Muscarinic cholinergic receptors promote growth of human prostate cancer cells.

BACKGROUND: Recent evidence suggests that muscarinic receptors induce mitogenesis in cells capable of undergoing cell proliferation. Human prostate gland is innervated by the autonomic nervous system and muscarinic receptors have been localized in the prostate gland. METHODS: Effects of carbachol (a stable analog of acetyl choline) on DNA synthesis of LNCaP cells (a human prostate cancer cell line) and primary prostate cells was examined. The DNA synthesis in the cultured cells was assessed using techniques of 3H-thymidine incorporation and bromodeoxyuridine (BrdU) incorporation immunocytochemistry. RESULTS: Carbachol induced a significant increase in BrdU- and 3H-thymidine incorporation of LNCaP cells. The effect of carbachol was completely reversed by atropine, a selective muscarinic antagonist. Subtypes of muscarinic receptors mediating carbachol-induced DNA synthesis were identified using selective receptor subtype antagonists. Pirenzepamine and gallamine did not affect carbachol action on LNCaP cells but diphenylpyralamine, an M3 receptor antagonist, completely blocked carbachol-induced DNA synthesis. Carbachol also stimulated DNA synthesis in primary prostate cells. Prostate carcinoma (PC)-derived primary prostate cells displayed a dramatically greater response to carbachol (a ten-fold increase in DNA synthesis) as compared to benign prostate hypertrophy (BPH)-derived cells (a two-fold increase in DNA synthesis). CONCLUSIONS: M3 receptors stimulate the proliferation of LNCaP cells, BPH-derived and PC-derived primary prostate cells. A dramatically higher response to carbachol by PC-derived prostate cells suggests that M3 receptors may be up-regulated in PC. M3 receptors may play a significant role in PC tumors growth and androgen-independent tumor progression.

Measuring disease-specific health status in men with benign prostatic hyperplasia. Measurement Committee of The American Urological Association.

In preparation for an outcomes study of benign prostatic hyperplasia (BPH), two measures of disease-specific health status were developed to supplement a symptom score and overall health status measures. The symptom problem index (SPI) captures how troublesome patients find their urinary symptoms. The BPH impact index (BII) measures how much their urinary problems affect various domains of health. A prospective revalidation of the refined instruments (N = 108 BPH patients and 50 controls) documented that both indices had good internal consistency (Cronbach's alpha = 0.88 and 0.79, respectively) and test-retest (r = 0.88 for both) reliabilities, correlated strongly with symptom scores (r = 0.86 and 0.77), and discriminated between BPH and control subjects (receiver-operating characteristic areas = 0.87 and 0.85, respectively). These indices were nearly as responsive as symptom scores in 50 men actively treated for BPH, and much more responsive than a non-disease-specific General Health Index (GHI), a Mental Health Index (MHI), and an Activity Index (AI). Finally, these measures capture most of the health status significance of BPH symptoms. In linear regression models constructed to predict scores on the GHI, MHI, and AI, symptom scores added little explanatory power to the SPI and, particularly, to the BII. These measures help clarify how BPH affects overall health status and function. Such measures have an important role to play in studies of the outcomes of treatment for BPH, and probably for other conditions that interfere with health status and function.

Calcitonin stimulates growth of human prostate cancer cells through receptor-mediated increase in cyclic adenosine 3',5'-monophosphates and cytoplasmic Ca2+ transients.

