Purpose: Therapies targeting the programmed death 1 (PD-1)/ programmed death ligand 1 (PD-L1) pathway promote antitumor immunity and have shown promising results in various tumors. Preliminary data further indicate that immunohistochemically detected PD-L1 may be predictive for anti-PD-1 therapy. So far, no data are available on PD-L1 expression in primary prostate cancer.Experimental Design: Following validation of a monoclonal antibody, immunohistochemical analysis of PD-L1 expression was performed in two independent, well-characterized cohorts of primary prostate cancer patients following radical prostatectomy (RP), and resulting data were correlated to clinicopathological parameters and outcome.Results: In the training cohort (n ¼ 209), 52.2% of cases expressed moderate to high PD-L1 levels, which positively correlated with proliferation (Ki-67, P < 0.001), Gleason score (P ¼ 0.004), and androgen receptor (AR) expression (P < 0.001).Furthermore, PD-L1 positivity was prognostic for biochemical recurrence [BCR; P ¼ 0.004; HR, 2.37; 95% confidence interval (CI), 1.32-4.25]. In the test cohort (n ¼ 611), moderate to high PD-L1 expression was detected in 61.7% and remained prognostic for BCR in univariate Cox analysis (P ¼ 0.011; HR, 1.49; 95% CI, 1.10-2.02). The correlation of Ki-67 and AR with PD-L1 expression was confirmed in the test cohort (P < 0.001).In multivariate Cox analysis of all patients, PD-L1 was corroborated as independently prognostic for BCR (P ¼ 0.007; HR, 1.46; 95% CI, 1.11-1.92).Conclusions: We provide first evidence that expression of the therapy target PD-L1 is not only highly prevalent in primary prostate cancer cells but is also an independent indicator of BCR, suggesting a biologic relevance in primary tumors. Further studies need to ascertain if PD-1/PD-L1-targeted therapy might be a treatment option for hormone-na€ ve prostate cancers.

Clinical classification of AK lesions using the system of Olsen does not accurately match histological classification of the same lesions using the system of Roewert-Huber. Consequently, it is not possible to draw conclusions about the histology of AK lesions from their clinical appearance. This finding reinforces the need to treat all AK lesions as well as field cancerization.

BACKGROUND. Most gangliogliomas (GGs) are benign tumors, but tumor recurrence and malignant progression are observed in some patients. METHODS. The authors analyzed their experience with 4 recurrent/progressive GGs (World Health Organization [WHO] grade I), 21 tumors with atypical features (WHO grade II), and 5 tumors with anaplastic histologic features (WHO grade III). Histopathologic findings (23 patients) were reviewed. The mean follow‐up was 5.9 years (median, 4.5 years; range, 0.5‐14.7 years). RESULTS. The 5‐year survival rates were only 79% for patients who had tumors with atypical features and 53% for patients who had WHO grade III tumors. Secondary glioblastomas were diagnosed in 5 of 11 patients (45%) who underwent surgery for tumor recurrence. Age at surgery <40 years (P = .007) was associated significantly with better overall survival (OS), but it was not associated with better progression‐free survival (PFS). Clinical presentation (drug‐resistant epilepsy vs all other patients with seizures vs no seizures) was associated significantly with better OS (P = .005) and PFS (P < .001). Patients who had extratemporal tumors had a significantly shorter PFS (P = .01) but not OS. A complete resection was correlated strongly with both OS (P = .002) and PFS (P = .001). Neuropathologic examination revealed the presence of a gemistocytic cell component (PFS, P = .025), a lack of protein droplets (OS, P = .04; PFS, P = .05), and focal tumor cell‐associated CD34 immunolabeling (OS, P = .03) as significant predictors of an adverse clinical course. CONCLUSIONS. The current data supported a 3‐tiered GG histopathologic grading system that included an intermediate diagnostic category (atypical GG, WHO grade II). Careful attention to histopathologic findings and clinical parameters usually will identify patients who are at risk for an adverse clinical course. Cancer 2008. © 2008 American Cancer Society.

