Clear Cell Type A and B Molecular Subtypes in Metastatic Clear Cell Renal Cell Carcinoma: Tumor Heterogeneity and Aggressiveness

Background

Intratumor molecular heterogeneity has been reported for primary clear cell renal cell carcinoma (ccRCC) tumors; however, heterogeneity in metastatic ccRCC tumors has not been explored.

pT2 classification for renal cell carcinoma. Can its accuracy be improved?

PURPOSE: The 2002 tumor classification for renal cell carcinoma (RCC) classifies pT2 tumors as more than 7 cm in greatest dimension, limited to the kidney. In this study we determined whether a size cutoff point exists within pT2 tumors and whether such subclassification would further improve the accuracy of the current tumor classification. MATERIALS AND METHODS: We studied 544 patients with unilateral, sporadic pT2 RCC treated with radical nephrectomy or nephron sparing surgery between 1970 and 2000. The association of tumor size with death from RCC was examined using martingale residuals from a Cox proportional hazards regression model to determine the optimal size cutoff point. RESULTS: There were 204 deaths from RCC a median of 3.8 years following nephrectomy. Univariately tumor size was significantly associated with death from RCC (risk ratio 1.08, 95% CI 1.04 to 1.13, p <0.001). A scatterplot of tumor size vs expected risk of death per patient suggested that a cutoff point between 9 and 10 cm was appropriate. When adjusted for regional lymph node involvement and distant metastases, the 10 cm cutoff point performed better than the 9 cm point (risk ratio 1.42, 95% CI 1.07 to 1.90, p = 0.017 vs 1.22, 95% 0.86 to 1.72, p = 0.268). Therefore, we propose using a 10 cm cutoff point to subclassify patients into pT2a and pT2b. CONCLUSIONS: Our data suggest that the prognostic accuracy of the 2002 pT2 tumor classification can be further improved by subclassifying patients with tumors greater than 7 and less than 10 cm into a pT2a category, and those with tumors 10 cm or greater into a pT2b category.     

Independent validation of the 2002 American Joint Committee on cancer primary tumor classification for renal cell carcinoma using a large, single institution cohort

PURPOSE: The primary tumor classification for renal cell carcinoma (RCC) was updated by the American Joint Committee on Cancer in 2002. To date the new classification has not been validated using an independent group of patients and, therefore, its accuracy for predicting patient outcome is unknown. In the current study we evaluated the 2002 primary tumor classification and compared its predictive ability with that of the 1997 classification. MATERIALS AND METHODS: We studied 2,746 patients treated with radical nephrectomy or nephron sparing surgery for unilateral, sporadic RCC between 1970 and 2000. Cancer specific survival was estimated using the Kaplan-Meier method. The predictive abilities of the 1997 and 2002 classifications were compared using the concordance index. RESULTS: There were 812 deaths from RCC a mean of 3.3 years following nephrectomy. Median followup in patients still alive at last followup was 9 years. Estimated 5-year cancer specific survival rates by the 2002 tumor classification were 97%, 87%, 71%, 53%, 44%, 37% and 20% in patients with pT1a, pT1b, pT2, pT3a, pT3b, pT3c and pT4 RCC, respectively. The concordance index for the association between the 2002 classification and death from RCC was 0.752 compared with 0.737 for the 1997 classification, indicating that the 2002 version contained more predictive ability. CONCLUSIONS: Our data suggest that the 2002 primary tumor classification with pT1 cancers subclassified into pT1a and pT1b provides excellent stratification of patients according to cancer specific survival and it has a predictive ability that is superior to that of the 1997 classification.     

The activation of the contact phase of coagulation by physiologic surfaces in plasma: the effect of large negatively charged liposomal vesicles

The endogenous, negatively charged surface that induces activation of the contact coagulation factors was investigated in plasmas taken from women in late pregnancy and control subjects of child-bearing age. The plasmas from the two groups of subjects were incubated at 4 degrees C for 24 hours either in plastic or in glass tubes and the factor VII coagulant activity (VIIc) was assayed in the treated plasmas. The activation of factor VII under these conditions involves the generation of enzymes derived from factor XII (XIIa). The contact surface is rate- limiting for the activation of factor VII in the plasmas in both groups of subjects and can be supplemented by large multilamellar liposomal vesicles carrying the appropriate density of negative charge. The size of these vesicles is within the range of sizes of the large lipoprotein particles (chylomicrons, very low and intermediate-density lipoproteins). The relationship between the density of negative charge on the liposomal vesicles and VIIc was similar in the late pregnancy and the control plasmas incubated in plastic tubes. At a saturating density of negative charge the observed relative VIIc was similar in both sets of plasmas. The incubation of late pregnancy or control plasma in plastic tubes in the presence of sodium stearate caused VIIc to increase with increasing concentration of the added fatty acid. These results suggest that large lipoprotein particles carrying the appropriate free fatty acid at a sufficient density of negative charge could provide the contact surface that induces the generation of factor XIIa and the subsequent activation of factor VII. Moreover, plasmas from women in late pregnancy have a higher concentration of potential surface and a higher density of negative charge than the plasmas from nonpregnant women.     