Our recent study has shown that a calcitonin (CT)-like immunoreactive substance(s) is secreted by cultured prostate cells, and secretion of this material is significantly higher in malignant than in benign prostate cells. To test the hypothesis that prostatic CT may serve as a paracrine/neuroendocrine factor, the present study investigated for the presence of CT receptors in the prostate gland. Signal transduction mechanisms activated by CT were examined, and the study also tested its effects on prostate cell proliferation, as assessed by [3H]thymidine incorporation. The results show that high affinity binding sites for [125I]salmon CT were present in plasma membrane fractions of human prostate tissue specimens and the prostate cancer LnCaP cell line. The maximal binding for CT receptors was 564 +/- 163 fmol/mg protein, and the apparent dissociation constant (Kd) was 2.89 +/- 0.58 nM. CT induced a dose-dependent increase in cAMP generation in LnCaP cells. The effect of CT on cytoplasmic Ca2+ transients of LnCaP cells was examined by videofluoromicroscopy. CT (100 nM) induced a rapid and sharp increase in cytoplasmic Ca2+ concentrations in LnCaP cells. The CT-induced increase in cytoplasmic Ca2+ transients appeared to be biphasic (spike and plateau), and this increase was 4- to 10-fold during the initial phase. The profile of this response is characteristic of the activated Ca2+/phospholipid second messenger system. CT also caused a dose-dependent increase in [3H]thymidine incorporation by LnCaP cells. These results suggest that a locally secreted CT-like peptide(s) induces mitogenic responses in prostate cancer cells. This action seems to be mediated through activation of signaling mechanisms, leading to the accumulation of two different second messengers, cAMP and calcium. Activation of dual second messenger systems by CT receptors suggests that the peptide hormone may play an important role in rapidly growing cell populations during the process of tumor formation.

Selection of the surgical procedure for management of benign prostatic hyperplasia.

The standard method of surgically treating obstructing benign prostatic hyperplasia is transurethral resection of the prostate. It is the gold standard by which other therapeutic modalities, medical and surgical, should be measured. In those patients with larger prostate, open prostatectomy is the procedure of choice. Transurethral incision of the prostate has been under-utilized and would be useful in the majority of patients. The procedure is best used in patients who have glands under 30 grams and preferably around 20 grams in size. Therefore, in a given patient, the surgical procedure will be dependent upon the patient's general condition, the anatomy and size of his prostate, and the surgeon's skill and experience. Newer less invasive procedures are currently under evaluation and must be compared to transurethral prostatectomy, so that we can determine their possible role in the armamentarium of the urologist. Prospective randomized studies, comparing these new modalities to TUR-P, are needed, particularly with long-term outcome data.

Comparison of patient-controlled analgesia versus intramuscular narcotics in resolution of postoperative ileus after radical retropubic prostatectomy.

Patient-controlled analgesia has become standard practice after major abdominal operations. The benefits of patient-controlled analgesia have been well documented. However, its possible effect of prolonging postoperative ileus has not been well examined. To determine if patient-controlled analgesia prolongs postoperative ileus when compared to conventional intramuscular narcotics, a retrospective review of length of postoperative ileus in 98 consecutive patients (62 using patient-controlled analgesia and 36 using intramuscular narcotics) undergoing bilateral pelvic lymphadenectomy and radical retropubic prostatectomy was done. The patients receiving patient-controlled analgesia resolved the postoperative ileus an average of 1.0 day later than the intramuscular injection group (5.2 days versus 4.2 days p < 0.0001). Overall hospital stay was not significantly affected. Our results show that patient-controlled analgesia use prolongs postoperative ileus.

Combined cholecystectomy and radical genitourinary cancer surgery.

We have routinely performed simultaneous cholecystectomy in patients with cholelithiasis undergoing selected radical genitourinary cancer surgery. A total of 31 patients have undergone cholecystectomy at the time of radical nephrectomy (25), radical cystectomy (5), and radical prostatectomy (1). Operative time was increased twenty-five to forty-five minutes. There was no significant increase in blood loss, postoperative total bilirubin, or number of complications. No complications were directly attributable to the cholecystectomy except for 1 patient who had prolonged drainage from a closed suction drain in the gallbladder fossa. We conclude that concomitant cholecystectomy at the time of radical genitourinary cancer surgery does not significantly increase morbidity and recommend that it be performed in the presence of cholelithiasis.

Prostate cancer: results of external irradiation.