Objective: We compared use of intravenous (IV) normal saline (NS) to sodium bicarbonate (NaHCO3) with or without oral N‐acetylcysteine (NAC) for prevention of contrast‐induced acute kidney injury (CI‐AKI). Background: CI‐AKI is associated with significant adverse clinical events. Use of NAC has produced variable results. Recently, intravenous hydration with NaHCO3 for CI‐AKI prophylaxis has been adopted as standard treatment for patients with stable chronic renal disease undergoing catheterization procedures. Methods: We prospectively enrolled 320 patients with baseline renal insufficiency scheduled to undergo catheterization. Patients were randomly assigned to receive either IV NS ± NAC (n = 161) or IV dextrose 5% in water containing 154 mEq/l of NaHCO3 ± NAC (n = 159). IV NS was administered at 1 ml/kg body weight for 12 hr preprocedure and 12 more hr postprocedure. IV NaHCO3 was administered at 3 ml/kg body weight for 1 hr preprocedure followed by 1 ml/kg body weight postprocedure. A 1,200 mg oral dose of NAC was given 2–12 hr preprocedure and 6–12 hr postprocedure in 50% of patients in each study arm. CI‐AKI was defined as an increase of >0.5 mg/dl or >25% above baseline creatinine. Results: Overall incidence of CI‐AKI was 10.3%. There was no significant difference in incidence among the two groups (NS ± NAC 11.8% vs. NaHCO3 ± NAC 8.8%, p = ns). Incidence of CI‐AKI increased with increasing age (p = 0.001), contrast agent use >3 ml/kg body weight (p = 0.038) and diuretic use (p = 0.005). Conclusion: Incidence of CI‐AKI was no different in the NaHCO3 group compared to NS group, and NAC did not reduce CI‐AKI in the two study arms. © 2011 Wiley Periodicals, Inc.

Glioneuronal malformations (malformations of cortical development [MCD]) include focal cortical dysplasias (FCD) as well as highly differentiated glioneuronal tumors (i.e. gangliogliomas) and constitute frequent findings in patients with pharmacoresistent focal epilepsies. Tailored resection strategies evolved as promising treatment options and allow a systematic neuropathologic and molecular biologic examination of the epileptogenic area in these patients. The histopathologic appearance and immunophenotype of glioneuronal lesions are, however, characterized by numerous similarities and suggest impaired proliferation, migration, and differentiation of neural precursor cells to play a pathogenetic role. Recent studies point toward molecular alterations within a variety of genes and pathways involved in development of the central nervous system, neuronal growth, and maturation. Compromised signaling within insulin- or reelin-transduction cascades are common findings and were associated with specific MCD entities. Unraveling pathogenic mechanisms may advance refined classification systems for epilepsy-associated malformations and open new avenues for the development of targeted treatment strategies in pharmacoresistent focal epilepsies associated with cortical malformations.

No abstract

Balloon cells of distinct focal cortical dysplasias type IIb (FCD(IIb)) and giant cells of cortical tubers in tuberous sclerosis (TSC) constitute neuropathological hallmarks and cytological similarities. In TSC, frequent mutations in the TSC1 or TSC2 genes result in mTOR-signaling activity. Here, we addressed whether Pi3K-pathway activation differentiates balloon cells from giant cells. We used immunohistochemistry with antibodies against p-PDK1 (S241), p-Akt (S473), p-tuberin (T1462), p-p70(S6K) (T389), p-p70(S6K) (T229) and phalloidin-staining to analyze stress fiber formation in balloon cells of FCD(IIb) (n = 23) compared with cortical tuber giant cells (n = 5) and adjacent normal CNS tissue as control. We have further established an in vitro assay to assess potential phosphorylation between Akt and S6. We observed phosphorylated (p-)PDK1, p-Akt, p-tuberin, and p-p70-kDa S6-kinase (p-p70(S6K); residue T229) in balloon cells, whereas giant cells showed only equivalent levels of p-tuberin, p-p70(S6K) and stress fibers. Furthermore, Pi3K-cascade activity in balloon cells may reflect pathway "cross-talk". An in vitro assay revealed S6, a major target of p70(S6K), to increase phosphorylation of Akt. Our data suggest recruitment of different Pi3K-cascade factors in the molecular pathogenesis of giant cells in cortical tubers vs. balloon cells in FCD(IIb) and provides new implications for the development of treatment strategies for these cortical malformations.

Currently, few prognostic factors are available to predict the emergence of castration-resistant prostate cancer and no curative options are available. Epigenetic gene regulation has been shown to trigger prostate cancer metastasis and androgen independence. Histone lysine demethylases (KDMs) are epigenetic enzymes that can remove both repressive and activating histone marks. KDM5 family members are capable of removing the histone H3 lysine 4 dimethylation-activating mark, rendering them potential players in the down-regulation of tumor suppressors and suggesting that their activity could repress oncogenes. Here, we systematically investigated KDM5C expression patterns in two independent radical prostatectomy cohorts (822 prostate tumors in total) by immunohistochemistry. Positive nuclear KDM5C staining was significantly associated with a reduced prostate-specific antigen relapse-free survival. Our study confirmed that nuclear KDM5C expression is an independent prognostic parameter. Most strikingly, the prognostic value of nuclear KDM5C expression for progression-free survival was exclusively pronounced for the Gleason group 7. In addition, KDM5C knockdown resulted in growth retardation of prostate cancer cells in vitro and induced regulation of several proliferation-associated genes. Our data indicate that KDM5C is functionally involved in proliferation control of prostate cancer cells and might represent a novel attractive therapy target. Moreover, overexpression of KDM5C is an independent new predictive marker for therapy failure as determined by biochemical recurrence in patients after prostatectomy.