冠状循环药理学

直到最近为止,冠心病的内科治疗原则仍是降低心肌需氧量。由于粥样硬化病变一直认为是固定不变的狭窄,不可能增加冠脉血流量,因此认为用药物扩张冠状动脉是徒劳的。在近几年内这些概念有了基本转变。然而仅能引起远端心肌内小动脉扩张的药物却起着相反的作用。当心外膜冠状动脉有粥样硬化时,冠状小动脉扩张可加重血流分布异常,导致心肌缺血。冠状循环由近端大冠状动脉及其分枝小动脉组成的心肌内动脉网构成。近端大冠状     

乙型肝炎肝组织血管病变组织及免疫组织化学的研究

乙型肝炎(HB)已成为我国危害最大的社会公共卫生问题.近年来,我们在分析、研究国内外有关病毒性肝炎文献后选择了以HB患者肝组织活检观察为主的研究方法,从肝组织学随访中研究各型HB肝实质变性坏死及肝纤维组织增生的动态变化规律[1-8],采用组织化学(组化)及免疫组织化学(免疫组化)染色方法对肝组织内HBsAg,HBcAg表达[3],不同类型纤维组织增生情况,血清HBeAg与抗-HBe转换及透明质酸,色氨酸代谢变化[9-13],进行了深入研究.     

Thrombopoietin stimulates megakaryocytopoiesis, myelopoiesis, and expansion of CD34+ progenitor cells from single CD34+Thy-1+Lin- primitive progenitor cells

Thrombopoietin (TPO) or MpI ligand is known to stimulate megakaryocyte (MK) proliferation and differentiation. To identify the earliest human hematopoietic cells on which TPO acts, we cultured single CD34+Thy- 1+Lin- adult bone marrow cells in the presence of TPO alone, with TPO and interleukin-3 (IL-3), or with TPO and c-kit ligand (KL) in the presence of a murine stromal cell line (Sys1). Two distinct growth morphologies were observed: expansion of up to 200 blast cells with subsequent differentiation to large refractile CD41b+ MKs within 3 weeks or expansion to 200-10,000 blast cells, up to 25% of which expressed CD34. The latter blast cell expansions occurred over a 3- to 6-week period without obvious MK differentiation. Morphological staining, analysis of surface marker expression, and colony formation analysis revealed that these populations consisted predominantly of cells committed to the myelomonocytic lineage. The addition of IL-3 to TPO-containing cultures increased the extent of proliferation of single cells, whereas addition of KL increased the percentage of CD34+ cells among the expanding cell populations. Production of multiple colony- forming unit-MK from single CD34+Thy-1+Lin- cells in the presence of TPO was also demonstrated. In limiting dilution assays of CD34+Lin- cells, TPO was found to increase the size and frequency of cobblestone areas at 4 weeks in stromal cultures in the presence of leukemia inhibitory factor and IL-6. In stroma-free cultures, TPO activated a quiescent CD34+Lin-Rhodamine 123lo subset of primitive hematopoietic progenitor cells into cycle, without loss of CD34 expression. These data demonstrate that TPO acts directly on and supports division of cells more primitive than those committed to the MK lineage.     

Wound healing effect of methanolic leaf extract of Napoleona vogelii(Family:Lecythidaceae) in rats

Objective:To investigate the wound healing properly of Napoleona vogelii leaf extract in folkloric medicine.Methods:Roth sexes of adult albino rats(n=25) were used in this study and another group(n=30) were subjected to acute toxicity test(LD_(50)) of the plant extract.For the LD_(50),three randomized groups of 5 rats were first treated with 10,100,1 000 mg/kg body weight(bw),orally.This w as followed by a second treatment of 1500,3000,and 5 000 mg/kg bw of the leaf extract with continual monitoring of the animals for mortality or non-mortality.Incision wounds(1.3cm) were created on the skin of five groups of 5 rals using surgical blade under anesthesia.The first group was topically treated with petroleum jelly alone,group 2 was topically applied 400 mg/mL w/v of the reference drug,Neobaein,while group 3-5 were topically treated with 5-50 mg/mL w/v of the plant extract,respectively.Results:The percentage yield of the extract was 49.80%w/w dry matter.The phytochemical analysis revealed several bioactive constituents including glycosides,tannins,alkaloids,perpenoids.saponins,steroids,proteins,and carbohydrates.The LD_(50) was beyond our experimental limit and was not determined.Increased concentrations(5,20,and 50mg/mL w/v) of the extract had significant(ANOVA,P0.05) healing effect on the incision wounds giving rise to 125%-140% while treatmentawith Neobacin resulted in 150% healing effect on the third treatment regimen compared to the control(100%).Conclusions:These data indicate that Napoleona vogelii leaf extract contains potent bioactive compounds containing wound healing activity,substantiating its use as a wound healer in folkloric medicine.