From 1975 to 1982, 205 patients with local prostate cancer were treated at the radiation oncology department, the University of Kansas Medical Center, Kansas City, Kansas. Patients' median age was 73 years. All of the patients were staged according to American Urologic staging criteria. Twenty-eight patients had stage A2 cancer, 91 patients had stage B cancer, and 86 patients had stage C cancer. All patients were treated using megavoltage radiation (dosage range: 6000 cGy to 7100 cGy). The follow-up period ranged from a minimum of 8 years to a maximum of 15 years (median: 9.4 years). The clinical local control was 96% for stage A2, 94% for stage B, and 90% for stage C disease. The overall and disease-free survival rates were 71% and 60%, respectively. Fourteen patients developed moderate complications with one patient (0.5%) requiring surgical intervention. The local control and survival rates reported in this study are comparable with surgical results, suggesting that external beam irradiation in prostate cancer is safe and effective.

The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association.

A symptom index for benign prostatic hyperplasia (BPH) was developed and validated by a multidisciplinary measurement committee of the American Urological Association (AUA). Validation studies were conducted involving a total of 210 BPH patients and 108 control subjects. The final AUA symptom index includes 7 questions covering frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete emptying and urgency. On revalidation, the index was internally consistent (Cronbach's alpha = 0.86) and the score generated had excellent test-retest reliability (r = 0.92). Scores were highly correlated with subjects' global ratings of the magnitude of their urinary problem (r = 0.65 to 0.72) and powerfully discriminated between BPH and control subjects (receiver operating characteristic area 0.85). Finally, the index was sensitive to change, with preoperative scores decreasing from a mean of 17.6 to 7.1 by 4 weeks after prostatectomy (p < 0.001). The AUA symptom index is clinically sensible, reliable, valid and responsive. It is practical for use in practice and for inclusion in research protocols.

Correlation of the American Urological Association symptom index with self-administered versions of the Madsen-Iversen, Boyarsky and Maine Medical Assessment Program symptom indexes. Measurement Committee of the American Urological Association.

We correlated the American Urological Association (AUA) symptom index with other indexes that have been used to measure symptoms for benign prostatic hyperplasia (BPH) and compared their psychometric properties. A self-administered questionnaire that allowed derivation of AUA, Maine Medical Assessment Program, Madsen-Iversen and Boyarsky symptom scores was completed by 76 men with clinically defined BPH, 59 younger control subjects, and 27 men before and after prostatectomy. The scores from the 4 indexes were strongly correlated (r = 0.77 to 0.93). All 4 indexes had good internal consistency and test-retest reliabilities. All indexes were predictive of patient global ratings of the degree of bother from the urinary condition. The AUA index discriminated BPH patients from controls significantly better than the Maine Medical Assessment Program index, and equivalently to the Madsen-Iversen and Boyarsky indexes (despite having fewer items). All 4 indexes were responsive when BPH patients underwent prostatectomy, although the AUA and Madsen-Iversen indexes were significantly more sensitive.

Presence of calcitonin-like immunoreactivity (iCT) in human prostate gland: evidence for iCT secretion by cultured prostate cells.

Immunoreactive calcitonin (iCT) has been detected in human prostate tissue extracts as well as seminal plasma. The present studies were undertaken to examine whether iSCT (immunoreactive salmon CT-like human peptide) co-exists with iHCT (thyroid CT-like substance) in human prostate tissue extracts, and whether these substances are secreted by primary prostate cells in culture. Since the local secretion of these substances seems to increase in some neoplasms, a second objective of the study was to examine whether basal secretion of iCTs from primary prostate cells is increased in carcinoma. The present results have shown that both iHCT and iSCT were present in prostate tissue extracts. The mean iHCT levels in extracts of benign hyperplastic prostates (BPH) were 0.59 ng/g prostate, and these were significantly lower than iHCT concentrations in prostatic carcinoma (PC) (2.53 ng/g). No significant differences in their iSCT contents were observed. However, the results from culture of over 90 individual prostate tissue specimens from BPH or PC indicate that primary prostate cells secreted detectable quantities of iSCT and the basal release of this material from PC prostate cultures was almost four-fold higher than that from BPH prostate cultures. These results suggest that a CT-like immunoreactive material is secreted by primary prostate cells in culture, and the basal secretion of this material is significantly higher in PC cells as compared to BPH cells. Endogenous secretion of prostatic CT, and the elevation of its expression in PC suggest that it may serve as a regulatory factor in the pathophysiology of the prostate gland.

