Per-Anders Abrahamsson

Serum prostate specific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer.

Prostate specific antigen (PSA) in serum has recently been shown to occur in complex with alpha 1-antichymotrypsin and as an approximately 30 kDa. noncomplexed molecular form. We characterized PSA by 3 different assays in samples from 144 patients with benign prostatic hyperplasia (BPH) and 121 with carcinoma of the prostate. One of these noncompetitive assays measured total PSA by detecting PSA complexed to serine proteinase inhibitors and the noncomplexed molecular form, a second measured only PSA in complex with alpha 1-antichymotrypsin, whereas a third detected the noncomplexed form. PSA in complex with alpha 1-antichymotrypsin was the predominant form in all patient sera. Noncomplexed PSA constituted a minor fraction that was significantly smaller in patients with untreated prostate cancer than in those with BPH (p < 0.0001). The proportion of noncomplexed PSA does not correlate to the serum concentration of PSA or that of alpha 1-antichymotrypsin. In men with a serum PSA concentration of less than 10 micrograms./l. the combination of assays measuring total PSA immunoreactivity, the noncomplexed molecular form and PSA in complex with alpha 1-antichymotrypsin may facilitate discrimination between prostate cancer and BPH.

Neuroendocrine differentiation in prostatic carcinoma.

BACKGROUND Information is presented on prostatic neuroendocrine cells and neuroendocrine differentiation in prostatic carcinoma. The prognostic and therapeutic implications of neuroendocrine differentiation in prostatic carcinoma are reviewed. METHODS Data are presented that support the intriguing link between neuroendocrine differentiation, tumor progression, and androgen-independent prostate cancer. The hormones, and the receptors, expressed by prostatic neuroendocrine cells are investigated in order to elucidate their significance for prognosis and therapy. RESULTS The prognostic significance of neuroendocrine differentiation in prostatic malignancy has been controversial, but recent studies employing markers such as chromogranin A and neuron-specific enolase suggest that neuroendocrine differentiation, as reflected by increased tissue expression and/or blood levels of these neuroendocrine secretory products, correlates with poor prognosis, tumor progression, and androgen-independence. Since all malignant neuroendocrine cells are devoid of androgen receptors and since neuroendocrine phenotypic expression is not suppressed by androgen ablation, clonal propagation of androgen receptor-negative neuroendocrine cells may play an important role in the pathway towards the androgen-independent state of prostatic carcinoma. This would have significant implications for the treatment of prostate cancer, as several of the hormones known to be expressed by neuroendocrine-differentiated, malignant prostatic cells are potential candidates for drug therapy. A limited number of hormones have been tested in this context, in particular somatostatin, bombesin, and serotonin. CONCLUSIONS Neuroendocrine differentiation in carcinoma of the prostate appears to be associated with poor prognosis, tumor progression, and the androgen-independent state, for which there is currently no successful therapy. Therefore, new therapeutic protocols and trials need to be developed to test drugs based on neuroendocrine hormones and/or their antagonists. An evaluation of this new therapeutic approach against prostatic carcinoma with neuroendocrine differentiation, including hormone-refractory cancer, is easily justified, since these tumors are unresponsive to current modes of therapy.

Neuroendocrine differentiation in prostatic carcinoma

Information is presented on prostatic neuroendocrine cells and neuroendocrine differentiation in prostatic carcinoma. The prognostic and therapeutic implications of neuroendocrine differentiation in prostatic carcinoma are reviewed.

Three-month neoadjuvant hormonal therapy before radical prostatectomy: a 7-year follow-up of a randomized controlled trial

Objective  To describe the outcome, assessed as the level of prostate specific antigen (PSA), of a mature (more than half the events recorded) prospective randomized study with a median follow‐up of 82 months of neoadjuvant hormonal therapy before radical prostatectomy, as this has been suggested to decrease the rate of positive surgical margins (i.e. provide greater potential to completely excise the tumour).

