Malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor immunoreactivity in the surrounding stroma.

The cellular pathways involved in the pathogenesis of hormone resistance remain unclear. Studies evaluating the role of changes in human androgen receptor (hAR) expression in the progression of prostatic tumors have been inconclusive. Androgenic influence over prostatic growth is mediated via the regulation of interactions between stromal and epithelial cells. We hypothesized that neoplastic transformation of the prostate would be associated with alterations in hAR expression in the adjacent stroma. Using immunohistochemical techniques, we determined hAR positivity in the epithelium and adjacent stroma of sections from 17 benign and 39 malignant prostatic glands. We found that whereas the expression of the receptor decreased in both cellular compartments as the tissues dedifferentiated, the depletion was more pronounced in the stromal nuclei (P<0.0001). However, in sections from both untreated and hormone-resistant prostate cancer tissues, although heterogeneity of hAR expression in malignant epithelia was increased, there appeared to be a unique field effect around the cancerous prostate glands that resulted in a decreased expression of the receptor in the adjacent benign glands and its total loss in the surrounding stroma. The loss of hAR in the stroma adjacent to malignant prostatic epithelium may play an important role in prostate cancer progression. Furthermore, the similarity of the lack of stromal hAR expression in newly diagnosed and hormone-resistant prostate cancer (P = 0.85) may be an indication that the mechanisms responsible for the acquisition of hormone independence are established early in the malignant transformation process.

Further characterization of storage-related alterations in immunoreactivity of archival tissue sections and its implications for collaborative multicenter immunohistochemical studies.

Storage of unstained paraffin slides may lead to the deterioration of specimens and failure to detect cellular proteins immunohistochemically. Although the implication of age-induced alterations on multicenter immunohistochemical studies would be considerable, they have not been investigated previously. The current study was undertaken to examine the effect of this factor further and to explore new ways of overcoming the resultant shortcomings. The authors now report on the immunodetection of a host of antigens in similarly preserved unstained serial paraffin slides obtained from three centers using a panel of eight antibodies. Staining of recently prepared sections from the authors' centers resulted in similar strong patterns in seven of eight antibodies, with one antibody demonstrating variable immunoreactivity. However, storage of unstained paraffin sections at room temperature resulted in a variable but progressive decrease in expression of several tissue antigens. Although the loss in antigenicity was proportional to the length of storage, the effect was reversible if super antibody concentrations were used. The authors conclude that recently prepared paraffin sections from centers with similar fixation protocols have similar immunoreactivity and are suitable for use in comparative multicenter studies. However, in view of the delays that may attend tissue transportation during these projects, the authors suggest that test systems should be checked for age-induced antigen degradation by incubating sections with higher antibody concentrations.

Alterations in the expression of androgen receptor, wild type-epidermal growth factor receptor and a mutant epidermal growth factor receptor in human prostate cancer.

Prostatic carcinogenesis has been associated with alterations in the expression of the androgen receptor (AR) and the epidermal growth factor receptor (WT-EGFR), and over-expression of the constitutively active variant epidermal growth factor receptor (EGFRvIII). Changes in the expression of AR, WT-EGFR and EGFRvIII were evaluated in serial sections from 26 normal and 26 benign hyperplastic and 50 prostate cancer tissues using specific immunostaining techniques. The loss of AR expression in peri-epithelial stroma as prostatic tissues de-differentiated correlated strongly with the depletion of WT-EGFR and with increasing expression of the EGFRvIII in the adjacent epithelium. In contrast, changes in epithelial AR immunopositivity in these tissues correlated weakly with the changes in normal and variant EGFR levels. This is the first report correlating the changes in the expression of these three proteins in archival material from the different human prostatic tissue histotypes. The loss of expression of proteins that contribute to the regulation of prostatic homeostasis (AR and WT-EGFR) correlates strongly with the expression of a constitutively active variant EGF receptor (EGFRvIII) in human prostate cancer. These changes occur at an early stage of neoplastic transformation and may contribute to the progression of the disease to hormone independence.

Current dilemmas in overseas doctors' training.

International medical graduates (IMGs) are a remarkably successful professional group in the United Kingdom making up to 30% of the NHS work force. Their very success and media publicity about general practice and consultant shortages, has led to a large influx of inexperienced doctors seeking training opportunities in competitive specialties. In 2003 a record 15,549 doctors joined the medical register of which 9336 doctors were non-European Economic Area citizens. The number of candidates sitting PLAB part 1 and part 2 in 2003 rose by 267% and 283% respectively compared with 2001. Changes to Department of Health, Home Office, and deanery regulations with expansion of medical schools, implementation of European Working Time Directive, Modernising Medical Careers, and the future role of the Postgraduate Medical Education and Training Board, will have an important impact on IMGs' training. Dissemination of realistic information about postgraduate training opportunities is important as the NHS for some time will continue to rely on IMGs.

Surgical technique for inguinal surgery and its effect on fertility in the Wistar rat model.

