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To eliminate complicated procedures for taking blood samples in the field work for prostatic mass screening, we developed a method for PSA testing using blood samples taken from the ear lobe and dried on a filter paper. The stability, the diagnostic efficacy, and the cost-benefit effect of the method were confirmed in hospitalized patients, as well as in subjects from our mass screening program.

Background Direct mechanical characterization of tissue is the application of engineering techniques to biological tissue to ascertain stiffness or elasticity, which can change in response to disease states. A number of papers have been published on the application of these techniques to prostate tissue with a range of results reported. There is a marked variability in the results depending on testing techniques and disease state of the prostate tissue. We aimed to clarify the utility of direct mechanical characterization of prostate tissue in identifying disease states. Methods A systematic review of the published literature regarding direct mechanical characterization of prostate tissue was undertaking according to PRISMA guidelines. Results A variety of testing methods have been used, including compression, indentation, and tensile testing, as well as some indirect testing techniques, such as shear-wave elastography. There is strong evidence of significant stiffness differences between cancerous and non-cancerous prostate tissue, as well as correlations with prostate cancer stage. There is a correlation with increasing prostate stiffness and increasing lower urinary tract symptoms in patients with benign prostate hyperplasia. There is a wide variation in the testing methods and protocols used in the literature making direct comparison between papers difficult. Most studies utilise ex-vivo or cadaveric tissue, while none incorporate in vivo testing. Conclusion Direct mechanical assessment of prostate tissue permits a better understanding of the pathological and physiological changes that are occurring within the tissue. Further work is needed to include prospective and in vivo data to aid medical device design and investigate non-surgical methods of managing prostate disease.

Prostasomes are submicron-sized, membrane-bound organelles produced by the epithelial cells of the prostate and normally found in the secretion in the gland ducts. Their physiological role is in the promotion of sperm-function in human reproduction. This thesis contains four papers dealing with the production of prostasomes and some possible applications in clinical urology of the prostasome. Paper I and II provided an ultrastructural description of the synthesis, storage and secretion of prostasomes in benign as well as in malignant tissue. Most notable were the extracellular appearances of prostasomes in metastatic lesions whereby the prostasomes become exposed to the immune system of the patient. This supported findings in earlier studies in which patients with advanced prostate cancer had elevated levels of anti-prostasome antibodies. The results of paper III reinforced the view of the prostate-unique origin of the prostasome. In particular, there were no indications in SDS-PAGE patterns or flow-cytometric studies of material from seminal vesicle secretion that it contained components that could be associated with a production of prostasomes. Some possible clinical functions of the prostasomes were investigated in paper IV. Exposure of prostasomes to the immune system through mechanical and thermal trauma to the prostate did not induce an evident formation of anti-prostasome autoantibodies. Furthermore, the serum levels of anti-prostasome antibodies registered by assays with preparations of prostasomes from seminal plasma as antigen did not correlate with existing prostate cancer. Seminal prostasomes seemed not to function as substitute markers for prostate cancer in the test kit used. A possible explanation could be underestimated differences in antigen properties between seminal or prostate gland-derived prostasomes and prostasomes from tumor tissue.

BACKGROUND The incidence and mortality of prostate cancer are increasing at alarming rates, partially due to an aging population. Early detection of prostate cancer, using clinically sensitive procedures and/or tumor markers (e.g., prostate-specific antigen [PSA]), is of prime importance. However, the choice of therapeutic interventions for prostate cancer at the time of diagnosis is largely dependent on clinical and pathologic staging and prediction of the degree of aggressiveness of the disease. Clinically applicable prognostic markers are urgently needed to assist in the selection of optimal therapy. METHODS Literature review of the potential diagnostic and prognostic markers for human prostate cancer. RESULTS Well-established tissue prognostic indicators, including histologic grade, margin positivity, pathologic stage, intraglandular tumor extent, and DNA ploidy, are not reviewed in this paper. Recently, a number of novel markers have been identified. In this paper, we begin with a discussion of a number of well-established as well as investigational diagnostic markers and then focus on evaluation of prognostic markers. Diagnostic markers that have prognostic value and investigational prognostic markers are also discussed. CONCLUSIONS Currently, only PSA is utilized for early diagnosis and monitoring of prostate cancer. A number of potential prognostic markers warrant further investigation. Multimarker analysis is implicated. Prostate 31:264–281, 1997.© 1997 Wiley-Liss, Inc.

Objective To perform a systematic review of the literature concerning postoperative peripheral neuropathies associated with patient positioning during robot-assisted laparoscopic radical prostatectomy (RARP). Patients and methods A systematic review on articles published from January 1, 1990 to March 15, 2020 was performed in accordance with the PRISMA declaration (Preferred Reporting Items for Systematic Reviews and Meta-Analysis). The electronic search was done searching through the Cochrane Registry, PubMed/EMBASE, Medline, and Scopus. Relevant papers addressing postoperative peripheral neuropathies related to patient positioning during RARP were integrated into the analyses. Results After screening 4975 articles, one randomized controlled trial and five retrospective studies with a total of 63,667 patients were included in this review. Peripheral neuropathies of the upper extremities were documented in three articles with a total of 15 patients, peripheric neuropathies of the lower extremities were reported in five articles with a total of 76 patients. Analysis of the data was exploratory, since screening techniques, systematically reporting, and description of positioning techniques was not standardized or not reported. Conclusions The incidence of peripheral neuropathies at RARP varies between 1.3% and 10.8%. Lower extremities are more affected than upper extremities and the most important risk factors are intraoperative time duration, patients comorbidities, and ASA score. High-quality prospective randomized studies to better assess the impact of patient positioning during RARP on the development postoperative peripheral neuropathies are needed.

