Recombinant human uteroglobin inhibits the in vitro invasiveness of human metastatic prostate tumor cells and the release of arachidonic acid stimulated by fibroblast-conditioned medium.

Uteroglobin (UG) is a potent immunomodulatory and antiinflammatory secretory protein with high levels detected in human prostate tissue. We used three human prostate cancer cell lines (DU-145, PC3-M, and LNCaP) to test the hypothesis that UG may modulate invasiveness of prostatic carcinoma cells in the Boyden chamber assay for invasion through a reconstituted basement membrane preparation. Fibroblast-conditioned medium was used as the chemoattractant. The most invasive cell line was DU-145, followed by PC3-M, whereas the androgen-dependent LNCaP cell line exhibited extremely low invasive potential. Pretreatment of DU-145 and PC3-M cells for 24 h with 0.01, 0.1, or 1.0 microM recombinant UG had no effect on basal invasiveness but inhibited fibroblast-conditioned medium-stimulated invasion in a dose-dependent manner, reaching up to 60.2 and 87.9% inhibition of DU-145 and PC3-M, respectively. UG had no effect on either cell-reconstituted basement membrane adhesion or simple chemotaxis in the absence of reconstituted basement membrane. UG also strongly inhibited the biphasic release of [14C]-labeled arachidonic acid from fibroblast-conditioned medium-stimulated DU-145 cells. These results suggest that UG may modulate prostate tumor cell invasiveness and that the mechanism may include inhibition of the arachidonic acid signal cascade.

Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases.

Eicosanoids modulate the interaction of tumor cells with various host components in cancer metastasis. Their synthesis involves the release of arachidonic acid (AA) from cellular phospholipids by phospholipase A2 (PLA2), followed by metabolism by cyclooxygenases (COXs) and lipooxygenases (LOXs). This study aimed to identify the pathway(s) of AA metabolism that are required for the invasion of prostate tumor cells. DU-145 and PC-3 human prostate cancer cell lines were used to test the effect of inhibitors of PLA2, COX, or LOX on the invasion of prostate tumor cells through Matrigel in vitro using the Boyden chamber assay and fibroblast-conditioned medium as the chemoattractant. We used nontoxic doses that did not inhibit simple cell motility and did not decrease clonogenic survival. All of the inhibitors caused a significant reduction in AA release from treated cells compared with control cells, which indicated that the treatments were biochemically active. Invasion through Matrigel was inhibited by the PLA2 inhibitor 4-bromophenacyl bromide (4-BPB), the general COX inhibitor ibuprofen (IB), and the highly selective COX-2 inhibitor NS398. Inhibition of cell invasiveness by 4-BPB (1.0 microM), IB (10.0 microM), and NS398 (10.0 microM) was reversed by the addition of prostaglandin E2 (PGE2). PGE2 alone, however, did not stimulate invasiveness, which suggests that its production is necessary for rendering the cells invasive-permissive but not sufficient for inducing invasiveness. In contrast, we found no significant inhibition of invasion of prostate tumor cells treated with esculetin (1.0 microM) or nordihydroguiaretic acid (1.0 microM), which are specific inhibitors of LOX. We also tested the effect of 4-BPB, IB, NS398, and esculetin on the secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), as key enzymes in the proteolysis of Matrigel during invasion, using gelatin zymograms and Western blots. Cells that received 4-BPB, IB, or NS398, but not esculetin showed a significant reduction in the levels of proMMP-2, MMP-9, and proMMP-9 in the culture medium. DU-145 cells did not secrete TIMP-1, and the drugs did not alter the secretion of TIMP-2. This work highlights the role played by COX in disturbing the balance between MMPs and TIMPs in prostate cancer cells, and it points to the potential use of COX inibitors, especially COX-2 selective inhibitors, in the prevention and therapy of prostate cancer invasion.

Photodynamic therapy.

Photodynamic therapy (PDT) is an experimental cancer treatment modality that selectively destroys cancer cells by an interaction between absorbed light and a retained photosensitizing agent. This review discusses the basic components of photodynamic activity and examines the clinical applications of photodynamic therapy in cancer treatment. Treatment of superficial and early-stage malignancies is encouraging. Technologic advancement and further elucidation of the fundamental basis of photodynamic action should permit treatment of more advanced malignancies.

