Adiponectin and future coronary heart disease events among men with type 2 diabetes

Adiponectin, predominantly synthesized in the adipose tissue, seems to have substantial anti-inflammatory properties and to be a major modulator of insulin resistance and dyslipidemia, mechanisms that are associated with an increased atherosclerotic risk in diabetic patients. However, it is unknown whether higher levels of adiponectin are associated with a reduced risk for coronary heart disease (CHD) among diabetic individuals. We investigated the association between plasma adiponectin levels and incidence of CHD among 745 men with confirmed type 2 diabetes in the Health Professionals Follow-up Study. Participants were aged 46-81 years and were free of diagnosed cardiovascular disease at the time of blood draw in 1993/1994. During an average of 5 years of follow-up (3,980 person-years), we identified 89 incident cases of CHD (19 myocardial infarction and 70 coronary artery bypass surgery), confirmed by medical records. Levels of adiponectin were inversely associated with BMI and directly associated with age, alcohol intake, and duration of diabetes (P < 0.05). After adjustment for age, BMI, smoking, alcohol consumption, duration of diabetes, and other lifestyle factors, adiponectin was associated with a decreased risk for CHD events. The multivariate relative risk for CHD for a doubling of adiponectin was 0.71 (95% CI 0.53-0.95). Further adjustment for HDL cholesterol attenuated this association (0.78 [0.57-1.06]). The inverse association between adiponectin and CHD was consistent across strata of aspirin use, family history of myocardial infarction, alcohol consumption, insulin use, duration of diabetes, and levels of HbA(1c), triglycerides, C-reactive protein, and HDL cholesterol. Our study suggests that increased adiponectin levels are associated with a moderately decreased CHD risk in diabetic men. This association seems to be mediated in part by effects of adiponectin on HDL cholesterol levels.     

The histologic subtype of ovarian tumors affects the detection rate by pelvic washings

BACKGROUND: Since its introduction more than 45 years ago, the pelvic wash has gained widespread acceptance and is used routinely use at most centers. However, widely varying figures have been reported regarding its sensitivity for peritoneal involvement in ovarian tumors. In the current study, the authors evaluated a consecutive group of pelvic (peritoneal or abdominopelvic) washings performed in the evaluation of adnexal masses to determine whether histologic subtype significantly affects the tumor detection rate using this procedure. METHODS: Reports from all washes performed over a 5-year period in the evaluation of adnexal masses were evaluated and correlated with those of the synchronously obtained histologic specimens. The sensitivity for each histologic subtype was calculated, with ovarian surface involvement and/or tumoral involvement of any peritoneal surface defined as the criterion standard. Cases with cytologic and histologic concordance were defined as true-positive or true-negative. Statistical significance was determined using the Fisher exact test. RESULTS: In the current study, 185 of 846 (21.9%) total washes were associated with malignant (n = 161) or borderline (n = 24) tumors involving the ovary. For the malignancies, the overall cytology detection rate was 25%. A comparison of the cytology detection rates for the individual histologic subtypes with the overall rate demonstrated that the serous carcinomas were more likely (P = 0.0144) and the clear cell carcinomas were less likely (P = 0.0452) to be detected in pelvic washings. Cytology detection rates for mucinous, endometrioid, and undifferentiated carcinomas did not appear to differ significantly (P > 0.05) from the average detection rate. The cytohistologic correlation rate (efficiency), sensitivity, and specificity for the 5 most common histologic subtypes (n = 130) were 79.23%, 50.77%, and 93.33%, respectively. Differences also were observed in the calculated sensitivity for each subtype: serous (n = 57), 71.4%; endometrioid (n = 30), 58.33%; clear cell (n = 19), 20%; mucinous (n = 13), 50%; and undifferentiated (n = 11), 50%. Borderline tumors demonstrated a sensitivity and specificity of 80% and 100%, respectively. CONCLUSIONS: In the current study, the pelvic wash was found to be a specific, but only moderately sensitive, technique for detecting peritoneal involvement in ovarian tumors. The histologic subtype of the underlying ovarian tumor was found to have an effect on the likelihood of detection of peritoneal involvement using this diagnostic assay.     

Automated quantitative analysis of HDM2 expression in malignant melanoma shows association with early-stage disease and improved outcome

The incidence of cutaneous malignant melanoma continues to increase every year, and this disease remains the leading cause of skin cancer death in industrialized countries. Despite the aggressive nature of advanced melanoma, there are no standard biological assays in clinical usage that can predict metastasis. This may be due, in part, to the inadequacy of reproducible assessment of protein expression using traditional immunohistochemistry. We have previously described a novel method of quantitative assessment of protein expression (AQUA) with the continuity and accuracy of an ELISA assay but with maintenance of critical spatial information. Here, we modify this technology for the evaluation of protein expression in melanoma. Using a tissue microarray cohort of 405 melanoma lesions and 17 normal skin samples, we analyzed expression of HDM2, the human homologue of murine double minute 2 with automated quantitative analysis. We show that expression levels in the nucleus are significantly higher in primary melanomas than in metastatic lesions. Furthermore, high levels of expression are predictive of better outcome. This study demonstrates that quantitative assessment of protein expression is useful in melanoma to validate potential tissue biomarkers and suggests that human homologue of murine double minute 2 may be a valuable prognostic tool for management of malignant melanoma.     

