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PubMed1995

Up-regulation of the oligosaccharide sialyl LewisX: a new prognostic parameter in metastatic prostate cancer.

Metastatic prostate cancer has an unpredictable long-term prognosis. At present, there are few specific predictors to indicate the outcome for the individual patient. We have studied immunoreactivity for type-2 carbohydrate structures, known to be involved in various cell adhesion processes, in patients with metastatic prostate cancer. One group of patients (n = 26) did not progress within 3 years after orchiectomy, while another group of patients (n = 33) progressed within 1 year following castration and survived less than 2 years. Among the parameters studied, sialyl LewisX carbohydrate up-regulation was the only variable showing significant association with poor prognosis (P < 0.01). Sialyl LewisX discriminated between these two outcome groups with 71% predictability and 96% specificity. Our results indicate that up-regulation of sialyl LewisX is associated with hormonal-resistant, aggressive disease. This prognostic marker may, therefore, have an important role in selecting proper treatment for patients with metastatic prostate cancer.

Adenocarcinoma↗
PubMed2001

Anti-PSCA mAbs inhibit tumor growth and metastasis formation and prolong the survival of mice bearing human prostate cancer xenografts.

Prostate stem-cell antigen (PSCA) is a cell-surface antigen expressed in normal prostate and overexpressed in prostate cancer tissues. PSCA expression is detected in over 80% of patients with local disease, and elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence, including high expression in bone metastases. We evaluated the therapeutic efficacy of anti-PSCA mAbs in human prostate cancer xenograft mouse models by using the androgen-dependent LAPC-9 xenograft and the androgen-independent recombinant cell line PC3-PSCA. Two different anti-PSCA mAbs, 1G8 (IgG1kappa) and 3C5 (IgG2akappa), inhibited formation of s.c. and orthotopic xenograft tumors in a dose-dependent manner. Furthermore, administration of anti-PSCA mAbs led to retardation of established orthotopic tumor growth and inhibition of metastasis to distant sites, resulting in a significant prolongation in the survival of tumor-bearing mice. These studies suggest PSCA as an attractive target for immunotherapy and demonstrate the therapeutic potential of anti-PSCA mAbs for the treatment of local and metastatic prostate cancer.

Animals↗
PubMed1995

Differential expression of uPA in an aggressive (DU 145) and a nonaggressive (1013L) human prostate cancer xenograft.

Prostate cancer has a slow growing noninvasive phase, but, in general, is invasive on diagnosis. An initial step in the invasion of surrounding normal tissue is the activity of proteolytic enzymes such as components of the plasminogen activator system (PA). In cell culture, the primary human prostate cancer cell line 1013L expressed no urokinase type-PA (uPA), while DU 145, a cell line derived from a metastatic lesion, expressed high levels of uPA. The DU 145 cells grew easily as xenografts but the establishment of 1013L in the SCID mice was possible only with the aid of a gelatin sponge (Spongostan). The latency period was 42-64 days, followed by a slow growth phase before a fast growth phase occurred. This fast growth phase was characterized by rapid degeneration of tumor tissue, while high proliferation occurred around the blood vessels. On serial transplantation of tumor material, the growth pattern was similar. Furthermore, the 1013L tumor was encapsulated by connective tissue and no invasiveness could be detected. We found that 1013L tumor homogenates had hardly detectable levels of uPA, i.e., 300-fold lower than we found in the invasive prostate xenograft DU 145. In addition, no expression of uPA was found in the plasma of 1013L tumor-bearing mice whilst uPA antigen was detected in the plasma of DU 145 tumor-bearing mice. In conclusion, the 1013L cell line, which exhibits a nonaggressive pattern, could be a good model for studying progression of prostate cancer to a more aggressive phenotype in vivo and in vitro.

Animals↗
PubMed1996

Tyrosine kinase inhibitor as a novel signal transduction and antiproliferative agent: prostate cancer.

