Use of a solid-phase radioimmunoassay and formalin-fixed whole bacterial antigen in the detection of antigen-specific immunoglobulin in prostatic fluid.

The prostatic fluid of two patients with Escherichia coli bacterial prostatitis was analyzed for evidence of a local immune response to bacterial infection. A solid-phase radioimmunoassay was modified to measure the immunoglobulin (Ig)A and IgG antigen-specific antibody responses to infecting bacteria in serum and prostatic fluid from patient. Formalin-fixed whole E. coli were used as antigen. In one patient with acute E. coli prostatic infection, measurements of antigen-specific antibody confirm the presence of a systemic and local immune response. However, in another patient with a chronic E. coli prostatitis, a primarily local immune response was demonstrated. The response measured in the prostatic fluid appears to be locally stimulated and specific for the infecting bacteria. Furthermore, IgA was the predominant immunoglobulin involved in the local prostatic immune response to infection. Although elevations of serum IgA antigen-specific antibody levels were short-liver after treatment of prostatic infection, local IgA antigen-specific antibodies were detected for as long as 1 yr after the initial infection in both patients studied.

Serum levels of prostate-specific antigen among Japanese-American and native Japanese men.

BACKGROUND: Fourfold to sixfold higher prostate cancer rates in Japanese-American men in the United States compared with Japanese men in Japan have been cited to support a role for environmental risk factors in the etiology of the disease. To examine the hypothesis that part or all of the elevated prostate cancer rates in Japanese-American men may reflect more intensive prostate cancer screening in the United States than in Japan, we compared prostate-specific antigen (PSA) levels in community-based samples of serum from men without prostate cancer. METHODS: Japanese-American men aged 40-85 years and native Japanese men aged 40-89 years with no history of prostate cancer provided sera, respectively, in the United States from March 1990 through March 1992 (n = 237) or in Japan from January 1992 through December 1993 (n = 3522). Age-specific PSA levels were used to estimate the prevalences of undetected prostate cancer in the two populations. RESULTS: Age-specific mean PSA levels were significantly lower in Japanese-Americans than in native Japanese (two-sided P<.001). The prevalence of an elevated PSA level increased with age in both populations and exceeded 5% among men aged 60 years or more. Combined with data on prevalence of detected prostate cancer in the two populations, our data suggest that some 10.0% of Japanese-Americans aged 75 years have prostate cancer, with 31% of that fraction remaining undiagnosed. The corresponding estimates in Japan are a total cancer prevalence of 5.4%, of which 81% has not been detected clinically. CONCLUSIONS: The total cancer prevalence ratio 10.0/5.4 = 1.9 (95% confidence interval = 1.5-2.3) in Japanese-American men compared with Japanese men in Japan suggests an increased risk for Japanese-American men, but of less magnitude than the fourfold to sixfold increase indicated by the incidence data.

Keratin immunoreactivity in the benign and neoplastic human prostate.

Keratin immunoreactivity in the benign and neoplastic human prostate was examined immunohistochemically using two monoclonal antibodies with differing specificities. One of these antibodies stained only the basal cells of the normal and hyperplastic prostatic epithelium, with no reactivity in tumor cells of prostatic adenocarcinoma. The other monoclonal antibody recognized a keratin protein present in all normal and hyperplastic columnar (secretory) epithelial cells, as well as in all cancer cells regardless of degree of tumor differentiation. In addition, the second antibody stained acinar and ductal epithelial cells exhibiting premalignant changes. Our findings indicate that keratin immunoreactivity differs among the epithelial cell populations of the human prostate, probably reflecting expression of different keratin proteins. The distinctive patterns of staining obtained with these two antibodies may assist in distinguishing hyperplastic from neoplastic prostatic epithelium, as well as in the recognition of basal cell hyperplasia, transitional cell metaplasia, and premalignant changes.

Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells.

Cultures of adult human prostatic epithelial and fibroblastic cells were established from normal, benign hyperplastic, and malignant tissues. Vitamin D receptors were detected by ligand binding of [3H]1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in cytosolic extracts prepared from all types of cell cultures as well as from fresh prostatic tissues. Vitamin D receptor transcripts were demonstrated by Northern blot analysis. 1,25-(OH)2D3 inhibited the growth of epithelial cells with half-maximal inhibition at approximately 1 nM. The growth of fibroblasts was also inhibited by 1,25(OH)2D3 but to a lesser extent. This is consistent with the apparently lower level of vitamin D receptors in fibroblasts compared to epithelial cells determined by ligand binding and Northern analysis of RNA transcripts. The growth inhibition of epithelial cells by 1,25(OH)2D3 was irreversible even after a short 2-h exposure, but morphology and keratin expression were not appreciably altered by long-term exposure to the hormone. A physiological role for 1,25(OH)2D3 in the prostate is postulated, and the inhibitory effect of 1,25(OH)2D3 on cancer-derived prostate cells may provide a basis for new preventive or therapeutic strategies.

