PubMed Health⌕ Search

Biomedical subjects

M A Hudson

Publications and source records attributed to M A Hudson.

At least 19 recordsLinked to original sources
PubMed1999

Urokinase (u-PA) and the u-PA receptor. Modulation of in vitro invasiveness of human bladder cancer cell lines.

BACKGROUND: Urokinase (u-PA) and the u-PA receptor (u-PAR) influence tumor invasion and metastasis. PURPOSE: The purpose of this study is to determine whether u-PAR display in 4 human bladder cancer cell lines (RT4, 253J, EJ and T24) can be modulated with substances including phorbol 12-myristate 13-acetate, interferon gamma, epidermal growth factor, and transforming growth factor beta and to correlate changes with u-PAR expression with the ability of these cells to invade artificial basement membrane (Matrigel). METHODS: u-PAR display was determined using flow cytometry and immunohistochemical staining with an anti-u-PAR monoclonal antibody (Mab3936). Matrigel invasion chamber assays were used to assess the invasive capacity of the cell lines. RESULTS: The T24, EJ and 253J cells expressed the u-PAR while the RT4 cells did not. The EJ cells (expressing the highest u-PA antigen levels and the u-PAR) invaded Matrigel. The T24 cells, which expressed the u-PAR but do not produce u-PA, invaded Matrigel only when pretreated with high molecular weight urokinase (HMW u-PA). HMW u-PA pretreatment of EJ and 253J cells also enhanced their invasive potential. Blocking u-PA/u-PAR attachment with an anti-u-PAR monoclonal antibody (Mab3936) inhibited invasion. Modulation of u-PAR expression on cell lines displaying the u-PAR directly affected in vitro invasiveness of the cell lines. The RT4 cells which lack the u-PAR were not invasive under conditions tested. Thus, bladder cancer cell lines require both u-PA and the u-PAR to invade Matrigel and modulation of u-PAR display directly affects their in vitro invasive capacity. CONCLUSIONS: This study shows that bladder tumor cells produce u-PA and express the u-PAR and require both for in vitro invasion to occur. When bladder cancer cells express the u-PAR, invasiveness can be enhanced by exogenous u-PA and inhibited by anti-u-PAR antibodies. Modulation of u-PAR expression on the cell surface of bladder cancer cells can also affect their ability to invade Matrigel. IMPLICATIONS: Histologically similar bladder tumors show differences in their propensity to invade locally or metastasize. Intrinsic differences in the tumor cells such as the production of u-PA antigen and u-PA receptor on the cell surface and extrinsic differences in the tumor cell environment such as substances influencing u-PAR display or antibodies blocking the u-PAR may affect the biological potential of human bladder cancers and offer one explanation for the aggressive or indolent tumor behavior observed in individual patients.

Basement Membrane↗
PubMed1998

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.

Adjuvants, Immunologic↗
PubMed1997

Urokinase and the urokinase receptor: association with in vitro invasiveness of human bladder cancer cell lines.

BACKGROUND AND PURPOSE: The plasminogen activators urokinase and tissue plasminogen activator are enzymes that degrade proteins in tissue basement membranes and the extracellular matrix (a biomolecular complex surrounding individual cells in tissues that serves as a barrier between the cells and the vascular and lymph systems). The action of these enzymes allows tumor cells to escape their local environment and metastasize. Plasminogen activator activity can be influenced by the urokinase receptor, which is expressed on the surface of cells, and by the plasminogen activator inhibitors 1 and 2. Because bladder tumors differ in their propensity to invade local areas and distant sites, we studied the expression of both plasminogen activators, the two plasminogen activator inhibitors, and the urokinase receptor in four human bladder cancer cell lines (RT4, 253J, EJ, and T24) to see if there was an association between the expression of these proteins and tumor cell invasiveness in vitro. METHODS: The expression of urokinase, tissue plasminogen activator, and the two inhibitors was measured by enzyme-linked immunosorbent assays of serum-free, cell-conditioned media (i.e., culture fluids). Cell surface expression of the urokinase receptor was assayed by flow cytometry, using an anti-receptor monoclonal antibody (Mab3936). The invasive capacity of untreated cells and of cells exposed to exogenous, high-molecular-weight urokinase was analyzed by use of Matrigel invasion chambers. RESULTS: The four bladder cancer cell lines demonstrated differential expression of both plasminogen activators and both inhibitors; three of the cell lines (T24, EJ, and 253J) expressed the urokinase receptor. The four cell lines differed in their invasive potential in vitro. Neither expression of tissue plasminogen activator nor production of the inhibitors appeared to influence Matrigel invasion. EJ cells and 253J cells produced the highest levels of urokinase and demonstrated the greatest propensity for invasion; T24 cells, which produced only small amounts of urokinase, exhibited a low invasive potential. Pretreatment of T24 cells with exogenous high-molecular-weight urokinase markedly increased their invasiveness. Similar pretreatment of EJ and 253J cells increased their invasiveness as well. RT4 cells, which lacked urokinase receptor expression but produced moderate amounts of urokinase, were not invasive and did not become so after exposure to exogenous high-molecular-weight urokinase. Binding of Mab3936 to urokinase receptors inhibited Matrigel invasion. CONCLUSIONS: To our knowledge, this is the first study demonstrating that bladder tumor cells express the urokinase receptor and that both receptor expression and urokinase expression are required for bladder tumor cell invasion in vitro.

