No abstract

Context. In men with prostate cancer (PCa) treated with curative intent, controversy exists regarding the impact of biochemical recurrence (BCR) on oncological patient outcomes. Objective. To perform a systematic review of the existing literature on BCR after treatment with curative intent for non-metastatic PCa. Objective 1 is to investigate whether oncological outcomes differ between patients with or without BCR. Objective 2 is to study which clinical factors and tumor features in patients with BCR have an independent prognostic impact on oncological outcomes. Evidence acquisition. Medline, Medline In-Process, Embase, and the Cochrane Central Register of Controlled Trials were searched. For objective 1, prospective and retrospective studies comparing survival outcomes of patients with or without BCR following radical prostatectomy (RP) or radical radiotherapy (RT) were included. For objective 2, all studies with at least 100 participants and reporting on prognostic features in patients with BCR were included. Risk-of-bias and confounding assessments were performed according to the Quality in Prognosis Studies (QUIPS) tool. Both a narrative synthesis and meta-analysis were undertaken. Evidence synthesis. Overall, 77 studies were included for analysis, of which 14 studies addressed objective 1, recruiting 20406 patients. Objective 2 was addressed by 71 studies with 29057, 11301 and 4272 patients undergoing RP, RT or a mixed population (mix of patients undergoing RP or RT as primary treatment) respectively. There was low risk of bias for study participation, confounders and statistical analysis. For most studies, attrition bias, prognostic and outcome measurements were not clearly reported. BCR was associated with worse survival rates, mainly in patients with a short PSA Doubling Time (PSA-DT) and high final Gleason score after RP or a short Interval to Biochemical Failure (IBF) after RT and high biopsy Gleason score. Conclusion. BCR has an impact on survival, but this effect appears to be limited to a subgroup of patients with specific clinical risk factors. A short PSA-DT and high final Gleason score after RP and a short IBF after RT and high biopsy Gleason score are the main factors which have a negative impact on survival. Patient summary. This review looks at the risk of dying in men who have a rising PSA blood test after curative surgery or radiotherapy. For many men a rising PSA does not mean they are at a higher risk of dying from prostate cancer in the longer term. Men with a PSA that rises shortly after they were treated with radiotherapy or a rapidly rising PSA after surgery and a high tumor-grade for both treatment modalities are at the highest risk of dying.

A mouse monoclonal antibody against the N-terminal region of human androgen receptor (AR) was used to identify receptors by immunoperoxidase staining in frozen serial sections of skin from scalp, face, limb and genitalia of men and women aged 30-80 years. AR staining was restricted to cell nuclei. In sebaceous glands, AR were identified in basal and differentiating sebocytes. The percentage of receptor-positive basal sebocyte nuclei in the temple/forehead region was greater in males (65%) than in females (29%). AR staining was restricted to the cells of dermal papillae in anagen and telogen hair follicles. The percentage of dermal papillae containing AR was greater in males (58%) than in females (20%). The number of positively stained dermal papillae was lowest in female scalp skin. In 163 hair follicles sectioned, AR were absent from germinative matrix, outer root sheath (including the bulge region), inner root sheath, hair shaft and hair bulb, and from the capillaries present in some large dermal papillae. AR were present in pilosebaceous duct keratinocytes, suggesting that androgens may influence pilosebaceous duct keratinization. AR were also identified in interfollicular epidermal keratinocytes and dermal fibroblasts although, in both cell types, intensity and frequency of staining were greatest in genital skin. AR were identified in luminal epithelial cells of apocrine glands in genital skin and in certain cells of the secretory coils of eccrine sweat glands in all body sites. This study indicates that androgens regulate sebaceous gland and hair growth by acting upon two different types of target cells, the epithelial sebocytes of sebaceous glands and the mesenchymal cells of the hair follicle dermal papilla.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

We describe the reconstruction of bladder tumor development in individual patients spanning periods of up to 17 years. Genomic alterations detected in the tumors were used for hierarchical cluster analysis of tumor subclones. The cluster analysis highlights the clonal relationship between tumors from each patient. Based on the cluster data we were able to reconstruct the evolution of tumors in a genetic tree, where tumors with few aberrations precede those with many genetic insults. The sequential order of the tumors in these pedigrees differs from the chronological order in which the tumors appear. Thus, a tumor with few alterations can be occult for years following removal of a more deranged derivative. Extensive genetic damage is seen to accumulate during the evolution of the tumors. To explain the type and extent of genetic damage in combination with the low stage and grade of these tumors, we hypothesize that in bladder cancer pathogenesis an increased rate of mitotic recombination is acquired early in the tumorigenic process.

BACKGROUND To study the metastatic behavior of human prostate cancer cell lines, orthotopic injection in nude mice was performed. METHODS Local tumor growth, metastasis formation, prostate‐specific antigen, and androgen receptor expression were examined. RESULTS Hormone‐independent cell lines (PC‐3, PC‐3‐125‐1L, and TSU‐Pr1) were highly tumorigenic and had a higher rate of lymph node metastasis after orthotopic than after subcutaneous implantation. PC‐3 cell lines also consistently metastasized to the lungs. The androgen‐sensitive LNCaP cell line showed local growth in 7 of 10, and lymph node metastasis in 4 animals. Significant serum PSA levels and strong receptor expression in primary and metastatic tumor tissues were observed. CONCLUSIONS These results demonstrates that orthotopic implantation of human prostate cancer cell lines, including LNCaP, reproducibly leads to metastasis formation in nude mice. Prostate 31:168–174, 1997. © 1997 Wiley‐Liss, Inc.