Dietary factors may affect development and progression of prostate cancer. Experimental and epidemiological studies have suggested an effect of phytoestrogens on prostate cancer. Lignans are the predominant phytoestrogen in a Western diet. The effects of a diet rich in phytoestrogens and in particular lignans, as compared to a control diet, were assessed in several prostate cancer models. In paper I, 70 athymic nude mice with transplanted subcutaneous LNCaP tumours, an androgen sensitive human prostate cancer cell line, were fed one out of six phytoestrogen rich diets or a control diet after tumour injection. The rye diet, with high lignan content, decreased tumour take and growth, decreased secretion of prostate specific antigen and increased apoptosis. Addition of fat to the rye diet decreased the beneficial effects. In paper II, transgenic mice designed to develop prostate cancer (TRAMP) were fed rye bran or a control diet from the age of four weeks. Rye bran decreased prostate epithelial cell volume by 20%, and increased cell apoptosis by 31% as compared to the control diet. In paper III, we examined the effects of 7-hydroxymatairesinol (HMR), a purified lignan, in nude mice with subcutaneous LNCaP tumours in two different concentrations as compared to a control diet. Mice on the HMR diets had a reduced tumour take rate, lower total tumour volume, increased proportion of non-growing tumours, and increased apoptosis as compared to the control diet. Paper IV was a three week intervention study exploring the effects of rye bran bread vs. a control diet in men with prostate cancer. The men in the rye group had increased levels of plasma enterolactone and in biopsies from the prostate after the intervention an increase in apoptosis was observed in comparison with biopsies obtained before the intervention. In paper V, we examined the association between plasma levels of enterolactone, and risk of prostate cancer in a nested case control study. In the Northern Sweden Health and Disease Cohort, enterolactone concentrations were measured in plasma obtained at a mean time of 5 years before diagnosis from 265 cases of prostate cancer, and from 525 matched controls. We found no significant association between plasma enterolactone and risk of prostate cancer. Men with very low enterolactone levels (bottom decile) however, had significantly higher risk of prostate cancer. Phytoestrogen rich diet including soy, rye bran, substances purified from rye, and a purified lignan (HMR) all inhibited prostate tumour growth. However, it cannot be concluded that the effects observed were due solely to lignans as other components in rye grain such as tannins, phytic acid, ferulic acid, vitamins and minerals may have contributed to the beneficial effects. Thus, additional studies are needed to further elucidate the effects of phytoestrogens on prostate cancer development and progression.

The incidence and mortality of prostate cancer are increasing at alarming rates, partially due to an aging population. Early detection of prostate cancer, using clinically sensitive procedures and/or tumor markers (e.g., prostate-specific antigen [PSA]), is of prime importance. However, the choice of therapeutic interventions for prostate cancer at the time of diagnosis is largely dependent on clinical and pathologic staging and prediction of the degree of aggressiveness of the disease. Clinically applicable prognostic markers are urgently needed to assist in the selection of optimal therapy.Literature review of the potential diagnostic and prognostic markers for human prostate cancer.Well-established tissue prognostic indicators, including histologic grade, margin positivity, pathologic stage, intraglandular tumor extent, and DNA ploidy, are not reviewed in this paper. Recently, a number of novel markers have been identified. In this paper, we begin with a discussion of a number of well-established as well as investigational diagnostic markers and then focus on evaluation of prognostic markers. Diagnostic markers that have prognostic value and investigational prognostic markers are also discussed.Currently, only PSA is utilized for early diagnosis and monitoring of prostate cancer. A number of potential prognostic markers warrant further investigation. Multimarker analysis is implicated.

This paper contains the first part of an attempt to quantitate the impact on prognosis of various parameters used in grading of prostatic cancer. Out of 346 patients of Elmer Belts series, 113 were identified whose tumors showed homogeneity with respect to single characteristics of a total of 12 parameters applied for grading in Mostofi's system. By this procedure it was possible to eliminate the possible influence on prognosis of the presence of several tumor formations within the same tumor. By using overall and intercurrent death corrected survival as end points, the impact of each of the 12 parameters on prognosis was studied. Only the architecture of the tumor (the parameter “glands”), variation in size and shape of the nucleus (anaplasia), and grade significantly influenced overall survival. In addition, corrected survival was significantly dependent on the amount of tumor seen and on the presence of mitoses. Subsequently, an attempt was made to replace “grade” by single parameters which had been shown previously to be of prognostic significance. It turned out that this was not possible. Grade is largely dependent on architecture and nuclear pleomorphism, but neither one of these parameters alone can reproduce “grade.” Multivariate analysis was next used to further determine the prognostic weight of the individual parameter, and, if possible, to construct a new, more efficient grading system. These results will be reported separately [8]. It is unknown at the present time what the impact of several architectural formations within the same tumor on prognosis may be. The number of different formations found ranges from 1 to 4 in this material; 668 different formations belonging to 346 tumors were graded. The results of this analysis will be reported in part two of this series of papers [7].

BACKGROUND Irreversible electroporation (IRE) is (virtually) always called non-thermal despite many reports showing that significant Joule heating occurs. Our first aim is to validate with mathematical simulations that IRE as currently practiced has a non-negligible thermal response. Our second aim is to present a method that allows simple temperature estimation to aid IRE treatment planning. METHODS We derived an approximate analytical solution of the bio-heat equation for multiple 2-needle IRE pulses in an electrically conducting medium, with and without a blood vessel, and incorporated published observations that an electric pulse increases the medium's electric conductance. RESULTS IRE simulation in prostate-resembling tissue shows thermal lesions with 67–92°C temperatures, which match the positions of the coagulative necrotic lesions seen in an experimental study. Simulation of IRE around a blood vessel when blood flow removes the heated blood between pulses confirms clinical observations that the perivascular tissue is thermally injured without affecting vascular patency. CONCLUSIONS The demonstration that significant Joule heating surrounds current multiple-pulsed IRE practice may contribute to future in-depth discussions on this thermal issue. This is an important subject because it has long been under-exposed in literature. Its awareness pleads for preventing IRE from calling “non-thermal” in future publications, in order to provide IRE-users with the most accurate information possible. The prospect of thermal treatment planning as outlined in this paper likely aids to the important further successful dissemination of IRE in interventional medicine. Prostate 75:332–335, 2015. © 2014 The Authors. The Prostate Published by Wiley Periodicals, Inc.