Elevated levels of insulin-like growth factor-binding protein-2 in the serum of prostate cancer patients.

We have previously documented the presence of specific insulin-like growth factor (IGF)-binding protein (IGFBPs) in seminal plasma and prostate epithelial cell-conditioned medium IGFBP-2 is the prevalent IGFBP in both fluids. To assess whether patients with prostate carcinoma have alterations in serum IGFP levels related to the production of IGFBPs by their tumors, we performed Western ligand blots (WLB) and IGFBP-2 RIA on serum samples from 32 patients with prostate carcinoma of various degrees of clinical severity and compared them to results in 16 healthy age-matched controls. We have also measured serum IGF-I and -II by RIA. The mean level of IGFBP-2 in the prostate cancer patients was 170% of control levels by WLB analysis and 195% of control levels by RIA (P < 0.01). The degree of elevation of IGFBP-2 was related to the stage of the tumor and the levels of the serum tumor marker, prostate-specific antigen. Serum IGFBP-3 levels determined by WLB and serum IGF-I and IGF-II levels measured by RIA after acid chromatography were not different among the subjects with cancer and the normal controls. We conclude that IGFBP-2, which is the main IGFBP produced by prostate epithelial cells, is elevated in the serum of patients with prostate carcinoma, and that the degree of this elevation is related to serum prostate-specific antigen levels and the stage of the tumor. We speculate that prostate-derived IGFBPs may be secreted by prostate tumors and could e of value in understanding the pathophysiology of prostatic tumor growth as well as provide potential diagnostic markers.

Management of infection stones: the Stanford experience.

In summary, 46 renal lithotomies were performed in 40 patients for struvite infection stones. All patients had documented urinary tract infections at the time of surgery; all stones were cultured, demonstrated to contain bacteria and proved crystallographically to be composed primarily of struvite with smaller amounts of apatite. The recurrence rate in a mean followup period of 7 years was 2.5% (one patient). The negligible recurrence rate emphasizes that struvite stones are caused by urea-splitting bacteria, rather than metabolic disorders, and that a comprehensive approach that emphasizes biochemical, bacteriologic, and roentgenographic techniques is more important than the type of surgical procedure used to remove the stones. We believe that our routine of leaving a small polyethylene nephrostomy tube in every patient, combined with postoperative plain-film tomograms regardless of the results of intraoperative radiography, and the liberal use of hemiacidrin irrigation to dissolve any residual struvite particles with their entrapped bacteria, accounts for the virtual absence of stone recurrences in our series.

The natural history of symptomatic recurrent bacteriuria in women.

In 23 adult women having uncomplicated recurrent urinary tract infections treated with 10 days of appropriate antibiotic for each infection, the following findings were noted. 1. The attack rate was 0.17 infections per month. 2. 94% of infections has associated symptoms. 3. 73% of symptomatic episodes had an associated infection. 4. 21% of infections had less than 10(5) bacteria per ml. 5. 34% of all infections were followed by an infection-free interval of at least six months and averaged 12.8 months. All but one patient had at least one infection-free interval. 6. Long infection-free intervals were followed by further infections; a remission is not a cure. 7. Between infection-free intervals the infections tended to occur in clusters with an attack rate of 0.47 infections per month. 8. Prophylaxis is less costly if begun at the second infection within a six-month period.

Effect of combined transient androgen deprivation and irradiation following radical prostatectomy for prostatic cancer.