In prostate cancer cells, the binding of peptide growth factors to specific receptors increases tyrosine kinases (TK) activity to regulate cell proliferation, cell differentiation, and signaling processes. To determine whether inhibition of receptor TK activity inhibits tumor growth, we studied the effects of a tyrosine kinase inhibitor, RG-13022 (tyrphostin), on cultured human prostate cancer cells. RG-13022 significantly inhibited TGF alpha-induced phosphorylation of EGF receptor (EGFR). This compound inhibited TGF alpha-stimulated [3H]thymidine incorporation in a dose-dependent manner with IC50 being 30 microM. Clonogenicity in soft agar was reduced in the presence of RG-13022. Inhibitory effects were also observed in androgen-positive LNCaP cells and androgen-negative PC3 cells. RG-13022 not only inhibited TGF alpha-induced growth but also growth stimulated by epidermal growth factor (EGF), acidic fibroblast growth factor (aFGF) and serum. In addition, RG-13022 also blocked androgen-stimulated cell proliferation, suggesting that functioning TK pathways are required for androgen-induced growth. This novel synthetic inhibitor may be useful in providing a new strategy for future therapeutic intervention for prostate cancer.

Androgens↗
PubMed2003

[Controversial guidelines in early diagnosis of prostate cancer].

In prostate cancer prevention the American College of Physicians has endorsed a clinical practice guideline: it is recommended that physicians share the decision with the patient. There is no information about its adaptation to actual circumstances and particularly in our country. This presentation has the aim of analyzing the evidence and introduces a local perspective. There is no demonstration of survival or life quality improvement in preventing prostate cancer. Therapeutic interventions have a high rate of associated morbidity and mortality. Although desirable, sharing decisions has not yet proved its validity. In our country, due to the fragile equilibrium between risks and benefits, it seems advisable to wait for stronger scientific evidence. It is recommended to the clinician to: abstain from offering early diagnosis in the healthy adult, be reluctant when asked, share decisions when it seems advisable based on patient's characteristics and inform about the probability of prostate cancer in high risk groups.

Decision Making↗
PubMed2003

The memorial anxiety scale for prostate cancer: validation of a new scale to measure anxiety in men with with prostate cancer.

BACKGROUND: The psychological difficulties facing men with prostate cancer are acknowledged widely, yet identifying men who may benefit from mental health treatment has proven to be a challenging task. The authors developed the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) to facilitate the identification and assessment of men with prostate cancer-related anxiety. This scale consists of three subscales that measure general prostate cancer anxiety, anxiety related to prostate specific antigen (PSA) levels in particular, and fear of recurrence. METHODS: Ambulatory men with prostate cancer (n = 385 patients) were recruited from clinics throughout the United States. Prior to routine PSA tests, participants completed a baseline assessment packet that included the Hospital Anxiety and Depression Scale; the Distress Thermometer; the Functional Assessment of Cancer Therapy Scale, Prostate Module; and measures of role functioning, sleep, and urinary functioning. PSA values from the last three tests also were collected. Follow-up evaluation was completed within 2 weeks after patients learned of their PSA test result using a subset of these scales. RESULTS: Analysis of the MAX-PC revealed a high degree of internal consistency and test-retest reliability for the total score and for the three subscales, although reliability was somewhat weaker for the PSA Anxiety Scale. Concurrent validity was demonstrated by correlations between the MAX-PC and measures of anxiety. Overall changes in PSA levels were correlated only modestly with changes in MAX-PC scores (correlation coefficient, 0.13; P = 0.02). CONCLUSIONS: The MAX-PC appears to be a valid and reliable measure of anxiety in men with prostate cancer receiving ambulatory care.

Anxiety↗
PubMed1999

Future prospects in prostate cancer.

BACKGROUND: Prostate cancer has displayed an increase in incidence unparalleled by any other tumor in the last two decades, with a steady, more gradual increase in mortality rate. Current curative strategies are focused on the detection and treatment of early-stage (T1-2 N0 M0), clinically significant tumors. METHODS: To this aim, refinement of surgical approaches, with appropriate adjuvant therapies, will ensure more complete cancer control, while minimizing associated morbidity. New delivery systems for radiotherapy, as well as other energy sources, are evolving, while a number of promising pharmacological agents, including angiogenesis inhibitors and drugs which alter signal transduction pathways, are currently under investigation. Early detection is also being facilitated by a more widespread implementation of screening programs. Advances in tumor markers, and imaging and biopsy techniques, will allow more accurate preoperative staging. These, coupled with improvements in prognostic markers, aid the physician and patient alike in deciding on the suitability of treatment options with better estimation of outcome. Perhaps the most exciting developments in prostate cancer will come from knowledge of the molecular mechanisms underlying carcinogenesis. The potential for the development of diagnostic and therapeutic tools is immense. The efficacy of treatment can be studied at a molecular level, and strategies for preventing or slowing the development of malignancy can be formulated. RESULTS AND CONCLUSIONS Application of this knowledge in the form of gene and cellular therapy and in the development of novel systemic agents is beginning to enter the realm of clinical practice, and it may be in this field that means for cure and prevention of prostate cancer will eventually be found.