In this paper we would like to present probably the first surgery performed on the prostate gland followed by microscopic analysis of the obtained tumor tissue sample. We based on the existing correspondence between Ludwig von Hammen and Johann N. Pechlin, and their successors in this field as well. Von Hammen seems to be a pioneer in the area of not only urological surgery but in directing this part of medical practice from “lithotomists” to physicians, much better educated than barbers in physiology but first of all in anatomy. This 17th century physician from Gdansk tried to set new standards both for surgical medical practice but histopathological examination of the excised material as well. Due to the change of the operational skills and procedures von Hammen's work got almost forgotten, but remains remembered due to the work of historians of the medicine from following centuries. Prostate 74:1465–1470, 2014. © 2014 Wiley Periodicals, Inc.

Improving our ability to predict cancer progression and response to conservative or radical intent therapy is critical if we are to prevent under or over treatment of individual patients. Whereas the majority of solid tumors now have a range of molecular and/or immunological markers to help define prognosis and treatment options, prostate cancer still relies mainly on histological grading and clinical parameters. We have recently reported that androgen receptor (AR) expression in stroma inversely associates with prostate cancer-specific survival, and that stromal AR reduces metastasis. For this paper, we tested the hypothesis that the AR-regulated gene FKBP51 could be used as a marker of AR activity to better predict outcome.Using immunohistochemistry on a cohort of 64 patient-matched benign and malignant prostate tissues, we assessed patient outcome by FKBP51 and AR levels. Immunoblot and RT-qPCR were used to demonstrate androgen regulation of FKBP51 in primary and primary human prostatic fibroblasts and fibroblast cell-lines.As predicted by FKBP51 level, high AR activity in cancer stroma was associated with longer median survival (1,306 days) compared with high AR alone (699 days), whereas those with low AR and/or low FKBP51 did poorly (384 and 338 days, respectively). Survival could not be predicted on the basis cancer epithelial AR levels or activity, and was not associated with immunoreactivity in patient matched benign tissues.FKBP51 improves the ability of stromal AR to predict prostate cancer-specific mortality. By adding additional immunological assessment, similar to what is already in place in a number of other cancers, we could better serve patients with prostate cancer in prognosis and informed treatment choices. Prostate 77:185-195, 2017. © 2016 Wiley Periodicals, Inc.

BACKGROUND. Various research groups have attempted to grow fresh, histologically intact human prostate cancer tissues in immunodeficient mice. Unfortunately, grafting of such tissues to the sub-cutaneous compartment was found to be associated with low engraftment rates. Furthermore, xenografts could only be established using high-grade, advanced stage, but not low- or moderate-grade prostate cancer tissues. METHODS. This paper describes methods for xenografting both benign and malignant human prostate tissue to severe combined immunodeficient (SCID) mice. We examine the efficiency and histopathologic consequences of grafting to the sub-cutaneous, sub-renal capsule, and prostatic orthotopic sites. RESULTS. Sub-renal capsule grafting was most efficient in terms of take rate (>90%) for both benign and malignant tissue. Orthotopic grafts consistently exhibited the best histopathologic differentiation, although good differentiation with continued expression of androgen receptors (AR) and PSA was also seen in the sub-renal capsule site. Sub-cutaneous grafting resulted in low take rates and the lowest level of histodifferentiation in surviving grafts. Grafted benign tissues in all sites appropriately expressed AR, PSA, cytokeratins 8, 18, and 14 as well as p63; carcinoma tissues did not express the basal cell markers. Grafting of tissues to castrated hosts did not affect

Background The management of hormone-insensitive locally advanced prostate cancer is difficult and complex and there is an urgent need for the development of effective chemotherapeutic agents intended for combination with currently available treatment modalities. Methods The present paper demonstrates the effectiveness of the monoterpene perillyl alcohol (POH) as potent radiosensitizer on DU145 and PC3 cell lines by performing clonogenic survival assays, cycle analysis, and assays to detect viability, apoptosis, and Fas receptor/ligand by flow cytometry. Results POH pretreatment resulted in a dose dependent sensitization to kill cell by radiation. Furthermore, POH treatment induced a transient G2/M arrest, enhanced the expression of the membrane bound form of the Fas ligand and sensitized the cells to Fas mediated apoptosis. Conclusions The unique manner of radiosensitization in addition to its low toxicity profile makes POH a promising new agent for preclinical evaluation as a potential radiosensitizer in the treatment of prostate cancer. Prostate 57: 14–23, 2003. © 2003 Wiley-Liss, Inc.

BACKGROUND Prostate cancer and benign prostatic hyperplasia are important age-related prostatic diseases that are under the influence of testicular hormones. However, the disparity between male and female life expectancy within the human population cannot be explained solely by the prevalence of prostatic disease-related mortality. The purpose of this paper is to explore the possibility that the testis exerts a detrimental effect on life span. METHODS First, we review previously published and unpublished data on the influence of the testis on the life span of dogs and men. Aging in pet dogs and men is then discussed in terms of evolutionary theory, emphasizing the significance of a prolonged postreproductive life span and possible consequences of late-acting deleterious genes in these two species. Finally, we present preliminary data that orchiectomy can reduce DNA damage within the brain of elderly male dogs. RESULTS AND CONCLUSIONS Taken together, these observations raise the intriguing possibility that interventions to antagonize the testis might have much broader therapeutic applications that will extend well beyond the treatment of prostate cancer. Prostate 43:272–277, 2000. © 2000 Wiley-Liss, Inc.

Endocrine treatment of prostate cancer can be performed under several different regimes. They all have side effects which in different ways influence quality of life and the patient's general health. This paper is a survey of the most important early side effects of the different modes of endocrine treatment, their etiology, and possible ways to avoid or treat them.