Carcinoma, Transitional Cell↗
PubMed1997

Effect of canarypox virus (ALVAC)-mediated cytokine expression on murine prostate tumor growth.

BACKGROUND: Canarypox virus, ALVAC, does not replicate in infected mammalian cells and has potential as a vector for gene therapy in the treatment of cancer. PURPOSE: Recombinant viruses carrying DNA sequences encoding interleukin 2 (ALVAC-IL-2), interferon gamma (ALVAC-IFN gamma), tumor necrosis factor-alpha (ALVAC-TNF-alpha), or the co-stimulatory molecule B7-1 (ALVAC-B7-1) were investigated as agents for the treatment of a newly defined mouse prostate tumor model. METHODS: RM-1 mouse prostate cancer cells, which are syngeneic (i.e., same genetic background) to C57BL/6 mice, were used. The expression of foreign gene products in vitro in infected RM-1 cells was measured by immunoprecipitation, bioassay, or flow cytometry. The effects of foreign gene product expression on RM-1 tumor cell growth in C57BL/6 mice were measured after subcutaneous injection (in the back) of 5 x 10(5) uninfected or infected cells; measurements included determinations of time to a measurable tumor size, tumor size as a function of time, and survival. The induction of protective immunity by uninfected and infected RM-1 cells was tested by injection of lethally irradiated (70 Gy) cells and subsequent challenge with uninfected cells. The generation of cytotoxic T cells was monitored by use of a 51Cr release assay. Severe combined immunodeficient (SCID) mice were used to determine whether T or B lymphocytes were involved in ALVAC vector-mediated antitumor responses. Data were analyzed by use of Pearson's modification of the chi-squared test and Kaplan-Meier survival methods. Reported P values are two-sided. RESULTS: The level of foreign gene product expression in ALVAC-infected RM-1 cells was dependent on the multiplicity of virus infection used; a multiplicity of five viruses per infected cell was chosen for subsequent experiments. RM-1 tumor growth in C57BL/6 mice was not affected by tumor cell expression of IL-2 alone, IFN gamma alone, or B7-1 alone; however, expression of TNF-alpha alone significantly delayed tumor growth at early time points (compared with parental ALVAC-infected tumors, P = .0001 at day 21 and P = .037 at day 28). Tumor cell expression of both TNF-alpha and IL-2 completely inhibited tumor growth in 60%-100% of treated mice. No protection against subsequent tumor challenge was detected in mice previously exposed to RM-1 cells expressing both TNF-alpha and IL-2. Cytotoxic T-lymphocyte activity toward RM-1 cells was not observed in C57BL/6 mice that rejected tumors. Tumor cell expression of TNF-alpha and IL-2 also resulted in tumor growth inhibition in SCID mice. CONCLUSIONS: RM-1 mouse prostate cancer cells are readily infected by ALVAC vectors, and foreign gene products are efficiently expressed. Inhibition of RM-1 tumor growth by tumor cell expression of TNF-alpha and IL-2 appears to involve nonspecific antitumor activity.

Animals↗
PubMed1997

Urinary interleukin-8/creatinine level as a predictor of response to intravesical bacillus Calmette-Guerin therapy in bladder tumor patients.