Clinical Trials as Topic↗
PubMed2006

Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence.

Prostate cancer biology varies from locally confined tumors with low risk for relapse to tumors with high risk for progression even after radical prostatectomy. Currently, there are no reliable biomarkers to predict tumor relapse and poor clinical outcome. In this study, we correlated expression patterns of the androgen receptor (AR) coactivators lysine-specific histone demethylase 1 (LSD1) and four and a half LIM-domain protein 2 (FHL2), AR, Gleason score, Gleason grade, and p53 expression in clinically organ confined prostate cancers with relapse after radical prostatectomy. Our data reveal that high levels of LSD1, nuclear expression of the FHL2 coactivator, high Gleason score and grade, and very strong staining of nuclear p53 correlate significantly with relapse during follow-up. No correlation exists with relapse and the expression of AR and cytoplasmic expression of FHL2. To confirm these data, we did quantitative reverse transcription-PCR and Western blot analyses in a subset of tumor specimens. Consistently, both LSD1 mRNA and protein levels were significantly up-regulated in high-risk tumors. We previously identified LSD1 and FHL2 as nuclear cofactors interacting specifically with the AR in prostate cells and showed that both stimulate androgen-dependent gene transcription. Our present study suggests that LSD1 and nuclear FHL2 may serve as novel biomarkers predictive for prostate cancer with aggressive biology and point to a role of LSD1 and FHL2 in constitutive activation of AR-mediated growth signals.

Aged↗
PubMed2005

Population-based risk assessment for other cancers in relatives of hereditary prostate cancer (HPC) cases.

BACKGROUND: To identify associations of other cancers with hereditary prostate cancer (HPC) we estimated relative risks (RRs) of 36 different cancers in relatives of prostate cancer cases in the Utah Population Data Base (UPDB), which combines genealogical and cancer data for Utah. METHODS: We utilized known genetic relationships between prostate cancer cases and their relatives with cancer, combined with age- and sex-specific cancer rates calculated internally from the UPDB, to estimate RRs for cancer in relatives of prostate cancer cases. RESULTS: Multiple other cancers were observed in excess in both first- and second-degree relatives of HPC cases including colon cancer, non-Hodgkins lymphoma, multiple myeloma, rectal cancer, cancer of the gallbladder, and melanoma (skin). CONCLUSIONS: This analysis supports the existence of heritable prostate cancer syndromes that include other cancers. We hypothesize that the study of homogeneous pedigrees co-segregating prostate cancer and another cancer could allow more straightforward localization and identification of the gene(s) responsible.

Adult↗
PubMed2005

Prostate cancer screening.

Prostate cancer is the leading noncutaneous cancer in men of the Western world. Because of its prevalence and ability to cause morbidity and mortality,prostate cancer screening continues to be an important area of focus in health care. This article covers the sensitivity and specificity of prostate-specific antigen and current techniques used to improve the test's validity, the importance of detecting clinically important cancers with screening, as well as the downward stage migration, decreased disease-specific mortality, and decreased metastases rate seen inpatients screened and treated for prostate cancer.

Cost-Benefit Analysis↗
PubMed2000

Telomerase activity in needle biopsies from prostate cancer and benign prostates.

BACKGROUND: Telomerase activation is thought to be essential for the immortality of cancer cells. It may be a prognostic factor in small volume well differentiated prostate cancers and hence a guide for the aggressiveness of the approach. The length of the chromosome tips (telomeres) are maintained by a specific enzyme (telomerase) independently of the normal cell division cycle. Although telomerase is not expressed in most normal human tissues, it is expressed in most human tumours. For the detection of telomerase in small prostate needle biopsy samples a recently developed telomeric repeat amplification protocol (TRAP) assay was used. The aim of the present study was: to measure telomerase activity in human prostate samples, and to evaluate the applicability of this assay on specimens from a prostate biopsy. MATERIALS AND METHODS: From 36 patients referred for lower urinary tract symptoms (LUTS) or suspicion of having prostate cancer a total of 288 prostate biopsy samples were obtained (8 in each patient). When the digital rectal examination was abnormal and/or when the PSA level was elevated in L.U.T.S., or asymptomatic patients' tissue samples were obtained by transrectal ultrasound (TRUS) guided biopsies. Samples were tested for telomerase activity by a modified TRAP and forwarded for histology. RESULTS: In 19 out of 36 patients prostate cancer was diagnosed on histology. In 11 of these 19 tumours substantial telomerase activity was detected, whereas only very low telomerase activity existed in 2 of 17 samples from benign prostatic hypertrophy (BPH) patients. In this small series the relative telomerase activity in prostate cancer correlated with histopathological grade. CONCLUSIONS: Our results show the applicability of a TRAP assay to measure telomerase activity in small needle biopsied prostate samples. In poorly differentiated and metastatic cancer we observed that levels of telomerase activity were high. To establish accuracy and to distinguish the 'relative good from the ugly' further study is needed.