Loss of uteroglobin expression in prostate cancer: relationship to advancing grade.

We have shown previously that the secretory protein uteroglobin (UG) is highly expressed in normal human prostate tissue but this expression is either lost or altered in human prostate cancer cell lines. Treatment of these cell lines with recombinant human UG inhibits their ability to invade human reconstituted basement membrane by up to 90%, implying that the loss of normal UG expression may be related to the invasive potential of prostate cancer. Because invasion represents a critical step in metastasis, the expression patterns of UG could provide a unique and relevant indicator of cancer progression. In this study, we present the immunohistochemical analyses of fresh frozen prostate tissues from surgical specimens taken from 50 patients. Eight slides per patient were analyzed for UG staining. Slides from 26 patients showed evidence of prostate cancer, whereas slides from the remaining 24 patients showed only benign glands. The results demonstrate UG immunoreactivity in normal prostate, benign prostatic hyperplasia, and prostatic atrophy; low but clearly positive expression in prostatic intraepithelial neoplasia; positive expression in cancerous glands of Gleason's pattern

Primary small noncleaved cell lymphoma of kidney.

The kidney is the second most common site for metastasis of lymphoma though it remains asymptomatic and is not commonly detected with cross-sectional imaging studies. Primary renal lymphoma is a very rare lesion whose existence is controversial. The lymphoma reported here presented as a solitary renal mass without any other evidence of disease. Lymphoma should be included in the differential diagnosis for solitary renal masses even though the usual presentation is bilateral. Renal involvement with lymphoma requires a thorough search for extrarenal disease.

Malignant osteoclast-like giant cell tumor of the kidney.

Osteoclast-like giant cell tumors are rare mesenchymal tumors that typically present in osseous tissue and are remarkable because of their slow growth. We report the sixth documented case of a malignant osteoclast-like giant-cell tumor primary to the kidney of an 81-year-old man with a 5-month history of hematuria. Postnephrectomy analysis of the tumor, including immunohistochemical stains and electron microscopy, confirmed the diagnosis. Although the patient died of unrelated complications, metastatic disease was suspected.

Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette-Guérin.

OBJECTIVES: Bropirimine is an oral immunomodulator that has demonstrated anticancer activity in transitional cell carcinoma in situ (CIS) in both the bladder and upper urinary tract. Activity also has been documented in patients after prior therapy with bacille Calmette-Guérin (BCG). To more accurately estimate bropirimine's efficacy in BCG-resistant bladder CIS, a Phase II trial was performed. A separate analysis was performed in additional patients intolerant of BCG toxicity. METHODS: Patients received bropirimine 3.0 g/day by mouth for 3 consecutive days, weekly, for up to 1 year. Bladder biopsies and cytologic examination were performed quarterly. Complete response (CR) required negative biopsy and cytology results. RESULTS: Twenty-one of 86 patients entered were not evaluable. CR was seen in 21 (32%; 95th percentile confidence interval [CI], 21% to 44%) of 65 evaluable patients, including 14 (30%, CI 17% to 43%) of 47 BCG-resistant, and 7 (39%, CI 16% to 61%) of 18 BCG-intolerant patients. Overall, by intent-to-treat analysis, CR was thus seen in 21 (24%) of 86 subjects. Most BCG-resistant patients were failures to BCG without relapse, and had received 12 to 36 (median 12) BCG treatments; intolerant patients had received 4 to 11 treatments (median 6). Response duration ranged from 65 to 810 days, with median not yet reached (but greater than 12 months). Thirteen (15%) of 86 stopped bropirimine due to toxicity. Progression to invasive or metastatic disease during or immediately after therapy was documented in only 4 patients (6%), all nonresponders. CONCLUSIONS: Bropirimine may be an alternative to cystectomy for some patients with bladder CIS who have failed or have not tolerated BCG. Further evaluation to improve responses and durability is warranted.

Photodynamic therapy of rabbit endometrial transplants: a model for treatment of endometriosis.