Geographic and patient variation in receipt of surveillance procedures after local excision of cutaneous melanoma

Little is known about variation in surveillance practices following the diagnosis of invasive melanoma. The objective of this study was to characterize geographic, patient, and tumor variation in the use of follow-up surveillance testing in patients with local or regional stage melanoma. A cohort of Medicare beneficiaries > or =65 y diagnosed with invasive melanoma during 1992 to 1996 living in a Surveillance, Epidemiology, and End Results registry area was studied. Outpatient and inpatient Medicare claims 3 mo following diagnosis were examined for up to 2 y for surveillance procedures of interest. Use of chest X-ray, chest computed tomography scan, abdominal and/or pelvic computed tomography scan, abdominal ultrasound, head computed tomography scan, head magnetic resonance imaging, laboratory testing, and skin examinations were compared between patient groups and geographic regions. A total of 3389 patients were identified for the analysis. Surveillance testing was relatively common, ranging from 13% for abdominal ultrasound to 80% for laboratory testing. Follow-up skin examinations were performed in 70% to 90% of patients. The use of most surveillance procedures was associated (p<0.01) with younger age, male gender, regional stage tumors, and geographical area, with up to 2-fold differences observed. In contrast, there was much less variability in the receipt of skin examinations. Further studies are needed to determine the etiology and impact of such disparities, and the influence of surveillance procedures on morbidity and mortality.     

Her2/neu is not a commonly expressed therapeutic target in melanoma -- a large cohort tissue microarray study

Melanoma is among the most chemotherapy-resistant malignancies. Numerous new agents have been developed that target specific molecules on cancer cells, including the monoclonal antibody trastuzumab, which targets Her2/neu and has been very beneficial in the treatment of breast cancer. There are conflicting reports in the literature about Her2/neu expression in melanoma specimens, but all of the cohorts studied have been small. We therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients. Immunohistochemical staining was performed on two tissue microarrays, together containing 600 intact specimens. Expression was evaluated semi-quantitatively and correlated with tumour stage and other clinicopathological data. Of the 600 specimens in the cohort, 31 patients (5.2%) had positive Her2/neu expression. Among the primary cutaneous specimens (n=269), 7% had positive Her2/neu staining, while 3.6% of the recurrent or metastatic specimens (n=331) had positive Her2/neu staining (P=0.06). Among the primary lesions there was no significant correlation between Her2/neu expression, Clark level and ulceration; however, Her2/neu expression was associated with lesions with a Breslow depth of < 2 mm (P=0.05). Using this very large cohort of melanoma specimens, we found only a few cases with aberrant Her2/neu expression, many of them being primary cutaneous lesions rather than recurrent or metastatic lesions. Our findings suggest that drugs that specifically target Her2/neu are not likely to be useful for the treatment of metastatic melanoma or as adjuvant therapy for melanoma patients at high risk for recurrence.     

Quantitative analysis of breast cancer tissue microarrays shows that both high and normal levels of HER2 expression are associated with poor outcome

Using a tissue microarray cohort of 300 breast cancers and 84 samples of normal breast epithelium, we analyzed HER2/neu expression and compared traditional clinical (manual) scoring with a recently developed system for the quantitative measurement of immunohistochemical stains (AQUA). As expected, both methods identified a population (10-15%) of high-HER2-expressing tumors with poor 30-year disease-related survival. Using AQUA analysis, we found that normal epithelium expresses a low but detectable level of HER2 and that 17.5% of tumors exhibit similar low-level HER2 expression. This low group was not definable by manual scoring. Surprisingly, HER2-normal tumors were as aggressive as HER2-overexpressing tumors. Our studies suggest that in situ quantitative measurement of HER2 stratifies breast tumors into three expression levels: normal, intermediate, and high, where both normal and high levels are associated with a worse outcome.     

Truncated DCC reduces N-cadherin/catenin expression and calcium-dependent cell adhesion in neuroblastoma cells

The deleted in colorectal cancer (DCC) protein is important in the pathway guidance of cells and cell processes during neural development, and DCC has also been implicated in the aberrant cellular migrations of neuroblastoma dissemination. We attempted to further define DCC protein function by the overexpression of full-length and truncated DCC constructs in a human neuroblastoma cell line. Overexpression of the truncated DCC protein resulted in a less epithelioid morphology. This was accompanied by decreases in expression of N-cadherin and alpha- and beta-catenin by immunoblot and Northern blot analysis. Levels of desmoglein were relatively less affected, whereas endogenous DCC protein levels were increased in the truncated transfectants. N-cadherin immunofluorescence was consistent with the immunoblot studies and localized the protein to the cytoplasm and sites of cell-cell contact. Cell aggregation studies demonstrated diminished calcium-dependent aggregation in the truncated transfectants. In conclusion, overexpression of a truncated DCC protein in neuroblastoma cells resulted in the loss of an epithelioid morphology, diminished expression of N-cadherin and alpha- and beta-catenin, and diminished calcium-dependent cell adhesion. These studies provide the first evidence of an apparent functional link between DCC and N-cadherin/catenin-dependent cell adhesion.