Androgen insensitivity syndrome encompasses a wide range of phenotypes, which are caused by numerous different mutations in the AR gene. Detailed information on the genotype/phenotype relationship in androgen insensitivity syndrome is important for sex assignment, treatment of androgen insensitivity syndrome patients, genetic counseling of their families, and insight into the functional domains of the AR. The commonly accepted concept of dependence on fetal androgens of the development of Wolffian ducts was studied in complete androgen insensitivity syndrome (CAIS) patients. In a nationwide survey in The Netherlands, all cases (n = 49) with the presumptive diagnosis androgen insensitivity syndrome known to pediatric endocrinologists and clinical geneticists were studied. After studying the clinical phenotype, mutation analysis and functional analysis of mutant receptors were performed using genital skin fibroblasts and in vitro expression studies. Here we report the findings in families with multiple affected cases. Fifty-nine percent of androgen insensitivity syndrome patients had other affected relatives. A total of 17 families were studied, seven families with CAIS (18 patients), nine families with partial androgen insensitivity (24 patients), and one family with female prepubertal phenotypes (two patients). No phenotypic variation was observed in families with CAIS. However, phenotypic variation was observed in one-third of families with partial androgen insensitivity resulting in different sex of rearing and differences in requirement of reconstructive surgery. Intrafamilial phenotypic variation was observed for mutations R846H, M771I, and deletion of amino acid N682. Four newly identified mutations were found. Follow-up in families with different AR gene mutations provided information on residual androgen action in vivo and the development of the prepubertal and adult phenotype. Patients with a functional complete defective AR had some pubic hair, Tanner stage P2, and vestigial Wolffian duct derivatives despite absence of AR expression. Vaginal length was functional in most but not all CAIS patients. The minimal incidence of androgen insensitivity syndrome in The Netherlands, based on patients with molecular proof of the diagnosis is 1:99,000. Phenotypic variation was absent in families with CAIS, but distinct phenotypic variation was observed relatively frequent in families with partial androgen insensitivity. Molecular observations suggest that phenotypic variation had different etiologies among these families. Sex assignment of patients with partial androgen insensitivity cannot be based on a specific identified AR gene mutation because distinct phenotypic variation in partial androgen insensitivity families is relatively frequent. In genetic counseling of partial androgen insensitivity families, this frequent occurrence of variable expression resulting in differences in sex of rearing and/or requirement of reconstructive surgery is important information. During puberty or normal dose androgen therapy, n...

We describe the immunohistochemical detection of the human androgen receptor (AR) in routinely p d , pataffinembedded tissue with the monoclonal antibody (MAb) F39.4. Deparaffrnized d o n s were heated in a microWave oven for antigen retrieval. A panel of human male-and female-derived tissues was investigated. We observed a nuclear staining pattern consistent with previous results on frozen sections. Moreover, we studied the possibility of detecting AR in prolonged formalin-fmed tissue and in paraffin-embedded archival m a t e d . After prolonged fmhtroduction Androgens play an important role in the development and function of the male reproductive system. They mediate their function by binding to the intracellular androgen receptor (AR). Studies on AR distribution in human reproductive and non-reproductive tissues may provide essential information about its role in disease processes that arise in tissues which express the AR.Over the past years, AR distribution in human tissues has been the subject of many immunohistochemical studies (2,4,7,10,13,17). Both polyclonal and monoclonal antibodies (MAb) directed against human AR have been used to visualize the receptor at the cellular level. U e d a et al. (17) studied the immunohistochemical localization of the AR in frozen sections of different tissues, using both MAb and polyclonal antibodies. Ruizeveld de Winter et al. (13) used MAb F39.4 to study AR expression in frozen sections of different human tissues. Kimura et al. (7) investigated the immunohistochemical localization of the AR in paraformaldehyde-fixed, paraffin-embedded human tissues with a polyclonal antibody. In the latter study, decreased or absent immunoreactivity was found (12) studied the immunohistochemical identification of the AR in germ cell neoplasia using MAb ANI-15 and F39.4 on frozen and formalin-fixed tissue. Both antibodies showed a positive reaction on frozen sections. However, on paraffii sections, MAb F39.4 showed no reaction and MAb ANI-15 showed strong nuclear immunoreactivity of all testicular nuclei including lymphocytes, suggesting the possibility of a nonspecific reaction. Recently, Nakada et al. (11) were able to detect the AR in neuroendocrine cells in Amexprocessed (14) but not in formalin-fixed, paraffin-embedded human prostate tissue with MAb AN1-15.Until recently, to our knowledge, it has been impossible to detect the human AR in routinely formalin-fixed, paraffin-embedded tissue with an MAb. This is of great advantage because of the highly consistent specificity of MAb in combination with the optimal morphology achieved in paraffii sections and the possibility of reuospective studies. The present study describes the detection of human AR with MAb F39.4 in routinely formalin-fued, paraffin-embedded tissue, after a simple antigen retrieval treatment (16). A panel of human male-and female-derived tissues was investigated for the presence and distribution of the AR. The results were compared 1169