BACKGROUND Three regions of chromosome 13 were previously identified for having loss of heterozygosity (LOH) in human prostate cancer. One of them, at 13q33, was defined by LOH at markers D13S158 and D13S280. The XPG/ERCC5 gene, a DNA repair gene that when mutated in the germline leads to xeroderma pigmentosum, has been mapped to 13q33, within one megabase of D13S158 and D13S280. This paper describes LOH and mutational analysis of the XPG gene in human prostate cancers, in order to determine whether the XPG gene is involved in the development of prostate cancer. METHODS LOH of the XPG gene was analyzed in 40 primary prostate cancers and 14 metastases by using the microsatellite assay, and its mutations were examined in 5 cell lines, 14 metastases, and 8 tumors with LOH at 13q33 by using the single-strand conformation polymorphism (SSCP)-direct DNA sequencing analysis. RESULTS Four of the 29 (14%) informative primary tumors and 4 of 8 (50%) metastases showed LOH for the XPG gene. Analysis of the 8 tumors with LOH at the 13q33 region, 14 metastases, and 5 cell lines of prostate cancer revealed two polymorphisms but no mutation of the gene. The polymorphism in exon 2 did not change the amino-acid sequence of the XPG protein, but the exon 15 polymorphism altered codon 1104 from histidine to aspartic acid. The two polymorphisms also occurred in individuals without prostate cancer. CONCLUSIONS LOH at XPG in prostate cancer supports the conclusion that the 13q33 region contains a gene important in the development of prostate cancer, while lack of mutations of the gene suggests that XPG is not the target gene involved. Prostate 41:190–195, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND While the traditional goal in the management of patients with prostate cancer has been to maximize survival, the recent advent of the medical outcomes movement has underscored the importance of patient-centered issues, such as health-related quality of life (HRQOL). METHODS In this paper we present a comprehensive approach to the study of HRQOL in men with prostate cancer. We begin by defining HRQOL in general, discussing its measurement, and placing it in the context of prostate cancer. We then describe the primary goals of HRQOL research and present examples of validated instruments. We finish by proposing a quality of life research agenda for the next two decades. RESULTS Contemporary perspectives on HRQOL are based on the World Health Organization's definition of health as not merely the absence of disease, but as a state of physical, emotional, and social well-being. HRQOL measurement must adhere to the strict methodological principles of survey psychometrics and is best accomplished with any of several validated instruments. Once collected, HRQOL information is useful for prostate cancer patients facing difficult treatment decisions. CONCLUSIONS A solid foundation for HRQOL research has been built in early- and late-stage prostate cancer. It includes the development of new instruments and the establishment of descriptive data. This groundwork will allow investigators to address more complex research issues, such as interpreting interactions among HRQOL domains, presenting HRQOL data to future patients, optimally timing HRQOL data collection, uncovering innate and alterable factors that influence HRQOL, and exploring the intercultural nuances of HRQOL assessment. Prostate 41:58–67, 1999. © 1999 Wiley-Liss, Inc.

BACKGROUND In this paper we describe our program for the immune monitoring of phase II participants given dendritic cell (DC)/prostate-specific membrane antigen (PSMA)-based immunotherapy, and we also present some initial findings. METHODS Phase II subjects received six administrations of autologous dendritic cells exogenously pulsed with two peptides derived from PSMA. Prior to the initial infusion, and following each treatment, peripheral blood mononuclear cells (PBMC) were collected for the generation of dendritic cells as well as for comprehensive immune monitoring. RESULTS Thus far, an increase in PSMA-peptide-specific as well as overall cellular reactivity has been observed in several patients receiving DC plus PSM-P1 and -P2, as measured by delayed-type hypersensitivity (DTH) test and enzyme-linked immunosorbant assay (ELISA). CONCLUSIONS Our initial observations using an ELISA and DTH test indicate that we are enhancing cellular immunity in prostate cancer patients following infusion with DC plus PSMA-derived peptides. Several methods are underway to comprehensively monitor both cell-mediated and humoral immune responsiveness, including: determining anti-PSMA serum antibody titers, testing immunogen-restricted responder-cell proliferation and cytotoxicity, assessing aberrations in signal transduction, antigen processing, and presentation, and measuring soluble factors that may promote tumor outgrowth. Prostate 35:144–151, 1998. © 1998 Wiley-Liss, Inc.

BACKGROUND α1-adrenoceptor antagonists (blockers) are now commonly used in the treatment of the symptoms of lower urinary tract obstruction. Originally phenoxybenzamine, a non-selective antagonist at both α1- and α2-adrenoceptors, was used by Marco Caine. In an attempt to minimize side effects, selective α1-antagonists, e.g. prazosin, were subsequently developed. More recently, agents such as alfuzosin, doxazosin, terazosin, and tamsulosin have been introduced and claims of “uroselectivity” and “prostate” selectivity have emerged. METHODS This review attempts to put these claims into perspective and represents a comprehensive analysis of all pre-clinical and clinical data including several papers from the Japanese literature. An attempt is made to define what is meant by selectivity at various levels including the test tube, in the laboratory animal and, most importantly, in the clinical context of the whole patient. CONCLUSIONS The conclusions are interpreted within the context of the subdivision of the α1-adrenoceptor into α1A, α1B and α1D subtypes. Prostate 30:202–215, 1997. © 1997 Wiley-Liss, Inc.

In a population-based case-referent study, carried out in The Netherlands, the relationship between socioeconomic status (SES) and urbanization grade on the one hand and prostate cancer incidence on the other has been investigated. Two explanations for a potential association have been taken into account. First, there is a relationship with SES class (or with urbanization grade) in the past, referring to an effect on the induction or promotion of prostate cancer caused by variation in exposure to particular risk factors. Second, there is a relationship with current SES (or urbanization grade), resulted in differences in medical screening. Study data were obtained by means of a validated mailed questionnaire, which has been completed and returned by 345 cases (with histologically confirmed prostate cancer) and 1,346 referents (patients with benign prostate hyperplasia). The response was 79%. No clear relationship was observed with SES, based on the major job held between 1960-1970 (the period of cancer induction), nor was this the case with SES based on the longest-held job (as a proxy for current SES). A slight, but statistically non-significant, trend was found of higher risks in subjects living in rural areas, with an urban/ rural ratio of 0.79. Considering the results of this study and those of previous studies reviewed in this paper, it might be doubted that any relationship is to be found between prostate cancer risk and SES or urbanization grade. © 1994 Wiley-Liss, Inc.

This paper describes a serum-free defined medium (Gc) that was initially designed to support growth of the human prostatic carcinoma cell line LNCaP. Our studies indicate that this medium formulation is capable of supporting short-term, long-term, and clonal growth of the LNCaP cell line. Component deletion experiments have shown that the three most critical components for LNCaP short-term growth are insulin, triiodothyronine (T3), and fetuin. Additionally, this medium was found to support short-term and clonal growth of three other human prostatic carcinoma cell lines, DU 145, PC-3, and ALVA-31. The availability of such a medium should aid in the distinction of the regulatory factors involved in growth and differentiation of malignant prostatic epithelium.