This study has explored the relatively neglected effects of operative manipulation of the vas deferens on fertility. Following unilateral vasectomy the contralateral vasa of 52 4-week-old Wistar rats were subjected to 7 different manipulations. After 7 weeks a fertility trial was conducted. All sham operated rats (n = 18) were fertile. Of the remaining 34 rats, 22 (65%) were sterile. All of those with tight ring reconstruction (n = 6) were sterile, due initially to venous obstruction. Nine of 14 rats with acute clip trauma (65%) remained fertile but 11 of 14 (78%) with full mobilisation were sterile owing to extensive avascular fibrosis of the vas deferens. These results suggest that overzealous cord handling and operative technique in the immature animal is counterproductive and leads to vasal occlusion. This may have important repercussions in paediatric inguinal surgery, with a subsequent higher incidence of azoospermia and male subfertility.

Natural history and prognosis of prostate carcinoma in adolescents and men under 35 years of age.

Prostate cancer is extremely rare in men under 35 years of age. The tumour is invariably poorly differentiated and aggressive, with rapidly growing bulky soft tissue metastases and negative tumour markers. Bone metastases develop late and are usually osteolytic. The disease responds poorly to radiation or hormonal therapy and is too advanced at presentation for radical surgery. Chemotherapy appears to be of some benefit, though in the majority of cases death occurs within a year. We describe a 31-year-old man with carcinoma of the prostate. A review of the literature is presented. This is the first patient in whom the epithelial origin of the prostate cancer was confirmed by immunoperoxidase staining with prostatic specific antigen. Plasma prostatic specific antigen was normal despite a large tumour burden and widespread metastases. He did not respond to conventional treatment. The phenotypic expression and biological behaviour of these tumours are distinct from those occurring in men beyond the fourth decade.

Increased survival of patients with massive lymphadenopathy and prostate cancer: evidence of heterogeneous tumour behaviour.

The survival of patients with prostate cancer and radiologically detectable lymph node enlargement has been studied prospectively over an 8-year period. Computed tomography in 108 patients presenting with symptoms, signs or biochemical results suggesting lymphatic spread revealed pelvic or abdominal node masses in 60 patients; in 29 (48%), the masses measured more than 4 cm and the maximum node diameter was 15 cm. Two-thirds of patients had advanced (T3/T4) tumour stage. Following treatment, actuarial survival in all 60 patients with nodal enlargement was 40% at 5 years. Within this group, survival in 22 patients with lymphadenopathy but negative bone scans at diagnosis was significantly better than that of 38 patients with both node and bone disease (70% vs 20% at 5 years). This improvement was related both to an apparent inability of certain tumours initially to progress and seed within bone and to a marked sensitivity of the node masses to subsequent hormonal manipulation. Primary tumour grade was proportionally similar in both groups. Unexpectedly, 6 of the 38 patients with combined disease obtained a complete remission after treatment. The reason for this heterogeneous biological behaviour remains unclear; but these observations underscore the importance of vigorous treatment in all patients with advanced lymph node disease.

Outcome and prognostic factors in patients with advanced prostate cancer and obstructive uropathy.

In a series of 51 patients with prostate cancer and obstructive uropathy, unilateral or bilateral obstruction was identified in 22 (43%) and 29 (57%) respectively. This included a non-functioning kidney in 12 patients. In 86% of patients the T category was advanced. Bone metastases were present in 36 cases (71%); 19 patients (37%) had chronic retention. All patients with metastatic disease underwent hormonal manipulation and 43 underwent transurethral resection of the prostate. External beam radiotherapy, percutaneous nephrostomy and ureteric reimplantation were performed in 4, 5 and 1 patient respectively. Actuarial survival of all 51 patients was 57 and 25% at 2 and 5 years. Presentation with bilateral or non-function did not predict a worse prognosis in comparison with patients with unilateral hydroureteronephrosis. Raised alkaline phosphatase and prostatic acid phosphatase were of no prognostic value, while creatinine reached marginal significance. A positive bone scan and raised urea were strongly predictive of a poor outlook. It was concluded that prostate cancer and obstructive uropathy should not uniformly imply a terminal event, and interventional therapy is justified with a 25% 5-year survival rate.

A comparison of intramuscular ketorolac and pethidine in the alleviation of renal colic.

OBJECTIVE: To compare the analgesic efficacy of a single 30 mg intramuscular dose of ketorolac with that of intramuscular pethidine 100 mg, in a double-blind, parallel-group investigation of patients presenting with pain suggestive of renal colic. PATIENTS AND METHODS: Seventy-six patients (17 women, 15 men; mean age 45.2 years, range 20-80) were allocated by means of a pre-determined randomization schedule to receive ketorolac and 78 patients (20 women, 58 men; mean age 42.1, years range 18-70) to receive pethidine. Data from eight patients in the ketorolac group and six in the pethidine group were excluded from the efficacy analyses because of protocol violations. The severity of each patient's pain was assessed on a four-point verbal rating scale (VRS) and a 10 cm visual analogue scale at pre-dose and at 15 min intervals for the first hour post dosing. The time to first administration of rescue analgesic, up to 24 h following dosing with the study medication, was recorded. Adverse events were elicited by general questioning. RESULTS: Eighty-eight per cent of patients in each treatment group had improved according to the VRS of pain severity 1 h after dosing; the summed pain intensity differences up to 1 h were statistically significantly different in favour of ketorolac (P < 0.05). Fifty-six per cent of patients who were receiving ketorolac required rescue analgesia during the study period compared with 74% receiving pethidine. The incidences of adverse events were lower in the ketorolac group (28%) than the pethidine group (51%). CONCLUSION: Ketorolac can be considered a viable alternative to pethidine for the treatment of renal colic.