Biomarkers, Tumor↗
PubMed2000

Low frequency of allelic imbalance at the prostate cancer susceptibility loci HPC1 and 1p36 in Swedish men with hereditary prostate cancer.

The aim of this study was to investigate allelic imbalance at the major human prostate cancer susceptibility locus HPC1 at 1q24-25 and the recently reported, putative, susceptibility locus at 1p36 in prostate tumors from Swedish families with hereditary prostate cancer. We analyzed 31 prostate tumors and two lymph node metastases from 33 Swedish men in 22 families with hereditary prostate cancer for the presence of allelic imbalance using microsatellite markers D1S158, D1S422, and D1S238 for the HPC1 locus and D1S1597, D1S407, and D1S489 for the 1p36 locus. Frequencies of allelic imbalance at the two investigated loci were quite low, 3 of 27 informative tumors at the 1p36 locus and 3 of 27 informative tumors at the HPC1 locus. Interestingly, two tumors showed allelic imbalance at both loci investigated, suggesting that they may have lost a great part of chromosome 1. Taking this possibility into consideration, the specific loss of the two investigated loci may be even lower (1 of 27 informative tumors for either locus). The very low level of allelic imbalance found at HPC1 and 1p36 makes it unlikely that these loci encode genes that are acting as classic tumor suppressor genes in the initiation or progression of hereditary prostate cancer. Of the eight tumors from HPC1-linked families, only two showed AI at the HPC1 locus, one of which had lost the wild-type allele.

Allelic Imbalance↗
PubMed1995

Early detection of prostate cancer. Results of a prostate specific antigen-based detection program in Japan.

BACKGROUND: Prostate cancer increasingly is becoming a medical problem in Japan. To maximize the chance for cure, extensive effort is being made to detect prostate cancer while confined to the gland. METHODS: Determination was made of serum prostate specific antigen (PSA) in the early detection of prostate cancer in an Asian male population aged 55 years or older. Recommendation for biopsy was based solely on this parameter when its value exceeded 2.0 ng/ml in IMx immunoenzymetric assay. RESULTS: Of 1189 men, 150 (12.6%) had elevated values. The proportion of males with serum PSA greater than 4.0 ng/ml was only 3.4%. Of the 99 males who underwent ultrasound-guided biopsies, 16 cancers were detected, a cancer detection rate of 1.3%. Most of these (81.3%) were clinically localized cancers. Seven patients with cancer had serum PSA levels below 4.0 ng/ml including 5 less than 3.0 ng/ml. These tumors would have been overlooked if the conventional cutoff levels of 4.0 ng/ml had been applied. Radical prostatectomy was conducted on 13 patients. All had histologic features of clinically significant cancer and 69.2% were pathologically confined within the gland. CONCLUSIONS: Elderly Asian males appear to have lower serum PSA than their Western counterparts. The optimal cutoff of serum PSA for early detection should be examined further in Asian male populations. Differences in the incidence of prostate cancer between ethnic groups may have been overestimated in previous studies owing in part to unawareness by the physician and general public. Though the frequent use of more sophisticated diagnostic modalities will likely disclose greater numbers of prostate cancers in Japan, whether early detection reduces mortality by minimizing risk of death from cancer remains a point to be determined.

Aged↗
PubMed2002

Confirmation of the prostate cancer susceptibility locus HPCX in a set of 104 German prostate cancer families.