The potential of photodynamic therapy for endometriosis was evaluated by autotransplantation of endometrial tissue in 15 female virgin New Zealand white rabbits. After maturation, 14 animals were injected intravenously with 10 mg/kg of dihematoporphyrin ether (DHE) and, 24 hours later, transplants were exposed to 630 nm light at 100 to 210 mW/cm2. Sixteen transplants received 100 J/cm2, 10 transplants received 50 J/cm2; 13 untreated transplants served as controls. In the remaining animal that did not receive DHE, 3 transplants were irradiated with 100 J/cm2. Six days after treatment, transplants were harvested with the underlying musculature, and multiple sections were examined histopathologically. Complete endometrial epithelial destruction was seen in 13 of 16 transplants (81%) in the 100 J/cm2 group and in 6 of 10 transplants (60%) in the 50-J/cm2 group. Nearly complete endometrial epithelial destruction was seen in 2 other transplants in each group. No damage occurred in either the 3 transplants that received 100 J/cm2 without prior DHE or in the 13 transplants with DHE and no irradiation. The sensitivity of ectopic rabbit endometrial tissue encourages further evaluation of photodynamic therapy for the treatment of human endometrial disorders.

Fluorescent detection of rabbit endometrial implants resulting from monodispersed viable cell suspensions.

A model for early stage endometriosis was prepared in rabbits by intraperitoneal injection of monodispersed viable endometrial cells. With this model, we have found that DHE fluorescence increases the sensitivity of detection of endometrial tissue. The potential experimental and clinical significance of ectopic endometrial detection by porphyrin fluorescence is enhanced by the recent report of endometrial transplant destruction by PDT. Although caution must be exercised for extrapolation from animal experiments to human conditions, these results encourage further evaluation of photosensitization for the study and potential treatment of disorders involving endometrial tissue.

Preneoplastic lesions of the prostate-clinical, pathological and molecular biological aspects.

Needle biopsy is the mainstay of definitive diagnosis of prostate cancer (PCA). While prostate-specific antigen (PSA) screening has facilitated early diagnosis of PCA, it has also resulted in an increase in the proportion of prostate biopsies showing various preneoplastic lesions (PNLs). At times such lesions are the sole finding in the limited amount of tissue available for assessment in an individual biopsy. Hence accurate identification of these lesions is important to avoid errors in the diagnosis of prostatic malignancy and in patient management. Furthermore, some interesting observations have been made regarding the molecular biological aspects of various PNLs during the last decade. In parallel with anatomic and physiological differences in various human races, racial differences have also been observed regarding the incidence of prostatic intra-epithelial neoplasia. This review focuses on prostatic intraepithelial neoplasia (PIN), atypical adenomatous hyperplasia (AAH) and atypical prostatic glands or atypical small acinar proliferation (ASAP) as putative preneoplastic lesions of the prostate. These lesions are reviewed with reference to their overall incidence, histopathological findings, histological differential diagnosis, clinical significance and molecular biological aspects.

An evolving approach to the surgical management of superficial bladder carcinoma.

Malignant epithelial tumors of the urinary bladder are the fourth most common cancer among men, excluding squamous cell cancer of the skin, and are diagnosed in over 50,000 patients each year. Although the ratio is decreasing somewhat, bladder cancer is three times as common in males than in females and is responsible for over 10,000 deaths annually. White males may have an increased risk compared to Afro-American males though this appears to be true for superficial disease only. Well-documented risk factors for the disease include cigarette smoking, chemical carcinogens, schistosomiasis and chronic urinary tract infections, and a wide variety of occupations concentrated in the chemical, dye, rubber, and textile industries. Occupational exposure appears to be a contributory factor for the disease in nearly 25% of the male population in the United States with bladder carcinoma.

Practical aspects of photodynamic therapy for superficial bladder carcinoma.

Most clinicians equate laser use with direct thermal ablation of tissue, but the precise spatial and temporal control of laser energy has made possible a number of diagnostic and therapeutic applications for these unique light sources that do not involve nonspecific thermal destruction of tissue. One such application is the detection and treatment of tissue with compounds that absorb specific types of light, known as photodynamic therapy (PDT). This article examines the practical aspects of PDT for the treatment of superficial bladder carcinoma with an emphasis on dosimetry. The results presented are encouraging and suggest that patient who have diffuse superficial bladder carcinoma refractive to standard treatment methods should be given the benefit of whole bladder PDT before commitment to radical extirpative surgery. Close attention to dosimetry will be required. PDT remains experimental at this stage; it has been approved for general use only in Canada, though filings with regulatory agencies in both the United States and Europe are anticipated in the near future.

