Predictors of response to targeted therapy in renal cell carcinoma.

CONTEXT: The prognosis for patients with metastatic renal cell carcinoma is poor, with an average 5-year survival of approximately 10%. Use of traditional cytokine therapy, specifically high-dose interleukin 2, is limited by significant toxicity. Better understanding of the molecular pathogenesis of renal cell carcinoma has led to the development of targeted therapies to inhibit specific cellular pathways leading to tumorigenesis. These drugs provide improved survival with a more favorable toxicity profile. There is ongoing investigation of markers that predict response of an individual patient to different targeted therapies. OBJECTIVE: To explain the molecular basis for vascular endothelial growth factor inhibitor (antiangiogenic) and mammalian target of rapamycin inhibitor therapies for renal cell carcinoma, summarize the clinical trials demonstrating the effectiveness of these drugs, and describe the biomarkers shown to correlate with outcome in patients treated with targeted therapy. DATA SOURCES: All included sources are from peer-reviewed journals in PubMed (US National Library of Medicine). CONCLUSION: Emerging evidence shows promise that biomarkers will be useful for predicting an individual patient's response to targeted therapy, leading to a more personalized approach to treating renal cell carcinoma.

Expression analysis of putative stem cell markers in human benign and malignant prostate.

BACKGROUND: Stem cells were suggested to be present in human prostate cancer as a small population of distinct cells, which may contribute to carcinogenesis, tumor recurrence, and chemoresistance. To identify potential prostatic stem cells, we analyzed the expression of several potential stem cell markers in benign prostate and prostatic adenocarcinoma. METHODS: CD44, CD133, Oct4, SOX2, and EZH2 expression was detected by immunohistochemical (IHC) staining using tissue microarray assays (TMA) composed of benign (non-neoplastic) prostatic tissue, high grade prostatic intraepithelial neoplasia (HGPIN), and prostatic adenocarcinoma. Positive staining was defined as 1+ (<10%), 2+ (10-50%), or 3+ (>50%). RESULTS: We found CD44 staining in 97% and 72% of benign + HGPIN and malignant lesions, respectively. CD133 staining was detected in a small fraction (4 of 67) of prostate carcinomas. We found that Oct4 nuclear expression was strongly associated with benign lesions and HGPIN but not prostate cancer (P < 0.05). In most cases, nuclear expression of EZH2 and SOX2 was detected in less than 10% of cells in non-neoplastic prostate glands, HGPINs or prostate adenocarcinomas. Moreover, 27 of 33 SOX2 1+ prostate cancers were also EZH2 1+, whereas all 33 of these cases were CD44+. CONCLUSIONS: Expression of CD44 and Oct4 identified large populations of benign and malignant cells in the prostate, which did not fit the definition of stem cells as a small fraction of the total cell population. Our results suggest that combined expression of embryonic stem cell markers EZH2 and SOX2 might identify potential cancer stem cells as a minor (<10%) subgroup in CD44+ prostatic adenocarcinoma.

Rotavirus infection in small bowel transplant: a histologic comparison with acute cellular rejection.

Pediatric small bowel transplant recipients are susceptible to diarrhea due to rejection or infectious enteritis, particularly of viral etiology. The most common causes of viral enteritis in this setting are rotavirus, adenovirus, cytomegalovirus, and Epstein-Barr virus. This study is the first to compare the histologic findings of rotavirus infection with acute cellular rejection in small bowel transplant biopsies. Three patients with small bowel transplants had rapid stool antigen test-proven rotavirus infection. Endoscopic biopsies during infection were examined, including material from the allograft, native small bowel, stomach, and colon. Biopsies from 2 of the patients during unrelated episodes of mild acute cellular rejection were also evaluated. Blunting of villi was the most common finding in rotavirus infection. Additionally, there was a mononuclear infiltrate that was "top heavy," or denser towards the lumen. There were surface apoptoses but no increase in crypt apoptotic figures. In contrast, during mild acute cellular rejection, there was no villous blunting, the mononuclear infiltrate was diffuse, and there were increased crypt apoptosis. As expected, the changes of acute cellular rejection were confined to the graft, in contrast to rotavirus infection, in which case native bowel often had more pronounced changes. Although the small number of patients limits this study, several histologic features were helpful in identifying rotavirus infection. These were blunting of villi, distribution of the inflammatory infiltrate, number and location of apoptotic bodies, and anatomic location of the effect. A larger follow-up study would be valuable to confirm these findings.

Prenatal cocaine exposure and infant cognition.

The present study examined the relationship of prenatal cocaine exposure to infant information processing in the first year of life.In a prospective, longitudinal study of 177 cocaine-exposed and 175 non-exposed infants, the Fagan Test of Infant Intelligence (FTII) was used to measure attention, visual recognition memory and information processing speed at 6.5 and 12 months of age. Groups were compared over time using mixed linear model analyses.Prenatal cocaine exposure predicted poorer visual recognition memory at 12 months, with exposed infants obtaining lower mean scores and a higher percentage of scores in the risk range. Across exposure groups, information processing speed increased with age, demonstrating a developmental effect. Tobacco and marijuana exposures were related to faster looking times, which did not relate to visual recognition memory.Cognitive deficits and attentional problems noted in prior studies of cocaine-exposed children at later ages may be detectable in infancy.