PURPOSE: To evaluate whether transient androgen deprivation improves outcome in patients irradiated after radical prostatectomy for locally advanced disease, persistent or rising postoperative prostate specific antigen (PSA), or local recurrence. METHODS AND MATERIALS: Records of 105 consecutive patients who were treated with pelvic irradiation after radical retropubic prostatectomy between August 1985 and December 1995 were reviewed. Seventy-four patients received radiation alone (mean follow up: 4.6 years), and 31 received transient androgen blockade with a gonadotropin-releasing hormone agonist (4) androgen receptor blocker (1) or both (24) beginning 2 months prior to irradiation (mean follow-up 3.0 years) for a mean duration of 6 months. Two of these patients were excluded from further analysis because they received hormonal therapy for more than 1 year. Patients received a prostatic fossa dose of 60-70 Gy at 2 Gy per fraction; 48 patients also received pelvic nodal irradiation to a median dose of 50 Gy. Survival, freedom from clinical relapse (FFCR), and freedom from biochemical relapse (FFBR) were evaluated by the Kaplan-Meier method. Biochemical relapse was defined as two consecutive PSA measurements exceeding 0.07 ng/ml. RESULTS: At 5 years after irradiation, actuarial survival for all patients was 92%, FFCR was 77%, and FFBR was 34%. FFBR was significantly better among patients who received transient androgen blockade before and during radiotherapy than among those treated with radiation alone (56 vs. 27% at 5 years, p = 0.004). FFCR was also superior for the combined treatment group (100 vs. 70% at 5 years, p = 0.014). Potential clinical prognostic factors before irradiation did not differ significantly between treatment groups, including tumor stage, summed Gleason histologic score, lymph node status, indication for treatment, and PSA levels before surgery or subsequent treatment. Multivariate analysis revealed that transient androgen deprivation was the only significant predictor for biochemical failure. CONCLUSION: This retrospective study of irradiation after radical prostatectomy suggests that transient androgen blockade and irradiation may improve freedom from early biochemical and clinically evident relapse compared to radiotherapy alone, although more prolonged follow-up will be needed to assess durability of impact upon clinical recurrence and survival rates.

The histology of interstitial cystitis.

Several studies have reported histologic findings in interstitial cystitis (IC) bladder biopsy specimens. However, these studies used a variety of criteria to define IC, which may explain the variation noted in the histologic changes. Clinical experience shows that these biopsy specimens are often not helpful in confirming the diagnosis. Our study was designed to examine the histologic features identified in bladder biopsy specimens from patients with IC and compare them with biopsy specimens from a control population. Although IC patients as a group had a higher incidence and degree of denuded epithelium, ulceration, and submucosal inflammation, none of these findings was pathognomonic. In addition, these findings occurred only in interstitial cystitis patients with pyuria or small bladder capacity. The inflammatory infiltrate seen in IC was composed predominantly of lymphocytes, with increasing numbers of plasma cells as the degree of inflammation increased. There was no specific predilection for the inflammatory infiltrate to be perineural. Submucosal inflammation was associated with denuded epithelium, ulceration, pyuria, and a clinical response to therapy suggesting a pathophysiologic relationship. Epithelial and basement membrane thickness, submucosal edema, vascular ectasia, fibrosis, and detrusor muscle inflammation and fibrosis were not significantly different in the IC and control patients. These findings suggest that IC is a chronic submucosal inflammatory disease, at least in those patients with small bladder capacities or pyuria. IC is best diagnosed from its clinical features; the histologic changes identified in the bladder biopsy play a supportive role in this diagnosis. Mast cells play a limited role in the diagnosis of IC.

Capsular penetration in prostate cancer. Significance for natural history and treatment.

We established the location and extent of complete capsule penetration by prostate cancer in 176 radical prostatectomy specimens and related these findings to cancer volume, location of positive surgical margins, and presence of nodal metastases or seminal vesicle (SV) invasion. Extent of capsule penetration, cancer volume, and positive nodes/SV were strongly intercorrelated. It could not be shown that capsule penetration was related to prognosis independently of its correlation with cancer volume. Twelve cubic centimeters was a critical cancer volume; above that, combinations of extensive capsule penetration, positive surgical margins, and positive nodes/SV were almost universal. In cancers under 12 cc, positive surgical margins were only moderately correlated with cancer volume; they often represented surgical resection into the capsule rather than a complication of capsule penetration by tumor and were most common at the apex, where dissection is most difficult. In non-transition zone cancers (148 cases), capsule penetration was most common posterolaterally, where nerves penetrate the capsule. In transition zone cancers (28 cases), capsule penetration was much less common and was located more anteriorly. Apical positive margins were also relatively common in transition zone cancers, but seminal vesicle invasion was never seen.

Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread.

For 104 prostate glands obtained at radical prostatectomy for adenocarcinoma, we mapped the tumor outline and determined the tumor volume, grade, and location relative to the transition zone boundary and location of the central zone. Among the 88 cancers whose probable zone of origin could be identified, 68% arose in the peripheral zone, 24% arose in the transition zone, and 8% arose in the central zone. Transition zone carcinomas had usually been diagnosed by transurethral resection (TUR) and often appeared to arise within BPH nodules; only two of 67 non-transition zone carcinomas had been diagnosed at TUR. Two-thirds of 21 transition zone cancers showed a distinctive histologic appearance; they were made up of columnar clear cells lining glands of widely variable size and contour. The transition zone boundary appeared to act as a barrier to the spread of non-transition zone carcinomas. We conclude that carcinoma typically arises in the region of the prostate that is susceptible to benign prostatic hyperplasia and that the great majority of Stage A (TUR) cancers are transition zone cancers. Non-transition zone cancers detectable at TUR are predominantly large tumors that are poorly differentiated and lack the clear cell histologic pattern.

