LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial

Background Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary. Methods In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety. Results A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B. Conclusions AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P

Identification of Estrogen Receptor Dimer Selective Ligands Reveals Growth-Inhibitory Effects on Cells That Co-Express ERα and ERβ

Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ERα and ERβ, which elicit opposing roles in regulating proliferation: ERα is proliferative while ERβ is anti-proliferative. Exogenous expression of ERβ in ERα-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ERβ might oppose ERα's proliferative effects via formation of ERα/β heterodimers. Despite biochemical and cellular evidence of ERα/β heterodimer formation in cells co-expressing both receptors, the biological roles of the ERα/β heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ERα/β heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ERα/β heterodimer-selective ligands at defined concentrations, we demonstrate that ERα/β heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ERα and ERβ in human breast tissue microarrays, we demonstrate that ERα and ERβ are co-expressed in the same cells in breast tumors. The co-expression of ERα and ERβ in the same cells supports the possibility of ERα/β heterodimer formation at physio- and pathological conditions, further suggesting that targeting ERα/β heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ERα and ERβ

Nomogram for predicting survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy

BACKGROUND: The current study was conducted to develop a pretreatment prognostic model for patients with unresectable and/or metastatic urothelial cancer who were treated with first-line, cisplatin-based chemotherapy. METHODS: Individual data were pooled from 399 patients who were enrolled on 8 phase 2 and 3 trials evaluating cisplatin-based, first-line chemotherapy in patients with metastatic urothelial carcinoma. Variables selected for inclusion in the model were combined in a Cox proportional hazards model to produce a points-based nomogram with which to predict the median, 1-year, 2-year, and 5-year survival. The nomogram was validated externally using data from a randomized trial of the combination of methotrexate, vinblastine, doxorubicin plus cisplatin versus docetaxel plus cisplatin. RESULTS: The median survival of the development cohort was 13.8 months (95% confidence interval, 12.1 months-16.0 months); 68.2% of the patients had died at the time of last follow-up. On multivariable analysis, the number of visceral metastatic sites, Eastern Cooperative Oncology Group performance status, and leukocyte count were each found to be associated with overall survival (P<.05), whereas the site of the primary tumor and the presence of lymph node metastases were not. All 5 variables were included in the nomogram. When subjected to internal validation, the nomogram achieved a bootstrap-corrected concordance index of 0.626. When applied to the external validation cohort, the nomogram achieved a concordance index of 0.634. Calibration plots suggested that the nomogram was well calibrated for all predictions. CONCLUSIONS: Based on routinely measured pretreatment variables, a nomogram was constructed that predicts survival in patients with unresectable and/or metastatic urothelial cancer who are treated with cisplatin-based chemotherapy. This model may be useful in patient counseling and clinical trial design. Cancer 2013; 119: 3012-9. (C) 2013 American Cancer Society

Prävalenz der high-risk HP-Viren 16 und 18 in Plattenepithelkarzinomen des Larynx und deren Bedeutung als prognostischer Marker des Gesamtüberlebens: eine retrospektive Analyse

Einleitung: In den vergangenen Jahren konnte gezeigt werden, dass die Infektion mit dem humanen Papillomavirus einen unabhängigen Risikofaktor für die Entwicklung eines Oropharynx-Karzinoms darstellt. Für den Larynx ist die HPV-Prävalenz weit weniger gut untersucht. Wir untersuchten die Prävalenz der High risk-Typen HPV-16 und -18 in 118 Tumorgewebeproben des Larynx unserer klinikeigenen Gewebebank.Methoden: Insgesamt wurden 118 Gewebeproben mit gesichertem Plattenepithelkarzinom des Larynx untersucht. Der HPV-Nachweis erfolgte zunächst mittels einer Screening PCR. Die hier positiven Proben wurden in einer nachfolgenden zweiten PCR auf die high risk-Typen HPV 16 und HPV 18 untersucht. Desweiteren wurde immunhistochemisch die Expression von p16 untersucht. Das Gesamtüberleben wurde mittels unserer Tumordatenbank "AdOnco" und Abfragen bei den Standesämtern ermittelt.Ergebnisse: In den Gewebeproben des Larynx konnte in 20 Proben (17,0%) HPV-16 mittels PCR nachgewiesen werden. In der p16-Färbung erhielten wir 30 positive Ergebnisse (26,1%). Der Nachweis von HPV-18 konnte in keiner der untersuchten Gewebeproben erbracht werden. HPV positive Patienten wiesen ein im Schnitt ein um 30,1 Monate verlängertes Gesamtüberleben auf.Schlussfolgerungen: Unsere Untersuchungen weisen darauf hin, dass der high-risk Typ HPV-16 auch in der Carcinogenese von Larynxkarzinomen eine Rolle spielen könnte. Weiterhin sollte an größeren Kollektiven überprüft werden, ob sich das gezeigte verbesserte Gesamtüberleben reproduzieren lässt.Der Erstautor gibt keinen Interessenkonflikt an

Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice

The carboxypeptidase ACE2 is a homologue of angiotensin-converting enzyme (ACE). To clarify the physiological roles of ACE2, we generated mice with targeted disruption of the Ace2 gene. ACE2-deficient mice were viable, fertile, and lacked any gross structural abnormalities. We found normal cardiac dimensions and function in ACE2-deficient animals with mixed or inbred genetic backgrounds. On the C57BL/6 background, ACE2 deficiency was associated with a modest increase in blood pressure, whereas the absence of ACE2 had no effect on baseline blood pressures in 129/SvEv mice. After acute Ang II infusion, plasma concentrations of Ang II increased almost 3-fold higher in ACE2-deficient mice than in controls. In a model of Ang II–dependent hypertension, blood pressures were substantially higher in the ACE2-deficient mice than in WT. Severe hypertension in ACE2-deficient mice was associated with exaggerated accumulation of Ang II in the kidney, as determined by MALDI-TOF mass spectrometry. Although the absence of functional ACE2 causes enhanced susceptibility to Ang II–induced hypertension, we found no evidence for a role of ACE2 in the regulation of cardiac structure or function. Our data suggest that ACE2 is a functional component of the renin-angiotensin system, metabolizing Ang II and thereby contributing to regulation of blood pressure