PURPOSE: Our purpose was to determine whether urinary interleukin-8 (IL-8) levels could be used to predict a tumor-free response to intravesical bacillus Calmette-Guerin (BCG) therapy in bladder cancer patients. MATERIALS AND METHODS: A total of 46 patients with superficial bladder cancer underwent an initial 6-week course of intravesical BCG therapy after transurethral resection. Voided urine samples were collected immediately before BCG instillations 1 and 6. Urine samples were centrifuged at 1,500 rpm for 8 minutes, and the supernatant was stored at -20 C. An enzyme-linked immunosorbent assay technique was used to measure urinary IL-8 levels. The Jaffé method was used to measure urinary creatinine. Results were expressed as the IL-8/creatinine ratio. Patients were followed with cystoscopy and urinary cytology every 3 months to detect bladder tumor recurrence. RESULTS: IL-8/creatinine ratios were measured in 31 patients before BCG therapy and were undetectable in 15. After 5 weeks of intravesical BCG therapy, IL-8/creatinine ratios fell in 27 patients (59%), were unchanged in 10 (22%) and rose in 9 (19%). Mean followup was 20.9 months (range 3 to 48). There was no association between the direction of change in IL-8/creatinine ratio and response to intravesical BCG therapy (p = 0.5). CONCLUSIONS: Urinary IL-8 levels obtained before intravesical BCG therapy and after instillation 5 of BCG were not helpful in predicting tumor recurrences in bladder cancer patients.

Adjuvants, Immunologic↗
PubMed1997

Improved detection of recurrent bladder cancer using the Bard BTA stat Test.

OBJECTIVES: To evaluate the BTA stat Test in the detection of recurrent bladder cancer. METHODS: Sensitivity and specificity were determined using frozen voided urine samples from patients with recurrent bladder cancer, volunteers, patients with nonurologic conditions, and patients with a history of bladder cancer but free of disease. Results of cytology and the original BTA Test were compared with the sensitivity of the BTA stat Test in a large subgroup of the patients with cancer. RESULTS: The BTA stat Test detected 147 (67%) of 220 recurrent cancers. For those urine samples with previous cytologic and BTA Test results available, cytology had a sensitivity of 23%, the BTA Test 44%, and the BTA stat Test 58% for detection of recurrent cancer (P < 0.001, stat versus cytology). The specificity of the BTA stat Test was 72% for benign genitourinary disease and 95% in healthy volunteers. CONCLUSIONS: The BTA stat Test has high sensitivity and is significantly superior to voided urine cytologic analysis in the detection of recurrent bladder cancer.

Aged↗
PubMed1996

Bropirimine immunotherapy of upper urinary tract carcinoma in situ.

OBJECTIVES: Bropirimine has been shown to be effective in treating approximately 50% of patients with carcinoma in situ (CIS) of the bladder in recent clinical trials. Patients with upper tract CIS were treated with bropirimine to determine whether this oral drug might be effective in that setting. METHODS: Twenty-four patients with negative radiographic findings and positive cytologic evidence for upper tract CIS in one or both ureters received bropirimine (3.0 g/day orally) for 3 consecutive days each week for up to 1 year. Ureteral collection of urine or barbotage for cytologic analysis was performed quarterly thereafter. RESULTS: Ten (48%) of 21 evaluable patients had a negative ureteral cytologic analysis after 12 weeks (5 patients) or 24 weeks (5 patients). Of these 10 patients, 8 continue to have negative cytology for a period of 3 to 30 months (median, more than 9 months). In 2 patients, negative cytology reverted to positive at 6 and 9 months, respectively, during therapy. Twelve (50%) of the 24 patients reported no toxicity. Three patients stopped treatment at 2, 3, and 3 weeks due to pruritic rash, nausea and vomiting, and severe bone pain, respectively. Therapy was stopped in 1 additional patient between 4 and 5 months because of transient liver enzyme elevations, yet this patient has had a continuous negative cytologic analysis for more than 9 months. CONCLUSIONS: Orally administered bropirimine may be effective therapy for CIS of the ureter or renal pelvis, with acceptable toxicity in most patients. Further efforts to better define this activity as well as the possible need for maintenance or intermittent long-term therapy are warranted.

Adjuvants, Immunologic↗
PubMed1996

Optimized microvessel density analysis improves prediction of cancer stage from prostate needle biopsies.

