sclerosing adenosis-like changes, atypical apocrine adenosis-like changes, changes corresponding to usual ductal epithelial hyperplasia, epitheliomatosis with a streaming growth pattern, lamprocyte-like changes, clear cell change of the myoepithelium, foamy histiocyte reaction, and stromal fibrosis. Immunohistochemistry inferred that in the majority of cases oxyphilic metaplasia resulted from more lysosomes, whereas numerous mitochondria were detected in only 3 cases. Using 2 different PCR methods we identified HPV in 4 of 15 cases of hidradenoma with oxyphilic metaplasia. In addition, HPV was detected in 3 of 16 conventional papillary hidradenomas used as a control group. The following HPV types were identified: 16, 31, 33, 53, and 56. The last type was found in 5 cases. More than one HPV type from a single lesion was seen in 5 cases. Our observations are consistent with previous publications noting similarities between tumors of the breast and sweat glands. Oxyphilic metaplasia, areas with solid growth, and changes simulating atypical apocrine adenosis are rare and poorly recognized in hidradenoma papilliferum and may cause diagnostic difficulties; in our cases several submitting pathologists suspected malignancy. A causal role for HPV in hidradenoma papilliferum cannot be confirmed from our results, as the detection rate is too low. The exact role of the HPV in etiology and pathogenesis of this neoplasm has yet to be determined.     

A word of hope for ataxia trials in COVID-19 time and beyond

Journal of Neurology - The coronavirus disease 2019 (COVID-19) crisis confronted us, like many researchers worldwide, with an unforeseen challenge during the final stages of a randomized controlled...     

Impact of Ciprofloxacin and Clindamycin Administration on Gram-Negative Bacteria Isolated from Healthy Volunteers and Characterization of the Resistance Genes They Harbor

The aim of this study was to assess the impact of ciprofloxacin, clindamycin, and placebo administration on culturable Gram-negative isolates and the antibiotic resistance genes they harbor. Saliva and fecal samples were collected from healthy human volunteers before and at intervals, up to 1 year after antibiotic administration. Samples were plated on selective and nonselective media to monitor changes in different colony types or bacterial species. Following ciprofloxacin administration, there was a decrease of Escherichia coli in feces and after clindamycin administration a decrease of Bacteroides in feces and Leptotrichia in saliva, which all returned to pretreatment levels within 1 to 4 months. Ciprofloxacin administration also resulted in an increase in ciprofloxacin-resistant Veillonella in saliva, which persisted for 12 months. Additionally, 949 aerobic and anaerobic isolates purified from ciprofloxacin- and clindamycin-containing plates were screened for the presence of resistance genes. Resistance gene carriage was widespread in isolates from all three treatment groups, and no association was observed between genes and antibiotic administration. Although the anaerobic component of the microbiota was not a major reservoir of aerobe-associated antimicrobial resistance (AMR) genes, we detected the sulfonamide resistance gene sul2 in anaerobic isolates. The longitudinal nature of the study allowed identification of distinct Escherichia coli clones harboring multiple resistance genes, including one carrying an extended-spectrum β-lactamase bla_CTX-M group 9 gene, which persisted in the gut for up to 4 months. This study provided insight into the effects of antibiotic administration on healthy microbiota and the diversity of resistance genes harbored therein.