The association of estrogens with benign prostatic hyperplasia and prostatic cancer has been widely studied, but no conclusive evidence exists for a role of estrogens in prostatic disease. This paper reviews the literature and describes studies which have sought to show a correlation of estrogens and alterations in the prostates of humans and experimental animal models. Using the developmentally estrogenized mouse model, we propose an alternative role for estrogens as a predisposing factor for prostatic diseases: estrogen exposure during development may initiate cellular changes in the prostate which would require estrogens and/or androgens later in life for promotion to hyperplasia or neoplasia. Thus, the critical time for estrogen action would be during the development of the prostatic tissue. We further suggest that estrogen-sensitive cells may remain in the prostate and be more responsive to estrogens later in life or less responsive to the normal controlling mechanisms of prostatic growth.

A number of androgen effects on epithelial cells may be mediated by androgen-regulated paracrine factors produced by underlying mesenchymal cells. In previous studies we demonstrated that prostatic stromal cells and testicular peritubular cells, derived from immature rats, produce mediators of androgen action with identical effects on Sertoli cells. In the present paper we further compared the morphological and functional characteristics of both mesenchymal cell types. Cultured prostatic stromal cells and testicular peritubular cells look identical under phase-contrast microscopy, share the ability to form tubular structures and "balls" when cocultured with Sertoli cells, and contain proteins immunoreactive with an antiserum against alpha-smooth muscle isoactin. Two-dimensional gel electrophoresis shows that the pattern of proteins produced by both cell types is nearly identical. Conditioned media from stromal and peritubular cells contain a factor that stimulates transferrin and cGMP production in Sertoli cells. The behavior of the active principle in the media from both cell types is comparable. On reverse-phase HPLC the elution profile of this factor is comparable for media from both cell types. In conclusion, these data point to a striking similarity in the morphological and functional characteristics of mesenchymal cells cultured from the prostate and testis.

BACKGROUND PTEN is a well-characterized tumor suppressor that negatively regulates cell growth and survival through the modulation of PI3K/Akt pathway. METHODS In this paper, we investigated the effects of an PI3K/Akt inhibitor, perifosine, in human prostate cancer (PCa) cells analyzing cell proliferation, apoptosis, and the synergy with EGFR inhibitors. RESULTS Clinically achievable concentrations of perifosine, as well as Akt gene knockdown, induced a G0/G1 arrest and apoptosis in PTEN defective PCa cells. Although PTEN introduction was able to restore the control of Akt activity and to reduce cell proliferation, the manipulation of PTEN gene was not able alone to influence apoptosis. Perifosine induced apoptotic program also in PTEN positive cells when Akt activity was augmented by EGF suggesting the possibility that this drug could be used in combination with EGFR inhibitors. The combination treatment between erlotinib and pharmacological or molecular Akt knockdown, indeed, showed synergistic effects. This is the first demonstration that a pharmacological compound against Akt activity can restore the efficacy against EGFR inhibitors in PCa and has important therapeutic fallout since EGFR inhibitors have demonstrated very low effectiveness in PCa patients. CONCLUSIONS Taken together our data have an important clinical relevance in the treatment of advanced prostate tumors. However, further studies in the setting of combination therapies in advanced PCas are necessary. Prostate 68:965–974, 2008. © 2008 Wiley-Liss, Inc.

The International Consortium for Prostate Cancer Genetics (ICPCG) is an international collaborative effort to pool pedigrees with hereditary prostate cancer (PC) in order to replicate linkage findings for PC. A strength of the ICPCG is the large number of well-characterized pedigrees, allowing linkage analyses within large subsets. Given the heterogeneity and complexity of PC, the historical difficulties of synthesizing different studies reporting positive and negative linkage replication, and the use of different statistical analysis methods and different stratification criteria, the ICPCG provides a valuable resource to evaluate linkage for hereditary PC. To date, linkage of chromosome 20 (HPC20) to hereditary PC has been one of the strongest linkage signals, yet the efforts to replicate this linkage have been limited. This paper reports a linkage analysis of chromosome 20 markers for 1,234 pedigrees with multiple cases of PC ascertained through the ICPCG, and represents the most thorough attempt to confirm or refute linkage to chromosome 20. From the original 158 Mayo pedigrees in which linkage was detected, the maximum heterogeneity LOD (HLOD) score, under a recessive model, was 2.78. In contrast, for the 1,076 pedigrees not included in the original study, the maximum HLOD score (recessive model) was 0.06. Although, a few small linkage signals for chromosome 20 were found in various strata of this pooled analysis, this large study failed to replicate linkage to HPC20. This study illustrates the value of the ICPCG family collection to evaluate reported linkage signals and suggests that the HPC20 region does not make a major contribution to PC susceptibility.