Utilization of bone scans in conjunction with prostate-specific antigen levels in the surveillance for recurrence of adenocarcinoma after radical prostatectomy.

Follow-up evaluation of patients who have undergone radical prostatectomy routinely consists of serial bone scintigraphy and, more recently, prostate-specific antigen (PSA) levels. The utility of serial bone scans in combination with PSA levels is retrospectively reviewed in 118 men treated by radical prostatectomy for clinical Stage A or B disease who, at the time of surgery, had no evidence of metastatic disease. Of the 118 patients, 75.4% had no abnormality on either test (mean follow-up 32.4 mo), 9.3% demonstrated a detectable or rising PSA level with negative bone scan (mean follow-up 35 mo), and 8.5% exhibited a detectable and or rising PSA level and positive bone scan (mean follow-up 30.7 mo). Follow-up bone scans were read as either positive or indeterminate with undetectable PSA levels in 6.8% of patients (mean follow-up 27.3 mo). Critical review of the equivocal studies suggests that postoperative PSA levels more truly represent the clinical situation than bone scans. Following radical prostatectomy, routine bone scintigraphy provides little additional information when PSA levels are negative. If PSA becomes detectable or the patient develops symptoms, bone scintigraphy should then be performed.

Evolving patterns of tissue composition in benign prostatic hyperplasia as a function of specimen size.

The tissue composition in 36 transurethral resections and four prostate enucleations for benign prostatic hyperplasia (BPH) was quantitated by computerized morphometric techniques using 15 morphologic categories. Data were compared between seven consecutive weight ranges. Nodules of glandular and/or stromal tissue comprised only 5% of tissue in the smallest resections, while bladder neck and anterior fibromuscular tissue represented more than half the specimen. Non-nodular prostatic tissue from the transition zone was the dominant resected component in all but the largest specimens (enucleations) where nodules comprised most of the tissue. Though nodules comprised only 22% of the largest transurethral resections, their contribution to hyperplasia increased more rapidly than any other component. Glandular nodules with a high ratio of epithelium to stroma dominated at all weight ranges. It was concluded that tissue resected for BPH is quite heterogeneous, that nodules comprise most of the tissue only in specimens over 50 g in weight, and that the most common hyperplastic component is histologically normal tissue. Benign prostatic hyperplasia undergoes morphologic evolution with increasing weight, and epithelial-rich nodules are the most rapidly evolving component.

Microcarcinoma in the prostate: its association with duct-acinar dysplasia.

In a series of 100 prostatectomy specimens obtained for adenocarcinoma, 107 additional incidental microscopic (less than 0.05 cm3) carcinomas were identified. Their morphologic features including location, histologic grade, and associated premalignant changes were documented. In 51 cases there was strong evidence of transition between microcarcinoma and the premalignant lesion, duct-acinar dysplasia. Invasive cancer was usually related to dysplasia through a characteristic intermediate morphologic stage of transitive glands. These glands were smaller than prostatic ducts; they appeared to arise by budding from dysplastic duct walls and showed the same distinctive lining epithelium. They were distinguished from invasive glands by their pseudo-stratified epithelial lining and by consistent association with a sparse, discontinuous basal cell layer. Cytoplasmic differentiation at the point of junction of invasive cancer with transitive or dysplastic glands was studied by immunohistochemical staining for the differentiation markers prostate-specific antigen and pepsinogen II, and staining for mucin. Markedly reduced cytoplasmic differentiation was common in dysplastic and transitive glands. Invasion often coincided with an abrupt increase in cytoplasmic differentiation with expression of ectopic differentiation products. This sequence of biologic changes should be tested in other carcinomas where the exact point of invasion can be identified.

Mucinous differentiation in prostatic adenocarcinoma.

