Overexpression of calmodulin in pancreatic beta cells induces diabetic nephropathy

Recently, endothelial dysfunction induced by an uncoupling of vascular endothelial growth factor (VEGF) and nitric oxide has been implicated in the pathogenesis of diabetic nephropathy (DN). Investigating the pathogenesis of DN has been limited, however, because of the lack of animal models that mimic the human disease. In this report, pancreatic beta cell-specific calmodulin-overexpressing transgenic (CaMTg) mice, a potential new model of DN, are characterized with particular emphasis on VEGF and related molecules. CaMTg mice developed hyperglycemia at 3 wk and persistent proteinuria by 3 mo. Morphometric analysis showed considerable increases in the glomerular and mesangial areas with deposition of type IV collagen. Moreover, the pathologic hallmarks of human DN (mesangiolysis, Kimmelstiel-Wilson-like nodular lesions, exudative lesions, and hyalinosis of afferent and efferent arteries with neovascularization) were observed. In addition, increased VEGF expression was associated with an increased number of peritubular capillaries. Expression of endothelial nitric oxidase synthase was reduced and that of VEGF was markedly elevated in CaMTg mice kidney compared with nontransgenic mice. No differences in VEGF receptor-1 or VEGF receptor-2 expression were observed between CaMTg mice and nontransgenic kidneys. In summary, CaMTg mice develop most of the distinguishing lesions of human DN, and the elevated VEGF expression in the setting of diminished endothelial nitric oxide synthase expression may lead to endothelial proliferation and dysfunction. This model may prove useful in the study of the pathogenesis and treatment of DN.     

Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.     

Transmesenteric approach for laparoscopic endoscopic cooperative surgery for a duodenal adenoma located in the third portion of the duodenum

We report our experience in a patient with adenoma located in the horizontal part of the duodenum, which was effectively treated with the transmesenteric laparoscopic endoscopic cooperative surgery (LECS) approach. This approach, which entails incising the mesentery of the colon, simplified laparoscopic access to the horizontal part of the duodenum, which was minimally mobilized. Thus, the bulb and descending part of the duodenum were fixed to the retroperitoneum, facilitating stable handling of the endoscope and enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. This approach enabled safe and effective excision of an adenoma located in the horizontal part of the duodenum. The advantages of this method include a secure field of view, lower probability of damage to large vessels, and minimizing the defect to the intestine caused by the incision.     

Magnetic resonance-guided focused ultrasound surgery of breast cancer: reliability and effectiveness

BACKGROUND: Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a noninvasive technique that has been shown to coagulate benign and malignant tumors. The purpose of this study was to evaluate MRgFUS safety and effectiveness for the ablation of breast carcinomas. STUDY DESIGN: Thirty women with biopsy-proved breast cancer underwent MRgFUS treatment. Gadolinium-enhanced MR images were used for treatment planning and posttreatment radiologic assessment of treated tissue, and temperature-sensitive MR images provided real-time treatment monitoring. After MRgFUS, all 30 women underwent wide excision or mastectomy. The extent of thermal ablation was assessed with tumor histology. RESULTS: Treatment was well tolerated, with a minimum of adverse effects, especially when performed under local anesthesia. On pathologic examination, mean (+/-SD) necrosis of the targeted breast tumors was 96.9 +/- 4% (median 100%, range 78% to 100%) of tumor volume. Fifteen (53.5%) of 28 evaluable patients had 100% necrosis of the ablated tumor; only 3 patients (10.7%) had less than 95% necrosis. In 28 (93.3%) patients, 100% of the malignancy was within the treatment field, and 98% and 95% of tumor lay within the treatment field in 2 remaining patients. Retrospective analysis in two patients with residual tumor showed treatment was not delivered to the full recommended area, reaffirming the need for precise localization and the value of contrast-enhanced images for treatment planning. CONCLUSIONS: MRgFUS has great potential to become a viable noninvasive replacement for lumpectomy. Additional studies focusing on posttreatment image-based evaluation are needed.     

Endoscopic and Histologic Findings of Intraductal Lesions Presenting with Nipple Discharge

Abstract:   To improve the utility of mammary ductoscopy, we investigated the correlation between endoscopic findings and histologic findings using intraductal biopsy specimens. Seventy-one intraductal biopsy specimens obtained from 63 patients between October 2001 and March 2004 were analyzed retrospectively. All specimens were obtained from monotonous intraductal lesions immediately after observation by mammary ductoscopy and were composed of a pure histologic subtype. With regard to endoscopic findings, color was classified as yellow, red, white, or colorless, and morphology was classified as spherical, lobular, mulberry, or amorphous. The histologic subtype was classified as papillotubular, papillary, degenerated, papillary cancer, solid-type ductal carcinoma in situ (DCIS), or cribriform cancer. The relationship between histologic diagnosis, color, and morphology was investigated. Intraductal biopsy specimens included 25 specimens of carcinoma and 46 specimens of papilloma. There was no significant correlation between color and diagnosis. Fourteen of 25 carcinoma specimens were amorphous, and amorphous morphology was significantly suggestive of malignancy (p < 0.001). Further, cribriform cancer was associated with amorphous morphology and yellow color. Morphology may be a useful endoscopically delineated parameter for differentiating intraductal lesions.