BACKGROUND We and others have shown that the matrix metalloproteinases, MT1-MMP is overexpressed in human prostate PIN lesions and invasive cancers compared to normal prostate epithelium. However, the mechanism for this overexpression is not understood. Evidence from our laboratory and others has indicated that fibroblast growth factors (FGFs) can regulate the expression of certain matrix metalloproteinase. In addition, human prostate fibroblasts are known to express certain FGFs, including FGF-1. The purpose of the work in this paper was to determine the mechanism involved in FGF-1 induced MT1-MMP expression in prostate carcinoma cells. METHODS We tested the ability of recombinant FGF-1 to induce MT1-MMP expression in prostate carcinoma cell line, LNCaP cells. We measured the MT1-MMP message by using Northern analyses and protein levels by Western analysis after FGF-1 treatment. Downstream signaling was investigated using dominant negative constructs for FGFR-1 and signal transducer and activator of transcription-3 (STAT3). Transient transfection was performed using reporter plasmids of the MT1-MMP gene promoter region (7.2 kb) linked to the firefly luciferase gene in the pGL3-Basic vector. For dominant negative studies FGFR-1 dominant negative plasmid in PCEP4 vector or STAT3 dominant negative plasmid in pCMV-1 vector was co-transfected with the MT1-MMP reporter plasmid. RESULTS Recombinant FGF-1 significantly induced MT1-MMP expression in LNCaP prostate carcinoma cells. MT1-MMP message increased with FGF-1 treatment compared to that of untreated control LNCaP cells. Quantitation by digital image analysis revealed that this increase was twofold over untreated LNCaP cells. Treatment of pGL3-MT1-MMP-luciferase transfected cells with FGF-1 resulted in a twofold to fourfold increase in luciferase enzyme activity compared with untreated cells. Co-transfection of LNCaP with human MT1-MMP reporter construct and a dominant negative FGFR1 mutant showed that FGF-1-induced MT1-MMP expression in LNCaP cells was completely inhibited by the mutated FGFR-1, indicating that FGF receptor (FGFR) activation is necessary for induction of MT1-MMP. Further, expression of dominant negative STAT3 inhibited the FGF-1-induced transactivation of the human MT1-MMP 7.2-kb promoter. CONCLUSIONS From these data, we conclude that FGF-1 induces MT1-MMP expression in prostate carcinoma cells through a transcriptional mechanism mediated through the FGFR and the transcription factor, STAT3. These results confirm earlier data indicating that acidic FGF and STAT3 are involved in the signaling leading to the expression of a MMP. Our findings support the idea that paracrine and autocrine factors play an important role in the regulation of MT1-MMP in human prostate carcinoma cells. © 2003 Wiley-Liss, Inc.

Prostate cancer and benign prostatic hyperplasia are important age-related prostatic diseases that are under the influence of testicular hormones. However, the disparity between male and female life expectancy within the human population cannot be explained solely by the prevalence of prostatic disease-related mortality. The purpose of this paper is to explore the possibility that the testis exerts a detrimental effect on life span.First, we review previously published and unpublished data on the influence of the testis on the life span of dogs and men. Aging in pet dogs and men is then discussed in terms of evolutionary theory, emphasizing the significance of a prolonged postreproductive life span and possible consequences of late-acting deleterious genes in these two species. Finally, we present preliminary data that orchiectomy can reduce DNA damage within the brain of elderly male dogs. RESULTS AND CONCLUSIONS Taken together, these observations raise the intriguing possibility that interventions to antagonize the testis might have much broader therapeutic applications that will extend well beyond the treatment of prostate cancer.

BACKGROUND An endpoint for clinical trials of prostate cancer which simplifies traditional endpoints (response of measurable lesions, progression rates, and death) is urgently needed. This is especially true for hormone-unresponsive disease, for which many new drugs are presently in a development phase. This paper presents a rationale for the use of prostate-specific antigen (PSA) in clinical trials of progressive prostate cancer under endocrine treatment. METHODS The study is based on 84 patients who progressed after radical prostatectomy or node dissection, of whom 24 showed increasing PSA levels under subsequent endocrine treatment. An average linear relationship between (log-transformed) PSA and time and a subject-specific deviation from this average relationship were assessed. The predictive value of the subject-specific parameters of the linear fit with respect to time to prostate cancer-specific death was determined. The outcomes of the fitting procedure were used to calculate sample sizes for future studies (duration, 6 months) using PSA increase over time in hormone-unresponsive prostate cancer as a marker for treatment efficacy. RESULTS The average PSA doubling time in this population was 4 months (corresponding time constant = 0.25). The assessed variance of the time constants equalled 0.04; the overall residual variance equalled 0.265. The subject-specific rate of change of the log-transformed PSA value in hormone-unresponsive prostate cancer was a highly significant predictor of prostate cancer-specific death. This suggests the potential usefulness of PSA as an endpoint in trials of hormone-unresponsive prostate cancer. Depending on conditions chosen (e.g, desired power and changes in log PSA slope), 18–70 participants per arm will be necessary in future phase III studies. A suggestion (algorithm) for the use of PSA in drug development is presented. CONCLUSIONS Relatively small PSA-based trials in patients with hormone-unresponsive prostate cancer are possible if a similar patient population is utilized. As long as surrogacy is not established, such studies cannot be considered conclusive with respect to effectiveness of treatment, but are likely to be useful as a screening tool for new drugs. Experimental confirmation in human prostate cancer model systems of synergism between PSA decrease and tumor control by a given test treatment is likely to enhance the level of certainty of PSA-based drug evaluation. Prostate 42:107–115, 2000. © 2000 Wiley-Liss, Inc.

Three regions of chromosome 13 were previously identified for having loss of heterozygosity (LOH) in human prostate cancer. One of them, at 13q33, was defined by LOH at markers D13S158 and D13S280. The XPG/ERCC5 gene, a DNA repair gene that when mutated in the germline leads to xeroderma pigmentosum, has been mapped to 13q33, within one megabase of D13S158 and D13S280. This paper describes LOH and mutational analysis of the XPG gene in human prostate cancers, in order to determine whether the XPG gene is involved in the development of prostate cancer.LOH of the XPG gene was analyzed in 40 primary prostate cancers and 14 metastases by using the microsatellite assay, and its mutations were examined in 5 cell lines, 14 metastases, and 8 tumors with LOH at 13q33 by using the single-strand conformation polymorphism (SSCP)-direct DNA sequencing analysis.Four of the 29 (14%) informative primary tumors and 4 of 8 (50%) metastases showed LOH for the XPG gene. Analysis of the 8 tumors with LOH at the 13q33 region, 14 metastases, and 5 cell lines of prostate cancer revealed two polymorphisms but no mutation of the gene. The polymorphism in exon 2 did not change the amino-acid sequence of the XPG protein, but the exon 15 polymorphism altered codon 1104 from histidine to aspartic acid. The two polymorphisms also occurred in individuals without prostate cancer.LOH at XPG in prostate cancer supports the conclusion that the 13q33 region contains a gene important in the development of prostate cancer, while lack of mutations of the gene suggests that XPG is not the target gene involved.