Use of the Collings knife electrode for percutaneous access in difficult endourology cases.

Percutaneous endourological techniques for the removal of upper urinary tract calculi and for the closed treatment of ureteropelvic junction obstruction are well described. These techniques are dependent on satisfactory percutaneous access and nephrostomy tract dilation. We used the Collings knife electrode for the creation of a nephrostomy tract in 17 patients (19 renal units) with difficult percutaneous access due to scarification, or the inability to advance a guide wire sufficiently for stabilization and dilation by conventional means. A nephrostomy tract was established successfully in all 19 procedures requiring an average of 12 minutes. Two major complications occurred that required blood transfusion and an open operation. Endourological treatment was successful in the remaining 17 cases. We believe that this technique provides an alternative to an open operation when standard access and dilation methods for endourological procedures are unsuccessful.

Testicular neoplasms: seminoma.

From 1969 to 1984, 58 patients with a diagnosis of testicular seminoma were seen and treated at the University of Kansas Medical Center. The median age was 34 years (range of 20 to 62 years). The American Joint Committee on Cancer Staging System was followed: stage I (34 patients); stage II (6); stage III (8); and stage IV (10). Forty-two patients had typical seminoma, and 16 had anaplastic histology. Nine patients had elevated B subunit of human chorionic gonadotropin, and nine had a history of cryptorchidism. Fifty-six patients received radiation treatment, and seven received chemotherapy with or without radiation. The median follow-up was 7 years (range 3 to 16 years). The overall disease-free (absolute) survival according to stage was: stage I, 91% (100%); stage II, 66% (80%); stage III, 75% (85%); and stage IV, 50% (50%). There were no late complications. The survival for patients with anaplastic histology or with elevated B subunit of human chorionic gonadotropin was not significantly different from that of typical seminoma.

Transurethral prostatectomy.

Transurethral prostatectomy is one of the most common operations today. In the United States, more than 90 per cent of patients with bladder outlet obstruction from BPH have their surgery done transurethrally. The operation is associated with a very low mortality rate, and the immediate postoperative results are excellent. The long-term results also appear to be satisfactory according to chart review data. However, insurance claims data suggest higher later mortality and reoperation rates than have been reported previously. Further studies, such as a randomized trial, will be necessary to evaluate the long-term outcome of transurethral prostatectomy further.

Analysis and management of chronic testicular pain.

A total of 45 patients was seen in consultation between May 1980 and April 1989 for chronic unilateral or bilateral orchialgia, defined as intermittent or constant testicular pain 3 months or longer in duration that significantly interferes with the daily activities of the patient so as to prompt him to seek medical attention. We analyzed 34 patients available for followup in terms of socioeconomic parameters, etiology and duration of pain, associated urological symptomatology, specific treatment and results of therapy. Of the patients 31 underwent surgical treatment after failing medical management (24 orchiectomies, 10 epididymectomies, 5 orchiopexies and 1 hydrocelectomy). Of 10 patients who underwent epididymectomy 9 underwent subsequent orchiectomy as definitive treatment. Of 15 patients who underwent inguinal orchiectomy 11 (73%) reported complete relief of pain, while 4 had partial relief. Of the 9 patients who underwent scrotal orchiectomy 5 (55%) reported complete relief of pain, 3 had partial relief and 1 denied improvement. On the basis of these results we recommend inguinal orchiectomy as the procedure of choice for the management of chronic testicular pain when conservative measures are unsuccessful.