Diabetes mellitus affects response to neoadjuvant chemoradiotherapy in the management of rectal cancer.

INTRODUCTION: Although diabetic patients with rectal cancer have poorer outcomes than their nondiabetic counterparts, few studies have looked at diabetics' response to therapy as an explanation for this disparity. This study compares the neoadjuvant chemoradiotherapy (CRT) response in diabetic and nondiabetic patients with locally advanced rectal cancers. METHODS: This is a single-institution, retrospective review of rectal cancer patients who received CRT followed by resection from 1995 to 2006. Pretreatment tumor-node-metastasis (TNM) staging was determined using endorectal ultrasound, computed tomography (CT) scan, and magnetic resonance imaging (MRI); post-treatment staging was determined by pathological review. RESULTS: 110 patients were included; seventeen had diabetes and 93 were nondiabetics. Pretreatment staging was similar in both groups. Sixteen of the diabetics (94%) completed CRT compared to 92% (86/93) of the nondiabetics. Tumor downstaging rates were similar in the two groups (53% in diabetics, 52% in nondiabetics). Nondiabetic patients had a higher rate of nodal downstaging although not statistically significant (67% versus 27%, P = 0.80). While none of the diabetics patients achieved a pathologic complete response (pCR), 23% (21/93) of the nondiabetics did (P = 0.039). Local progression rates were higher in the diabetic group (24% versus 5%, P = 0.046). CONCLUSION: Our study shows that neoadjuvant chemoradiotherapy in rectal cancer is less effective in diabetic patients than in nondiabetics. While minimal differences are found in the rate of downstaging, the rate of achieving a complete pathologic response was significantly higher in nondiabetic patients, and in fact was not seen in any of our diabetic patients. This may explain the poorer outcomes seen in diabetic patients with rectal cancer.

Polymorphisms in the prostate-specific antigen gene promoter do not predict serum prostate-specific antigen levels in African-American men.

A major problem with the use of serum prostate-specific antigen (PSA) in predicting prostate cancer risk is the considerable variability of such measurements. Cramer et al. identified a set of single-nucleotide polymorphisms (SNPs) in the upstream regulatory region of the PSA gene that were each associated with increased promoter activity and serum PSA, further suggesting that genotyping these SNPs could be useful in improving the predictive value of PSA screening. In order to replicate this finding, DNA samples from 475 African-American men were genotyped for the same SNPs and no association was observed with either serum PSA level or prostate cancer diagnosis.

The influence of hypothyroidism and thyroid replacement therapy on stimulated parotid flow rates.

OBJECTIVE: The purpose of this study was to determine, through use of cross-sectional and longitudinal data, whether hypothyroidism and its treatment with thyroid hormones have a significant effect on the production of stimulated parotid flow rates. STUDY DESIGN: From the Baltimore Longitudinal Study of Aging (NIA, NIH), subjects with hypothyroidism taking and not taking thyroid replacement therapy were evaluated for the production of 2% citrate-stimulated parotid saliva in a cross-sectional and longitudinal investigation. Comparisons were made with nonmedicated healthy control subjects. RESULTS: Cross-sectional analyses revealed that stimulated parotid flow rates were not significantly different between healthy controls, subjects with hypothyroidism on thyroid replacement therapy, and subjects with hypothyroidism not on thyroid replacement therapy. In general, longitudinal analyses revealed no significant differences over time in stimulated parotid flow rates between healthy controls and subjects with hypothyroidism. CONCLUSIONS: Hypothyroidism and the concomitant use of thyroid replacement therapy do not cause significant changes in the production of stimulated parotid saliva.

Noninvasive evaluation of hand circulation before radial artery harvest for coronary artery bypass grafting.