BACKGROUND: Several prostate cancer (PCa) susceptibility loci have been reported, but attempts to confirm them in independent data sets have produced inconsistent results. It is not yet clear, how much of this variation is due to differences between different populations. HPCX was originally identified in a combined data set of PCa families from the USA and Scandinavia. Considerable differences in the frequency of linked families were observed in this heterogeneous family sample as well as in following studies. METHODS: In order to estimate the significance of HPCX in the German population, DNA samples from 104 PCa families were genotyped at six polymorphic markers spanning a region of approximately 14 cM on Xq27-28, which includes the proposed HPCX candidate locus. RESULTS: In the entire data set, a maximum NPL Z score of 1.20 (P = 0.11) at marker DXS984 was observed. Statistically significant evidence for linkage was obtained in the subset of 63 families with early-onset disease (i.e., < or = 65 years) with a maximum NPL Z score of 2.32 (P = 0.009) at the same location. CONCLUSION: Our results confirm the existence of a prostate cancer susceptibility gene on Xq27-28 also in the German population.

Age Factors↗
PubMed1998

Racial variation in cancer care: a case study of prostate cancer.

Prostate cancer is one of several cancers that affects U.S. racial and ethnic groups differently with Blacks experiencing a higher incidence and mortality rate than Whites. Observational studies indicate that black patients with prostate cancer are less likely to receive definitive therapy. This pattern of care appears to be attributable primarily to the later clinical stage of disease at presentation; socioeconomic considerations as such relate to access to care (e.g., ability to pay) appear to play a lesser role. Other patient related factors, for example, preferences for certain therapies, have not been well studied; consequently, their ability to explain racial variations in use of therapies for this disease is unclear. Potential areas for future research should focus on the reasons for the detection of the disease at a later clinical stage and, hence, with worse prognosis.

Ethnicity↗
PubMed1994

The American Cancer Society's National Prostate Cancer Detection Project.

As a significant public health problem, prostate cancer meets nearly all the criteria for screening. While concerns about incomplete natural history, progression rates and need for better prognostic factors are valid, important social and public health issues also need consideration. If future expenditures for terminal cancer care are minimized via reductions in therapy choices or coverage, no economic benefit for prostate cancer screening should exist. Narrowly focused attempts at cost reduction could inappropriately discourage highest risk groups from participating in early detection programs, thereby eliminating the greatest potential benefit of screening. The ACS-NPCDP has demonstrated that early detection of prostate cancer produced distinct stage migration to earlier, more curable disease through optimized use of DRE, TRUS and PSA. PSA is the most objective test and detects tumors of significant biologic potential. Current cost savings are possible with improved public health education about the appropriateness of early detection in the oldest age groups or those with significant pre-existing medical conditions. Prostate cancer control perhaps requires a tailored approach of screening in high risk groups and more appropriate "case finding" in the lower risk general population. The initial combination of PSA and DRE represents an ethical and economical choice for individual patients consulting with informed physicians.

Age Factors↗
PubMed2001

Health technology assessment and screening in The Netherlands: case studies of mammography in breast cancer, PSA screening in prostate cancer, and ultrasound in normal pregnancy.

OBJECTIVE: To review the assessment and implementation of three screening methods: mammography for breast cancer, screening for prostate cancer, and routine use of ultrasound in pregnancy. METHODS: To review policy documents and published papers dealing with prevention and screening in the Netherlands, focusing on the three screening methods specified. RESULTS: The results indicate that the Netherlands has an active establishment devoted to health technology assessment (HTA). The Netherlands government has also made prevention a high priority in the health services system. Within prevention policy, HTA is given an important place. The general policy is that prevention programs should meet high standards of effectiveness and efficiency, as well as ethical, legal, and social acceptability. In addition, the Netherlands may be unique in the world in having a specific law requiring that proposals for population screening must be carefully assessed before they are implemented. CONCLUSIONS: The three cases examined in this paper have all been assessed, and the conclusions are similar to those presented in the synthesis published in this issue (33). In the case of mammography, the assessment was followed by a rational implementation of a national screening program for breast cancer. In the other two cases, however, despite negative conclusions from assessment, the tests are frequently carried out, especially in what has been termed opportunistic screening. Prostate cancer screening seems to be spreading rapidly. Use of ultrasound in pregnancy is frequent, not necessarily for medical reasons but because parents wish to have a picture of their fetus. The conclusion is that HTA is well established in the Netherlands, as illustrated in these three cases, and policy is based on the assessments done. However, practice is not in accord with the assessment in the cases of prostate cancer and routine ultrasound. Policies to deal effectively with opportunistic screening are difficult to imagine.

Adult↗