Inhibition of the contractile responses of isolated human and rat bladders by clenbuterol.

PURPOSE: We investigated the inhibition of the contractile responses of human continent and unstable detrusor muscle by the beta2 agonist clenbuterol as well as the inhibition of electrical field stimulation evoked contractile responses of isolated rat bladder muscle strips by orally administered clenbuterol. MATERIALS AND METHODS: The contractile responses of human continent and unstable detrusor muscle strips to electrical field stimulation (0.05 milliseconds, 0.5 to 80 Hz.) were measured before and after adding 10(-9) to 10(-4) M. clenbuterol in vitro. In addition, 6 rats per group were dosed orally with 2 microg x kg(-1) clenbuterol daily acutely (1 dose) or chronically (1 dose daily for 8 days), or with distilled water to serve as controls. The contractile response to electrical field stimulation of strips of isolated detrusor muscle was then measured. Serum clenbuterol levels were analyzed in duplicate by enzyme-linked immunosorbent assay and high performance liquid chromatography. RESULTS: In vitro clenbuterol significantly inhibited the electrical field stimulation evoked contractile responses of detrusor muscle strips from unstable but not continent human bladders. A significant inhibitory effect of clenbuterol on the electrical field stimulation evoked contractile response of rat detrusor muscle was observed after chronic but not acute oral dosing (p <0.01). Serum clenbuterol levels measured by enzyme-linked immunosorbent assay and high performance liquid chromatography were not significantly different. CONCLUSIONS: Clenbuterol or related beta2-adrenoceptor agonists may represent a useful therapeutic strategy for detrusor muscle overactivity.

Humoral hypercalcaemia in renal carcinoma due to parathyroid hormone related protein.

Parathyroid hormone related protein (PTHRP) has been implicated in humoral hypercalcaemia of malignancy (HHM). We describe a patient with a renal carcinoma and hypercalcaemia, and for the first time have demonstrated a 4-fold PTHRP concentration gradient across a renal tumour bed. This provides further strong evidence that the primary tumour was the source of the PTHRP. The PTHRP 1-86 content of the tumour tissue was 4.8 ng/g, similar to that previously found in tumours associated with HHM. In PTHRP-secreting tumours, PTHRP may be a useful oncological marker after surgical resection.

UK studies on suramin therapy in hormone resistant prostate cancer.

New insights regarding the biology of hormone resistant CaP have shown that major growth factors other than testosterone are responsible for cellular proliferation of androgen resistant prostate cancer cells. In vitro studies have confirmed the efficacy of growth factor inhibitors such as suramin in reducing cellular proliferation of androgen dependent LNCaP and independent PC-3 CaP cell lines as well as CaP cells obtained by primary culture. Initial clinical trials using high dose suramin (peak serum concentration 250-300 micrograms/ml) as monotherapy in patients with hormone resistant CaP have shown some promise, but the duration of response to therapy has been short lived and suramin toxicity is a problem. To minimize toxicity without reducing anti-tumour activity, studies evaluating its use in combination with other cytotoxic drugs are attractive in CaP. Suramin and doxorubicin, tumour necrosis factor and EMP have shown synergy in vitro. However, in a phase II clinical trial using combination therapy with low dose suramin (140 micrograms/ml) and mitomycin C in 32 patients, there was one complete response and six partial responses, and in 15 patients, the disease had stabilized. The median time to treatment failure was 103 days, and the median survival was 209 days. This regimen caused significant toxicities. The present study has shown that the combination of EMP 280 mg twice a day and suramin 1 g weekly infusions for 6 weeks, compared to EMP 280 mg alone, showed a statistically significant difference in the rate of depression of PSA levels after 3 and 6 months of treatment (p < 0.01) and a statistically significant reduction in bone pain and requirement for analgesics in patients on combination therapy-100% compared to 0% for patients on EMP alone.

Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer.

Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant prostatic tissues were examined at the mRNA and protein levels for the presence of this mutant receptor. The results demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the level of expression of this variant protein increased progressively with the gradual transformation of the tissues to the malignant phenotype. The selective association of high EGFRvIII levels with the cancer phenotype underlines the role that this mutant receptor may maintain in the initiation and progression of malignant prostatic growth, and opens the way for new approaches in the management of this disease including gene therapy.