Long-Term Prediction of Prostate Cancer Up to 25 Years Before Diagnosis of Prostate Cancer Using Prostate Kallikreins Measured at Age 44 to 50 Years

PURPOSE We examined whether prostate-specific antigen (PSA) forms and human kallikrein 2 (hK2) measured at age 44 to 50 years predict long-term risk of incident prostate cancer. METHODS From 1974 to 1986, 21,277 men age 50 years in Malmö, Sweden, enrolled onto a cardiovascular study (74% participation). The rate of PSA screening in this population is low. According to the Swedish Cancer Registry, 498 were later diagnosed with prostate cancer. We measured hK2, free PSA, and total PSA (tPSA) in archived blood plasma from 462 participants later diagnosed with prostate cancer and from 1,222 matched controls. Conditional logistic regression was used to test for association of prostate cancer with hK2 and PSA forms measured at baseline. RESULTS Median delay between venipuncture and prostate cancer diagnosis was 18 years. hK2 and all PSA forms were strongly associated with prostate cancer (all P < .0005). None of the 90 anthropometric, lifestyle, biochemical, and medical history variables measured at baseline was importantly predictive. A tPSA increase of 1 ng/mL was associated with an increase in odds of cancer of 3.69 (95% CI, 2.99 to 4.56); addition of other PSA forms or hK2 did not add to the predictive value of tPSA. tPSA remained predictive for men diagnosed > or = 20 years after venipuncture, and the predictive value remained unchanged in an analysis restricted to palpable disease. CONCLUSION A single PSA test at age 44 to 50 years predicts subsequent clinically diagnosed prostate cancer. This raises the possibility of risk stratification for prostate cancer screening programs.

The course of neuroendocrine differentiation in prostatic carcinomas: An immunohistochemical study testing chromogranin A as an “endocrine marker”

To gain further insight into the pathogenetic aspects of neuroendocrine (NE) differentiation in prostatic carcinoma, the incidence of NE manifestations was studied during tumour progression in the course of the disease. This follow-up took the form of semiquantitative assessment of the NE cells in carcinomas by means of repeat biopsies at intervals of a few years, correlating the findings with those of conventional histopathological grading of the prostatic tumours. Immunoreactivity to chromogranin A (ChrA) and the Grimelius silver-staining technique were used to detect NE cells. A strong correlation was observed in all the 25 carcinomas studied between the results obtained with the Gimelius silver-staining and those obtained on the basis of immunoreactivity to ChrA. In addition, cells immunoreactive to an antiserum against ChrA found in virtually all sections from 24 cases of hyperplastic prostatic glands were found to be almost invariably argyrophil. Most of the 25 carcinomas underwent marked tumour progression, while the number of NE cells concomitantly increased. An unequivocal relationship can be stated between the degree of NE differentiation and tumour progression in our series of prostatic carcinomas treated with steroids-i.e., the more anaplastic the prostatic carcinoma, the more numerous are its NE cells. ChrA may be considered to be a sensitive marker for NE cells both in hyperplasia and in prostatic carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential Benefits of Intermittent Androgen Suppression Therapy in the Treatment of Prostate Cancer: A Systematic Review of the Literature.

CONTEXT The well-known side-effect profile of androgen-deprivation therapy (ADT) has significant quality-of-life (QoL) implications. Intermittent androgen deprivation (IAD) alternates androgen blockade with treatment cessation to allow hormonal recovery between treatment cycles, thus potentially improving tolerability and QoL. OBJECTIVE To evaluate available evidence regarding the efficacy and tolerability of IAD and assess its value in the treatment of prostate cancer (PCa). EVIDENCE ACQUISITION Key phase 2/3 clinical trials of IAD in PCa published within the last 10 yr were identified on Medline using the terms prostatic neoplasms [MeSH], intermittent androgen suppression, intermittent hormonal deprivation, intermittent androgen deprivation, and intermittent hormonal therapy. Abstracts from trials reported at 2008-2009 conferences were also included. EVIDENCE SYNTHESIS Data from 19 phase 2 studies are discussed with respect to prostate-specific antigen values for treatment suspension/reinitiation, treatment regimens, cycle lengths, testosterone normalisation, and tolerability. Outcome data were promising: Most trials reported an improvement in QoL during the off-therapy periods. Interim data from eight phase 3 trials comparing IAD and continuous androgen deprivation (CAD) support the phase 2 results. IAD generally showed comparable efficacy to CAD with respect to various outcomes, including biochemical progression, progression-free survival, and overall survival. However, IAD was significantly better than CAD with respect to 3-yr risk of progression in one study, and it demonstrated tolerability benefits, particularly with respect to sexual function. Patients most likely to benefit from IAD and factors predictive of poor response are also discussed. CONCLUSIONS IAD seems to be as effective as CAD while showing tolerability and QoL advantages, especially recovery of sexual potency; however, there are as yet insufficient data to determine whether IAD has the potential to prevent or reverse the long-term complications associated with ADT.