OBJECTIVES: Clinical staging of prostate cancer is inaccurate, often with significant upstaging on final pathologic review. We previously demonstrated the ability to predict extraprostatic extension of cancer by use of the Gleason score and serum prostate-specific antigen (PSA) measurements. Herein we present an interim analysis of data from an ongoing multi-institutional study to determine the predictive power of an enhancement of microvessel density analysis in combination with Gleason score and serum PSA to predict extraprostatic extension. METHODS: We evaluated a total of 186 randomly selected biopsy samples and matched totally embedded radical prostatectomy samples with preoperative PSA concentrations and patient demographics. Gleason score and optimized microvessel density (OMVD) were determined from the needle biopsy samples; pathologic stage was verified by independent review of the radical prostatectomy samples. An automated digital image analysis system measured microvessel morphology and calculated the OMVD in the biopsy samples (Biostage; Bard Diagnostic Sciences, Seattle, Wash). RESULTS: Prediction of extraprostatic extension was increased significantly when OMVD analysis was added to Gleason score and serum PSA concentration (P = 0.003). CONCLUSIONS: Optimized microvessel density analysis significantly increases the ability to predict extraprostatic extension of cancer preoperatively when combined with Gleason score and serum PSA concentration. This method appears to be a useful tool that can assist with treatment decisions in selected patients.

Aged↗
PubMed1995

Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer.

OBJECTIVES: We compare the Bard BTA (bladder tumor antigen) test to voided cytology studies in patients undergoing surveillance cystoscopy for recurrent bladder cancer. MATERIALS AND METHODS: A prospective, blinded, multicenter trial was performed. RESULTS: A total of 499 patients underwent 1,014 cystoscopic examinations and tumor was identified in 151. The bladder tumor antigen test was more sensitive than cytology studies in detecting recurrent cancer (p < 0.001), being positive in 61 cases versus 25 for cytology. The trial in healthy volunteers and nonurological patients estimates bladder tumor antigen test specificity to be 95.9%. CONCLUSIONS: The bladder tumor antigen test is a simple, rapid and inexpensive adjunct to cystoscopy, and the results are equivalent or superior to those of voided cytology as performed in this trial.

Adult↗
PubMed1995

The status of bladder-preserving therapeutic strategies in the management of patients with muscle-invasive bladder cancer.

The recommended treatment for medically fit patients with muscle-invading bladder cancer is usually radical cystectomy. However, transurethral resection of the tumor, partial cystectomy, irradiation and systemic chemotherapy are each effective in some patients. These latter treatments allow bladder preservation and cure as an alternative to radical cystectomy although when used unselectively the survival rates are inferior to those of radical cystectomy. The updated results of conservative surgery, radiation therapy and systemic chemotherapy as monotherapy, as well as strategies of combined modality treatment were reviewed. Based on this review many areas of consensus were reached which include: 1. The primary goal of any treatment for a patient with muscle-invading bladder cancer is survival; bladder preservation in the interest of quality of life is a secondary objective. 2. Only a small proportion of carefully selected patients may be cured by transurethral surgery alone, or by partial cystectomy alone. 3. Radiation therapy is currently the standard bladder-preserving therapy against which all other bladder-preserving methods must be compared. 4. Systemic chemotherapy as monotherapy is inadequate and cannot be recommended. 5. The addition of cisplatin-containing systemic chemotherapy to radiation therapy or conservative surgery appears to improve local control. While no multi-modality therapeutic regimen has yet been shown to be clearly optimal with regard to local efficacy and minimizing toxicity, monotherapy for bladder preservation is probably not desirable as a routine approach. 6. Deferring the patient from immediate cystectomy does not appear to compromise survival, nor does the addition of primary systemic chemotherapy appear to significantly increase the morbidity of cystectomy or radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined Modality Therapy↗
PubMed1995

Derivation and application of upper limits for prostate specific antigen in men aged 50-74 years with no clinical evidence of prostatic carcinoma.