Morphologic and histochemical analysis was performed on 33 carcinomas with mucin-secreting areas that were identified among 100 carcinomas from radical prostatectomy specimens. The most common mucin-secreting pattern was Gleason grade 3, which usually showed distinctive luminal distention. The "colloid carcinoma" pattern with mucinous lakes was the only histologic pattern that was unique to mucinous areas. Its frequent association with cribriform Gleason grade 4 carcinoma suggests that it is a variant of grade 4 cancer, whose deviant appearance is a consequence of mucus hypersecretion. Collagenous stromal micronodules, found in 13 cases, are a previously undescribed and distinctive pattern thought to be a stromal reaction to contact with acidic extraluminal mucin. In grade 3 carcinoma, glands that secreted into the stroma rather than the gland lumen accounted for the stromal mucin, which appeared to lead to micronodule formation. In the grade 4 "colloid cancer" pattern, collagenous micronodules sometimes completely obliterated mucinous lakes, isolating residual cribriform glands in a "pseudo-grade 3" pattern. Lectin histochemical staining showed similar sialated and/or sulfated acidic mucin in all cases. Immunohistochemical staining showed downregulation of several differentiation antigens accompanying the alteration to mucinous differentiation.

Immunohistochemical evidence for impaired cell differentiation in the premalignant phase of prostate carcinogenesis.

Epithelial cell differentiation was evaluated in 15 samples of duct-acinar dysplasia, a putative premalignant lesion of the prostate, through immunohistochemical staining for five differentiation markers. Prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), Leu-7, pepsinogen II (PG II), and tissue plasminogen activator (t-PA) are all constituents of seminal fluid that are produced by prostatic epithelium. Dysplasia foci were classified into three grades of severity and their locations mapped by camera lucida drawings of each slide. The degree of abnormal staining with each antibody was recorded on the map, and its correlation with dysplasia grade was evaluated. PSA, PAP, and Leu-7 staining were reduced in dysplasia and often absent in severe dysplasia, indicating that reduced differentiation is an early change in prostatic carcinogenesis. PG II and t-PA stains were sometimes positive in a region where they are usually absent, suggesting that deregulation of differentiation markers may accompany reduction in differentiation in these preneoplastic lesions.

Endoscopic suspension of vesical neck for urinary incontinence.

Surgically curable urinary incontinence in women is achieved by restoration of the vesical neck from a dependent position in the pelvis to one high behind the symphysis pubis. Endoscopic suspension, which accomplishes this by elevating the internal vesical neck on both sides with two permanent buttressed nylon loops is effective for correcting primary or recurrent stress urinary incontinence and even total incontinence in over 90 per cent of patients. Technical advantages over retropubic vesical neck suspensions include less postoperative morbidity, functional measurements and anatomic visualization of a restored vesical neck during the procedure, easy access to the surgically difficult pelvis, and simultaneous repair of significant rectoceles or substantial cystoceles through the same operative field.

Interstitial cystitis: early diagnosis, pathology, and treatment.

In a retrospective review, 52 patients with interstitial cystitis have been studied. Patients with persistent lower tract irritative symptoms, repeatedly sterile urine, and negative urine cytology must be suspected of having interstitial cystitis, and a diagnosis of urethral syndrome in such patients is highly questionable until cystoscopy under anesthesia has been performed. We believe that the finding of multiple petechia-like hemorrhages (glomerulations) on the second distention of the bladder is the hallmark of interstitial cystitis, and that a reduced bladder capacity and a Hunner's ulcer represent a different (classic) stage of this disease. In all stages, the characteristic histologic finidng is submucosal edema and vasodilation. The presence of eosinophils and mast cells is variable, and even in the classic disease the muscularis often appears to be normal. Immuno fluorescent studies and laboratory tests, including the fluorescent antinuclear antibody test (FANA), have not helped us to diagnose (or investigate) interstitial cystitis. Bladder instillations with a 0.4 per cent solution of oxychlorosene sodium (Clorpactin WCS-90) have provided remarkable relief for many patients with this disease, particulary those with the classic form.

Unilateral medullary sponge kidney: cause of persistent bacteriuria.

A patient with twenty years of persistent bacteriuria secondary to unilateral medullary sponge kidney, and in whom no antibiotic would sterilize the urine, was cured of her infection by nephrectomy in the presence of contralateral hydronephrosis. A review of the literature shows 23 cases of unilateral medullary sponge kidney in which nephrectomy or partial nephrectomy was apparently equally successful, although no bacteriologic follow-up data are given.

Renal perfusion-excretion determination as "split-function study" in diagnosis of segmental renal artery stenosis in a child.

A case of renal artery stenosis (RAS) is described in a seven-year-old boy. The preoperative renal perfusion-excretion determination (RPED) was diagnostic of renal artery stenosis. In addition, after corrective surgery the postoperative RPED showed relatively normal values with a decrease in tubular transport time (TTT), an anticipated finding in patients with corrected RAS. This patient also represents an interesting example of intrarenal collateral vessel formation in an ischemic kidney.