In this paper we describe our program for the immune monitoring of phase II participants given dendritic cell (DC)/prostate-specific membrane antigen (PSMA)-based immunotherapy, and we also present some initial findings.Phase II subjects received six administrations of autologous dendritic cells exogenously pulsed with two peptides derived from PSMA. Prior to the initial infusion, and following each treatment, peripheral blood mononuclear cells (PBMC) were collected for the generation of dendritic cells as well as for comprehensive immune monitoring.Thus far, an increase in PSMA-peptide-specific as well as overall cellular reactivity has been observed in several patients receiving DC plus PSM-P1 and -P2, as measured by delayed-type hypersensitivity (DTH) test and enzyme-linked immunosorbant assay (ELISA).Our initial observations using an ELISA and DTH test indicate that we are enhancing cellular immunity in prostate cancer patients following infusion with DC plus PSMA-derived peptides. Several methods are underway to comprehensively monitor both cell-mediated and humoral immune responsiveness, including: determining anti-PSMA serum antibody titers, testing immunogen-restricted responder-cell proliferation and cytotoxicity, assessing aberrations in signal transduction, antigen processing, and presentation, and measuring soluble factors that may promote tumor outgrowth.

alpha 1-adrenoceptor antagonists (blockers) are now commonly used in the treatment of the symptoms of lower urinary tract obstruction. Originally phenoxybenzamine, a non-selective antagonist at both alpha 1- and alpha 2-adrenoceptors, was used by Marco Caine. In an attempt to minimize side effects, selective alpha 1-antagonists, e.g. prazosin, were subsequently developed. More recently, agents such as alfuzosin, doxazosin, terazosin, and tamsulosin have been introduced and claims of "uroselectivity" and "prostate" selectivity have emerged.This review attempts to put these claims into perspective and represents a comprehensive analysis of all pre-clinical and clinical data including several papers from the Japanese literature. An attempt is made to define what is meant by selectivity at various levels including the test tube, in the laboratory animal and, most importantly, in the clinical context of the whole patient.The conclusions are interpreted within the context of the subdivision of the alpha 1-adrenoceptor into alpha 1A, alpha 1B, and alpha 1D subtypes.

BACKGROUND This paper reviews the state of the art in analyzing race, social factors, and economic factors in cancer research, with an emphasis on prostate cancer and the role of socioeconomic status (SES) in racial differences in mortality. It analyzes the quality of articles in the literature that assess the role of SES in cancer mortality. METHODS English-language titles were identified using MEDLINE with publication dates from mid-1985 through July 1994. Articles in the references of these articles were also included in the final selection, based originally on title and ultimately on content, dating back to 1978. Articles that included SES information and distinguished between whites and African-Americans were chosen, resulting in a final selection of 21 articles. Articles are summarized with consideration of five criteria considered minimal requirements of a well-designed study of the role of race in cancer mortality: (1) SES measure(s) should be on an individual level, not census level; (2) SES should be controlled for when making comparisons between whites and blacks; (3) SES should include at least (individual level) measures of income and education; (4) sample sizes are sufficient for the relevant populations; and (5) specific cancer sites should be studied separately. RESULTS Of the articles reviewed, only two meet the minimum standards, neither of which studied prostate cancer. It is not clear whether observed racial differences in prostate cancer are directly attributable to race or reflect underlying social factor differences between whites and African-Americans. CONCLUSIONS In the future, specific characteristics of SES should be measured at the individual level; there is a need for expansion and standardization of data in terms of social and economic content; other methodological advances are needed in modeling to take into consideration the influence of SES in outcome research related to cancer. © 1996 Wiley-Liss, Inc.

To clarify the mechanism of action of Estracyt, we performed experiments using 3H_ estramustine of high specific activity. 3H-Radioactivity accumulated selectively in the ventral prostate of castrated male rats after the administration of 3H-estramustine. Estramustine and its metabolites were retained in the ventral prostate for long time periods. The uptake of 3H-radioactivity was almost totally localized in the cytosol fraction, but not in a purified receptor fraction. The apparent equilibrium dissociation constant of the estramustine binding protein was 18.9 nM, and the apparent equilibrium Bmax value was 0.76 nmoles/mg of cytosol protein. In addition, we wish to report in this paper the results of clinical trials of Estracyt® studied by a cooperative research group in Japan from 1977 to 1979. It was concluded that Estracyt was effective in 890/0 of previously untreated prostatic cancer patients and in 38% of reactivated cancer patients.

This second report in a series of three deals with the prognostic importance of the presence of multiple, histologically identifiable architectural patterns in prostatic carcinomas. In the previous paper three of 12 parameters studied were identified as being prognostically significant in patients with single architectural patterns (formations) present in their tumors. The three parameters are nuclear anaplasia, architecture (“glands”), and mitoses, if present. The questions of whether “the worst part of a tumor determines prognosis” or “the presence of differentiated formations improves prognosis” are investigated by applying these parameters to patients with multiple tumor formations. Overall and corrected survival served as parameters. It was shown that the parameters shown to be of importance for prognosis in tumors with single formations also have significant influence in patients with multiple formations. The worst formation determines prognosis, but patients with poorly differentiated tumors do significantly worse if their tumor is homogeneous. The presence of better-differentiated formations improves the prognosis of the worst formation. The observations made are discussed in view of the histopathogenesis of prostatic cancer.

Androgen receptor (AR) content in prostatic tissues from patients with either cancer or benign prostatic hyperplasia (BPH) is of interest from at least two standpoints: receptors may be a feature of the pathogenesis of these conditions, and they may be important to the management and prognosis of prostatic cancer patients. For these reasons, a quantitative autoradiographic assay for AR content in prostatic tissues has been developed. Application of autoradiography to rodent tissues yielded results that were highly correlated with those from biochemical assays. Thus, the autoradiographic analyses with human tissues reported in this paper were undertaken. Average AR content in 22 prostatic carcinomas was lower than that in tissues from 14 patients with BPH; the median values of the affinity index, the quantitative estimate of receptor content, were 7.0 and 12.0, respectively. For the cancer tissues, a trend of declining receptor content with advancing stage of disease appeared but was not statistically significant. No association between receptor content and degree of tumor aggressiveness as measured by Gleason score and MD Anderson score was evident. Patient age and race were not related to receptor content in either type of tissue.

