Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma.

PURPOSE: To evaluate the prognostic value of vascular endothelial growth factor (VEGF)-D and VEGF receptor (VEGFR)-3 in endometrial carcinoma. EXPERIMENTAL DESIGN: We assessed the levels of immunoreactivity for VEGF-D and VEGFR-3 in 71 endometrial carcinomas, 14 complex atypical endometrial hyperplasias, and 16 normal endometria by immunohistochemistry. RESULTS: VEGF-D was stained in both tumor cells and adjacent stromal cells. VEGFR-3 was stained in both tumor cells and adjacent endothelial cells. Immunoreactivity for VEGF-D in tumor cells and adjacent stromal cells became significantly stronger as lesions progressed from normal endometrium to advanced carcinoma. Similarly, immunoreactivity for VEGFR-3 in tumor cells and adjacent endothelial cells was significantly greater as lesions progressed from normal endometrium to advanced carcinoma. A strong correlation was found between high levels of VEGF-D immunoreactivity in carcinoma cells and VEGFR-3 in both carcinoma cells and adjacent endothelial cells. Similarly, high levels of VEGF-D immunoreactivity in stromal cells were significantly correlated with those of VEGFR-3 in both carcinoma cells and endothelial cells. High levels of VEGF-D in carcinoma cells and stromal cells, as well as those of VEGFR-3 in carcinoma cells and endothelial cells, were significantly related to myometrial invasion and lymph node metastasis. A strong correlation was found between poor survival and high levels of VEGF-D in both carcinoma cells and stromal cells and between poor survival and high levels of VEGFR-3 in carcinoma cells. Moreover, the high levels of VEGF-D in stromal cells and VEGFR-3 in carcinoma cells were independent prognostic factors in endometrial carcinoma. CONCLUSIONS: The presence of VEGF-D and VEGFR-3 in endometrial carcinoma may predict myometrial invasion and lymph node metastasis and may prospectively identify patients who are at increased risk for poor outcome. In addition, VEGF-D and VEGFR-3 may be promising targets for new therapeutic strategies in endometrial carcinoma.     

冬凌草甲素通过改变Bax/Bcl-xL表达激活caspase-3诱导A375-S2细胞凋亡

目的　研究冬凌草甲素诱导人黑色素瘤A375 S2细胞凋亡的作用原理。方法　形态学观察 ,DNA凝胶电泳法及WesternBlot法。结果　冬凌草甲素能明显诱导A375 S2细胞发生凋亡 ,其作用呈明显的量效关系和时间依赖性。形态学观察可见凋亡小体的形成 ,琼脂糖凝胶电泳可见凋亡典型的DNA梯带 ;caspase 3的抑制剂能阻止caspase 3的活力升高 ;免疫印迹结果显示冬凌草甲素作用A375 S2细胞 12h改变Bax与Bcl xL蛋白的表达 ;且发现caspase 3的底物PARP蛋白在 12h时被降解。结论　冬凌草甲素 (34 3μmol·L-1)诱导A375 S2细胞凋亡 ,这种作用是通过改变了Bax/Bcl xL的表达比率 ,激活caspase 3而实现的。     

Fas-Fas ligand system in the peripheral blood of patients with renal diseases

To clarify the role of the Fas-Fas ligand (FasL) system in the peripheral blood from patients with various renal diseases, the Fas and FasL expression on mononuclear cells (MNCs) and serum levels of soluble Fas (sFas) and soluble FasL were investigated. Patients were selected from those with various types of glomerular diseases showing various degrees of renal function. Fas expression on MNCs was analyzed by a FACScan, sFas and soluble FasL were measured with an ELISA kit, and FasL expression on MNCs was counted using a FACScan after a bioassay. Fas-positive MNCs and sFas increased with statistical significance concomitantly with deterioration in renal function. Moreover, there was a significant correlation between them. sFas- and FasL-positive MNCs were significantly correlated with proteinuria. However, the Fas expression percentage on MNCs and/or serum levels of sFas did not correlate with the number of TUNEL-positive cells in the glomeruli. Also, there was no disease specificity in the activation of Fas. These results indicate that Fas expression on MNCs is activated in accordance with the deterioration in renal function without disease specificity, corresponding to the elevation of serum sFas levels to protect against Fas-mediated apoptosis.     

Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan

BACKGROUND: Whether the type of diabetes, race, and year and age of diagnosis affect the incidence of diabetic vascular complications is unknown. That both type 1 and type 2 diabetes occur in the young Japanese population prompted us to investigate whether the type of diabetes and the year of diagnosis are related to the incidence of nephropathy. METHODS: Of the 17,256 diabetic patients who visited the outpatient clinic at our diabetes center between 1965 and 1990, 1578 (9.1%) had early-onset diabetes (diagnosed before the age of 30); of these, 620 (39%) had type 1, and 958 (61%) had type 2 diabetes. The incidence of nephropathy was analyzed in the patients according to postpubertal duration and year of diagnosis. RESULTS: The cumulative incidence of nephropathy after 30 years of postpubertal diabetes was significantly higher (P < 0.0001) in type 2 diabetic patients (44.4%, 95% CI, 37.0 to 51.8%) than in type 1 diabetic patients (20.2%, 95% CI, 14.9 to 25.8%). The incidence of nephropathy among type 1 diabetic patients has declined during the past two decades, whereas it has not among type 2 diabetic patients. The rate ratio for type 2 diabetic patients diagnosed between 1980 and 1984 relative to type 1 diabetic patients diagnosed in the same period was 2.74 (95% CI, 1. 17 to 6.41). CONCLUSIONS: The incidence of nephropathy has declined in Japanese patients with type 1 but not in those with type 2 diabetes. In young Japanese patients, because of the higher incidence of nephropathy in type 2 diabetes and the higher prevalence of type 2 than type 1 diabetes, type 2 diabetes is likely the major cause of diabetic nephropathy.     

Cytological changes induced by intravesical bacillus Calmette-Guérin therapy for superficial bladder cancer

To evaluate cytological changes of urothelial cells with intravesical instillation therapy of the bacillus Calmette-Guérin (BCG), cytological specimens of voided urine from patients with superficial bladder cancer (pTa and pT1) treated with intravesical BCG therapy were examined. The following three groups of patients who had no evidence of recurrence more than 2 years after the treatment were studied: groups 1 and 2, patients who were treated with BCG (n = 22) and epirubicin, a derivative of doxorubicin (n = 22), respectively, for prophylaxis of intravesical recurrence after transurethral resection (TUR); and group 3, patients receiving no intravesical therapy after TUR (n = 12). Sixteen cytological characteristics were studied before and after the treatment in each group. In group 1 patients translucent nuclei and prominent nucleoli, vacuolization of cytoplasm, and eosinophilic cytoplasmic inclusions were frequently observed in urothelial cells as well as an increase in granulocytes, especially within 3 months after BCG instillation therapy. In group 2 patients an increased nuclear/cytoplasmic ratio, hyperchromatic nuclei and prominent nucleoli of urothelial cells were transiently found within 1-2 months after intravesical epirubicin therapy. In group 3, translucent nuclei and prominent nucleoli of urothelial cells were found within 1-2 months after TUR. In conclusion, cytological changes induced by BCG therapy are nonspecific and reactive in nature, different from those due to chemotherapeutic agents and distinguishable from malignant changes of urothelial cells.     

Indispensability of Pelvic and Paraaortic Lymphadenectomy in Endometrial Cancers

The purposes of this study were to analyze the relationship between retroperitoneal lymph node (RLN) metastasis and clinical and pathologic risk factors in endometrial cancers, and to clarify the correlation between RLN metastasis and survival of patients with the disease. This analysis included 63 patients with endometrial cancer who underwent simultaneous pelvic lymph node (PLN) and paraaortic lymph node (PAN) dissection between April 1988 and December 1995. Patients with stage Ia grade 1 and stage IV disease were excluded from this analysis. Both PLN and PAN metastases were found in 10.0% (4/40) of patients with stage I (FIGO, 1988) disease. Of 14 cases with PLN metastases, 8 (57.1%) had PAN metastases simultaneously, whereas 4 (8.2%) of 49 cases without PLN metastases had PAN metastases. There was no significant relationship between the sites or numbers of positive PLN and PAN metastases. Multivariate analysis revealed that poor grade and deep myometrial invasion had an independent relationship with PAN metastases, whereas vascular space invasion and cervical invasion were independently associated with PLN metastases. When divided into the groups of stage I–II and stage III, the prognosis of patients with RLN metastases was significantly poorer than that of patients without RLN metastases in each stage. Furthermore, survival of patients with PAN metastases was significantly worse compared with that of patients with only PLN metastases (44.4 and 80.0%, respectively,P< 0.05). These results reveal that PLN and PAN metastases occur frequently even in early-stage endometrial cancer, and that RLN metastases, especially PAN metastases, have a serious impact on patient survival. In conclusion, systemically simultaneous pelvic and paraaortic lymphadenectomy is essential for all the patients with endometrial cancer except those with stage Ia grade 1 and stage IV to provide prognostic information and select suitable postoperative treatment as well as to perform accurate FIGO staging, provided the condition of the patient permits.