Longstanding Groin Pain in Athletes A Multidisciplinary Approach

SummaryIn 21 male athletes (age 20 to 40 years) with longstanding unexplained groin pain, a multidisciplinary investigation was performed in order to reveal the underlying cause. These examinations included general surgery for detection of inguinal hernia and neuralgia, orthopaedic surgery for detection of adductor tenoperiostitis and symphysitis, urology for detection of prostatitis, radiology for performing herniography and plain film of the pelvic bones, nuclear medicine for isotope studies of the pubic bone and symphysis. In 19 patients there was a positive diagnosis for 2 or more of the diseases (10 patients had 2 diseases, 6 patients had 3 diseases, 3 patients had 4 diseases). Two patients had only signs of symphysitis.Our results show the complexity of longstanding groin pain in athletes. It also explains why therapy for one specific disease entity may fail. We conclude that this clinical setting demands the recruitment of a team with experience of different aspects of groin pain.

Parathyroid hormone-related protein: A potential autocrine growth regulator in human prostate cancer cell lines

OBJECTIVE We recently demonstrated that parathyroid hormone-related protein (PTHrP) is widely expressed by human prostate cancer tissue, suggesting that PTHrP might be involved in the growth and development of prostate cancer. To study this further, the production of PTHrP and its biologic effect were investigated using human prostate cancer cell lines. METHODS The cell lines used were one androgen-dependent cell line, LNCaP, and two androgen-independent cell lines, PC-3 and DU-145. PTHrP secreted by cancer cells was measured by radioimmunoassay. The effect of PTHrP on DNA synthesis in these cells was determined by thymidine incorporation assay. RESULTS All cell lines secreted immunodetectable levels of PTHrP in the culture-conditioned media. PC-3 cells secreted significantly higher amounts than the other two cell lines. A synthetic peptide, PTHrP(1-34), stimulated thymidine uptake in PC-3 and DU-145 cells more than threefold the control under serum-free and steroid-free conditions, whereas LNCaP was not affected. However, in the presence of dihydrotestosterone, DNA synthesis of LNCaP cells was stimulated by PTHrP in a dose-dependent manner. Additionally, this PTHrP-induced DNA synthesis was completely neutralized by a validated mouse monoclonal antibody (8B12) raised against PTHrP(1-34). CONCLUSIONS Our data suggest that PTHrP may play a significant role in the growth of prostate cancer by acting locally in an autocrine fashion.

Staging of early prostate cancer: A proposed tumor volume-based prognostic index

Current staging of early prostate cancer separates patients into two groups: those with palpable and non-palpable tumors. Such staging relies on digital rectal examination in making this separation, despite the low sensitivity, low specificity, and low positive predictive value of this method. As an alternative, tumor volume may be useful for staging because of its powerful prognostic ability and its potential to be assessed clinically due to recent advances in imaging techniques such as transrectal ultrasound. In this study, we evaluate the utility of tumor volume in predicting progression of early prostate cancer based on the composite published evidence from nine pathologic studies of serially-sectioned prostates. Logistic regression revealed that tumor volume was a good positive predictor of all measures of tumor progression. There was a 10 percent probability of capsular invasion in tumors measuring about 0.5 cm3; 10 percent probability of seminal vesicle invasion in tumors measuring about 4.0 cm3; and 10 percent probability of metastases in tumors measuring about 5.0 cm3. These composite results suggest that tumor volume is a significant predictor of cancer progression. A volume-based prognostic index is proposed as an adjunct to staging for early prostate cancer.