The role of computerized tomography, magnetic resonance imaging, bone scan, and monoclonal antibody nuclear scan for prognosis prediction in prostate cancer.

The single most important issue in determination of treatment options for prostate cancer is accurate assessment of disease extent. Some prediction of probability is afforded by algorithms of patient and tumor characteristics, but definitive detection of disease extension before this decision often remains difficult. This is the critical issue in the healthy 58-year-old man depicted with relatively high-grade, high-volume prostate cancer and a moderately low serum PSA relative to these characteristics. Any combination of choices for evaluation and treatment of this patient is likely to generate some controversy. This article discusses both the changing trends in treatment patterns, which place more emphasis on noninvasive staging and the limited value of conventional radiographic evaluation to detect small volume or microscopic disease. Recent advances in imaging techniques with magnetic resonance and radiolabeled monoclonal antibodies may provide more precise localization of prostate cancer in these clinical circumstances. The relative merits and limitations of the current and selected emerging imaging technology for prostate cancer detection are provided in this article.

Free-beam and contact laser ablation of benign prostatic hyperplasia with the KTP/Nd:YAG laser: efficacy and versatility.

This report details the use of the free-beam Nd:YAG laser alone and in combination with contact vaporization for treatment of benign prostatic hyperplasia. Improvements in urinary flow rates and symptoms were noted along with a high degree of patient satisfaction. The portable KTP/Nd:YAG laser wavelengths and the variety of optical fiber configurations provide versatility to the surgeon. This study further supports the use of laser energy as a means to treat urinary outflow obstruction from prostatic enlargement in selected cases.

Expression of a uteroglobin-like protein in human prostate.

Phospholipase A2 (PLA2) is a key enzyme that initiates the arachidonic acid cascade responsible for the synthesis of prostaglandins and leukotrienes, compounds well known for their inflammatory properties. Inhibition of this enzyme may modulate prostaglandin and leukotriene tissue levels. Uteroglobin is a potent PLA2 inhibitor found in rabbit uterus, prostate, seminal vesicle, and tracheobronchial tree. Tissue from ten human patients undergoing prostatectomy was examined for presence of a uteroglobin-like protein. Seven patients underwent transurethral resection and three had an open prostatectomy. Preoperative diagnosis in nine of the 10 patients was benign prostatic hypertrophy. One suspected, poorly differentiated, adenocarcinoma was confirmed and one unsuspected, well differentiated, adenocarcinoma was discovered. Specimens were submitted for Western blot, electron microscopy with immunogold staining, radioimmunoassay, and immunofluorescence. Six patients had evidence of uteroglobin-like protein, three with high levels (greater than or equal to 1000 pg./mg. protein), two with moderate levels (75 to 250 pg.), one with a low level (less than or equal to 75 pg.). Uteroglobin-like protein was present in all three patients who underwent open prostatectomy and in three of the seven patients with transurethral resections. The uteroglobin-like protein level was 2.5 to five times greater in both prostatic utricle specimens. All four assays corroborated these results. Because rabbit uteroglobin coats sperm and masks spermatic antigenicity in the rabbit female genital tract, this report of biochemical and immunological evidence for uteroglobin-like protein in the human prostate may have implications for human male fertility.

A flexible cystoscope holder/surgical retractor that really works.

Stabilization of equipment during endoscopic procedures frequently presents a problem. Most attempts to anchor a cystoscope have been cumbersome or have afforded transient stability. We describe an easily adjustable, flexible cystoscope holder that may be attached readily and locked in place after positioning. The unique open-sided clamp allows for a firm but delicate grasp of fiberoptic instruments. In addition to this function the flexible cystoscope holder may be adapted easily to become a surgical retractor. Our experience with this instrument has led to greater versatility during endoscopic and open procedures.