The Oct-3/4 transcription factor sustains embryonic stem (ES) cell self-renewal and is a dose-dependent cell fate determinant. In the adult male, its expression is restricted to type A spermatogonia. We show that Oct-3/4 is expressed in all human testicular germ cell tumors (GCTs) tested, even in the early premalignant component. We demonstrate that Oct-3/4 dictates ES cells' oncogenic potential in a dose-dependent manner; high levels increase the malignant potential of ES cell-derived tumors while Oct-3/4 inactivation induces regression of the malignant component. Oct-3/4 expression in a heterologous cell system transforms nontumorigenic cells and endows tumorigenicity in nude mice. Our findings suggest that Oct-3/4 is not only a distinctive immunohistochemical marker for GCTs, but also plays a critical role in the genesis of these tumors.

The response to tissue injury involves the coordination of inflammatory and repair processes. IL-6 expression correlates with the onset and severity of acute kidney injury (AKI), but its contribution to pathogenesis remains unclear. This study established a critical role for IL-6 in both the inflammatory response and the resolution of AKI. IL-6 -deficient mice were resistant to HgCl 2 -induced AKI compared with wild-type mice. The accumulation of peritubular neutrophils was lower in IL-6 -deficient mice than in wild-type mice, and neutrophil depletion before HgCl 2 administration in wild-type mice significantly reduced AKI; these results demonstrate the critical role of IL-6 signaling in the injurious inflammatory process in AKI. Renal IL-6 expression and STAT3 activation in renal tubular epithelial cells significantly increased during the development of injury, suggesting active IL-6 signaling. Although a lack of renal IL-6 receptors (IL-6R) precludes the activation of classical signaling pathways, IL-6 can stimulate target cells together with a soluble form of the IL-6R (sIL-6R) in a process termed trans-signaling. During injury, serum sIL-6R levels increased three-fold, suggesting a possible role for IL-6 trans-signaling in AKI. Stimulation of IL-6 trans-signaling with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium and prevented AKI. IL-6/sIL-6R reduced lipid peroxidation after injury, suggesting that its protective effect may be largely mediated through amelioration of oxidative stress. In summary, IL-6 simultaneously promotes an injurious inflammatory response and, through a mechanism of transsignaling, protects the kidney from further injury.

Background. This study was performed to evaluate the effect of positive margins, Gleason grade, and capsular penetration on progression after radical prostatectomy. Methods. The authors followed 507 men with totally embedded retropubic prostatectomy specimens performed for clinical Stages A and B prostate cancer for a mean of 3.9 years. Results. Fifty‐nine percent of the specimens had negative margins, 37% had focally positive margins, and 4% had extensive positive margins. Although some positive margins were the result of extensive and/or high‐grade tumor, in many cases, the tumors only focally reached the capsular margin such that positive margins resulted from an inability to remove additional soft tissue surrounding the prostate. Gleason sum 7 tumors had a significantly higher progression rate compared with Gleason sum 5 or 6 ones, although historically Gleason sum 5–7 lesions had been considered together as intermediate‐grade tumors. In a multivariate analysis, positive margins and Gleason sum strongly correlated with progression, whereas capsular penetration did not. Only approximately 50% of patients with positive margins experienced disease progression during 5 years of follow‐up. The most common single sites of positive margins were distal (22%), posterior (17%), and posterolateral (14%); 22% of positive margins were extensive. Only four patients (0.8% of the total) had positive margins only in the region of the spared neurovascular bundle and experienced progression. Conclusions. The most likely explanation for the discrepancy between margins and progression is that some of these margins represented artifactually positive margins caused by the unique problems with handling and assessing radical prostatectomy specimens. Radical prostatectomy provided excellent local control, with only 8% of patients exhibiting local recurrence. Sixty‐one percent of men with progression had an elevated serum prostate‐specific antigen level as their only manifestation of progression. The significance of isolated elevated serum prostate‐specific antigen levels is uncertain, and long‐term morbidity and mortality will depend on whether these patients have local disease or occult distant metastases.

Focal atrophy is extremely common in prostate specimens. Although there are distinct histologic variants, the terminology is currently nonstandardized and no formal classification has been tested for interobserver reliability. This lack of standardization hampers the ability to study the biologic and clinical significance of these lesions. After informal and formal meetings by a number of the authors, focal atrophy lesions were categorized into 4 distinct subtypes as follows: (i) simple atrophy, (ii) simple atrophy with cyst formation, (iii) postatrophic hyperplasia, and (iv) partial atrophy. In phase 1 of the study, pathologists with varying levels of experience in prostate pathology were invited to view via the Internet a set of "training" images with associated descriptions of lesions considered typical of each subtype. In phase 2 of the study, each participant provided diagnoses on a series of 140 distinct "test" images that were viewed over the Internet. These test images consisted of the 4 subtypes of atrophy and images of normal epithelium, high grade prostatic intraepithelial neoplasia, and carcinoma. The diagnoses for each image from each pathologist were compared with a set of "standard" diagnoses and the kappa statistic was computed. Thirty-four pathologists completed both phases of the study. The interobserver reliability (median kappa) for classification of lesions as normal, cancer, prostatic intraepithelial neoplasia, or focal atrophy was 0.97. The median kappa for the classification of atrophy lesions into the 4 subtypes was 0.80. The median percent agreement with the standard diagnosis for the atrophy subtypes were: simple 60.6%, simple with cyst formation 100%; postatrophic hyperplasia 87.5%; partial atrophy 93.9%. The lower percentage for simple atrophy reflected a propensity to diagnose some of these as simple atrophy with cyst formation. Seven pathologists completed the phase 2 analysis a second time, and their intraobserver reproducibility was excellent. Three of 4 pathologists with low agreement with the standard diagnosis for simple atrophy improved their scores after repeating the analysis after re-examination of the "training set" of images. In conclusion, these criteria for variants of focal prostate atrophy may facilitate studies to examine the relation between various patterns of prostate atrophy and prostate cancer.