OBJECTIVE: Radial artery harvesting for coronary artery bypass may lead to digit ischemia if collateral hand circulation is inadequate. The modified Allen's test is the most common preoperative screening test used. Unfortunately, this test has high false-positive and false-negative rates. The purpose of this study was to compare the results of a modified Allen's test with digit pressure change during radial artery compression for assessing collateral circulation before radial artery harvest. METHODS: One hundred twenty-nine consecutive patients were studied before coronary artery bypass operations. A modified Allen's test was performed with Doppler ultrasound to assess blood flow in the superficial palmar arch before and during radial artery compression. A decreased audible Doppler signal after radial artery compression was considered a positive modified Allen's test. First and second digit pressures were measured before and during radial artery compression. A decrease in digit pressure of 40 mm Hg or more (digit DeltaP) with radial artery compression was considered positive. RESULTS: Seven of 14 dominant extremities (50%) and 8 of the 16 nondominant extremities (50%) with a positive modified Allen's test had a digit DeltaP of less than 40 mm Hg (false positive). Sixteen of 115 dominant extremities (14%) and 5 of 112 nondominant extremities (4%) with a negative Allen's test had a digit DeltaP of 40 mm Hg or more with radial artery compression (false negative). CONCLUSION: Use of the modified Allen's test for screening before radial artery harvest may unnecessarily exclude some patients from use of this conduit and may also place a number of patients at risk for digit ischemia from such harvest. Direct digit pressure measurement is a simple, objective method that may more precisely select patients for radial artery harvest. Additional studies are needed to define objective digital pressure criteria that will accurately predict patients at risk for hand ischemia after radial harvest.

pp60(c-src) is required for cell locomotion regulated by the hyaluronanreceptor RHAMM.

The tyrosine kinase pp60(c-src) has been implicated as a regulator of focal adhesion formation and cell spreading. Here we show that c-src also regulates cell motility and is a key component in the signaling pathway triggered by the motogenic hyaluronan receptor RHAMM, which has been shown to regulate focal adhesion turnover and to regulate ras. Fibroblasts derived from mice lacking src, (src (-/-)), have a random locomotion rate that is significantly slower than the corresponding wild-type fibroblasts. Cell locomotion in these mutant cells is restored by the expression of c-src containing a functional kinase domain, but not by the expression of a kinase-deficient src or by a truncated src containing only functional SH2 and SH3 domains. RHAMM is also required for the restoration of src (-/-) cell locomotion. Thus, the motility of cells expressing c-src is reduced to src (-/-) levels by anti-RHAMM blocking antibodies while the cell locomotion of src (-/-) fibroblasts remains unaffected by anti-RHAMM antibodies. We predict that src acts downstream of RHAMM in the regulation of motility, since the expression of a dominant negative src significantly inhibits RHAMM-dependent ras and serum regulated cell locomotion, the expression of v-src enhances cell motility in a RHAMM independent fashion, and there is a physical and functional assocation between src and RHAMM in ras-transformed cells. However, we suggest that RHAMM regulates focal adhesion turnover via additional src-independent mechanisms. Thus, v-src is unable to turnover focal adhesions in the absence of RHAMM. These results directly demonstrate for the first time a role for src in the regulation of cell locomotion and confirm a key and complex role for src in the regulation of the actin cycle.

Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation.

Overexpression of the RHAMM gene by transfection into fibroblasts is transforming and causes spontaneous metastases in the lung. H-ras-transformed fibrosarcomas transfected with a dominant suppressor mutant of RHAMM exhibit a so-called revertant phenotype and are completely nontumorigenic and nonmetastatic. Conversely, fibroblasts stably expressing low levels of RHAMM as a result of antisense transfection are resistant to ras transformation. Collectively, these results indicate that RHAMM acts downstream of ras. The loss of functional RHAMM ablates signaling within focal adhesions, in particular changes in focal adhesion kinase phosphorylation, and as a result these focal adhesions are unable to turn over in response to hyaluronan. These results provide evidence of the oncogenic potential of a novel extracellular matrix receptor and establish a functional link between transformation by ras and signaling within focal adhesions that are required for transformation by this oncogene.