Editorial Comment: This is a rather unusual paper dealing with a verbatim translation of the thesis by Maximillian J.F. Bruch on the diseases of the prostate gland first published in 1835 and apparently never translated into English. Since in all probability this is the first comprehensive treatise on prostatic disease, it is a welcome and important translation and presents the background as to how our thinking regarding prostatic disease developed for nearly 150 years. Although the manuscript is somewhat lengthy, we decided to publish it in total, since, if it were to be reduced in size, it would be difficult to decide which parts to remove and could run the risk of ruining the work of the authors. The authors have done an excellent job in translating this thesis from the complex Latin text. Avery A. Sandberg, MD James P. Karr, PhD This Latin dissertation on diseases of the prostate gland was written by the German physician Maximillian J.F. Bruch at the Freiderick Wilhelm University. This English translation permits a rare glimpse into the early medical thinking on prostatic diseases.

Sodium butyrate (NaBT) induces differentiation in several transformed cell lines. The present paper describes the effects of NaBT on some transformation-associated parameters in PC-3, a human prostatic carcinoma cell line. NaBT produces a reversible inhibition of cell proliferation, but anchorage-independent growth is more sensitive than monolayer growth. Soft agarose colonies are reduced by over 50% at 0.1 mM, a concentration that hardly affects growth on solid substrata. Monolayer cells respond to NaBT by spreading and flattening, as demonstrated by a combined light and electron microscopic, morphometric technique. After 4 days' exposure to 2 mM NaBT, the average cell covers an area of substratum that is approximately double that covered by control cells. The average cell volume, however, remains unchanged. This flattening is paralleled by an increase in the number of stress fibers, as seen by fluorescence microscopy. Only minor changes are observed in the microtubule and intermediate filament patterns. While control cells contain very little antifibronectin reactive material, substantial amounts of such material appear upon NaBT treatment. The amount of fibronectin increases up to 100-fold in cells exposed to NaBT. The changes observed correspond to a suppression of properties that are generally associated with the malignant phenotype.

With review of 393 consecutive cases of previously documented prostatic adenocarcinoma, the coexistence of intraglandular crystalloids was confirmed. The various morphologic appearances of these structures are described. Unequivocal crystalloids were identified in 10% of cases. They were most often located in the acini of malignant glands but occasionally were observed in benign glands adjacent to carcinoma. Of available clinical and demographic parameters analyzed, several unexplained statistical relationships were observed, but none of the variables could be used to characterize the patients with crystalloids. This paper suggests that these structures may be useful in the diagnosis of prostatic adenocarcinoma when only inadequate or equivocal biopsy material is available.

In this paper, studies by a large series of independent investigators are reviewed with regard to the basic structure and function of the prostate in an attempt to examine their relationship to prostatic cancer etiology. These studies demonstrate that the functional activities of the prostate involve secretion, transport, and reabsorption of a variety of materials into and out of the glandular lumen and that these activities are directly related to the basic structural organization of the gland. These functional activities are constantly occurring in the prostate even under basal (ie, nonejaculating) conditions. Due to these functional activities, the prostatic fluid in the glandular lumen is a complex mixture of a variety of components derived, not only from the synthetic activity of the glandular epithelial cells of the gland itself, but also from the blood serum. The levels of these components are continuously modulated, not only by the frequency of active ejaculation, but also, under basal conditions by the continuous interaction with the glandular prostatic cells lining the acinar lumen and ducts. A concept is presented that the initiation and/or promotion of prostatic carcinogenesis may well involve the chronic modulation/interaction of the prostatic glandular cells with their lumenal fluid.

During the past two decades several papers have described the changes in prostatic secretory capacity following vasectomy. Based upon results indicating a reduction of secretory function, it was suggested that even prostatic size and the incidence of benign prostatic hyperplasia (BPH) might be altered after the operation. In this study, which included 56 males who had been vasectomized 8 years previously and 56 age-matched control persons, transrectal ultrasonic scanning of the prostate was used for exact measurements of the prostatic volume and for the investigation of intraprostatic echo pattern. The total prostatic volume, the volume of the periurethral gland, and the volume of the peripheral zone were not influenced by the vasectomy; nor was the growth rate of these zones affected. In the vasectomy group, the frequency of adenomatous prostates was 19.6%, whereas 30.3% of prostates in the control group had ultrasonic signs of BPH. However, this is not a statistically significant difference. Subdividing the material according to age did not reveal altered BPH frequency in any age group when vasectomized and controls were compared.56 males who had been vasectomized 8 years previously and 56 age-matched control persons participated in this study designed to investigate the long-term influence of vasectomy on prostatic volume and morphology in man. All patients were vasectomized under local analgesia on an outpatient basis using bilateral scrotal incisions and resection of 1-2 cm of the vas deferens. The nonvasectomized men in the control group were selected at random. Transrectal ultrasonic scanning of the prostate was performed after 3 days of sexual abstinence. The patient/control person emptied his bladder by a normal voiding procedure immediately before the scanning, which then was performed with the person in the left lateral position. All prostates were scanned in the radial plane. A careful medical history was taken in all cases. Special attention was given to urogenital disorders and voiding symptoms. The 2 groups were comparable with respect to medical history, previous and current diseases and medication, tobacco and alcohol consumption, height, weight, and surface area. In the vasectomy group, 11 of 56 (19.6%) had ultrasonic signs of developing or established adenomas; of the control group, 17 of 56 (30.3%) prostates were adenomatous. The difference was not statistically significant. No statistically significant differences were found between the 2 groups when normal and adenomatous prostates were evaluated independently, with 1 exception. In vasectomized men with normal prostatic echopattern, the relative volume of the periurethral gland was found to be slightly but significantly larger then the corresponding value in controls. In each group, adenomatous prostates presented with significantly larger total volumes, larger volumes of the periurethral gland, and larger relative volumes of the periurethral gland. No change was found in the peripheral volume when adenomas developed. No statistically significant differences between the volumes were found in any age group when patients and controls were compared.

The study of the effect of hormones in seminal fluid upon prostate tissue is hampered by the lack of a suitable model. Such a model is described in this paper, and its possible usefulness is discussed. The vas deferens of the rat is moved from its normal position into a surgical incision into the ventral prostate. Squamous metaplasia of epithelium in prostatic acini at early stages is replaced by cuboidal epithelium. At later stages, normal-appearing glandular epithelium is seen as close as 50 micrometers to the vas deferens. The structure of the vas deferens is not affected.