OBJECTIVE: To derive age-specific upper limits for prostate specific antigen (PSA) level in men 50-74 years of age with no clinical evidence of prostatic carcinoma, and to test the sensitivity and specificity for cancer detection of these upper limits. SUBJECTS AND METHODS: A total of 6166 men were recruited for a multicentre study of prostate cancer detection and underwent a serum PSA determination and digital rectal examination (DRE). Men considered to be clinically free of prostatic carcinoma were those with a normal DRE and a PSA level < or = 4.0 ng/mL, and men with an abnormality in either parameter who underwent ultrasonography-guided prostate biopsy that revealed no evidence of carcinoma. By these criteria, 5469 men had no evidence of prostatic carcinoma. Dividing the population into 5-year age increments, three statistical methods were assessed to derive upper limits for serum PSA level by age; the mean +2 SD, the 99th percentile, and a 97.5% prediction interval based on linear regression. RESULTS: Newly-derived upper limits calculated by each method in the 50-54 and the 70-74 age group were 3.9 ng/mL and 7.6 ng/mL (mean +2 SD), 5.2 ng/mL and 14.0 ng/mL (99th percentile), and 4.7 ng/mL and 8.2 ng/mL (97.5% prediction interval). The sensitivity of the newly-derived upper limits was tested using receiver operating characteristic curves derived from men with no suspicious findings on DRE and a serum PSA concentration > 4.0 ng/mL. Although the specificity of the test increased with increasing PSA upper limits, no upper limits derived from these three methods yielded adequate sensitivity to detect cancer; sensitivities by age range were from 53 to 94%, using mean +2 SD, from 25 to 50% with the 99th percentile, and from 47 to 64% with the 97.5% prediction interval. CONCLUSION: We do not recommend age-referenced adjustments in upper limits for serum PSA concentration, but recommend that an upper limit of 4.0 ng/mL be used in all men 50-74 years of age.

Aged↗
PubMed1995

Anomalous ureteral insertion in VATER syndrome complicating renal transplantation.

We report a renal transplantation with uretero-ureterostomy to a normal ureter in a patient with VATER syndrome who had agenesis of the ipsilateral kidney. Anomalous insertion of the native ureter into the ejeculatory duct was subsequently identified when his post-operative course was complicated by an ureteric leak and hydronephrosis. To our knowledge, this anomaly has not been previously reported. Transplant function is now excellent following temporary percutaneous nephrostomy. Contrast delineation of genito-urinary anatomy is recommended, before utilizing existing anatomical structures in the urinary tract, in patients with VATER syndrome.

Abnormalities, Multiple↗
PubMed1994

Durability of the tumor-free response for intravesical bacillus Calmette-Guerin therapy.

The long-term efficacy of bacillus Calmette-Guerin (BCG) has not been established. We describe the tumor-free status of patients 11 years after BCG treatment. Long-term followup for the patient population (mean 74.3 +/- 3.5 months, range 6 to 129) yielded a 28% (29 of 104 patients) tumor-free status for a single 6-week course of BCG. Of 66 patients who received a second 6-week course of BCG for recurrent tumors after failing the initial 6-week course 27 (41%) have remained tumor-free. Overall, 56 of 104 patients (54%) remain tumor-free after 1 or 2 courses of BCG. Analysis of recurrences with respect to 3 intervals (2 or less, 2 to 5 and more than 5 years) revealed recurrence rates of 61% (63 of 104 patients), 23% (7 of 30) and 22% (5 of 23), respectively, after 1, 6-week course of BCG. Similarly, recurrence rates for the same periods for patients receiving a second 6-week course of BCG were 42% (28 of 66), 21% (6 of 28) and 23% (5 of 22), respectively. Patients receiving either 1 or 2, 6-week BCG courses who were tumor-free at 2 years experienced essentially identical recurrence rates during the 2 to 11-year followup (36% and 33%, respectively). Overall, 23 of 66 patients (35%) who were tumor-free at 2 years had recurrent tumors during the 2 to 11-year followup. We conclude that while BCG is effective therapy for superficial bladder tumors, a continuous potential for tumor recurrence exists for responding patients necessitating life-long followup.

Adult↗
PubMed1994

Effect of radiation therapy on detectable serum prostate specific antigen levels following radical prostatectomy: early versus delayed treatment.

Radiation therapy may be beneficial after radical prostatectomy in some patients with pathological stage C prostate cancer and in those with detectable postoperative prostate specific antigen (PSA) levels. A total of 64 men underwent postoperative radiation therapy following radical prostatectomy for pathological stage C disease (27), a detectable serum PSA level (11) or both conditions (26). Of the 27 men treated prophylactically for pathological stage C disease 18 (67%) had no evidence of recurrence after radiation within the first 6 months postoperatively (median followup 40 months, range 17 to 97). Of 22 men treated for delayed PSA elevation 15 (68%) currently are disease-free (median followup 27.5 months, range 15 to 47). Of 15 men treated within the first 6 months after radical prostatectomy for persistently detectable PSA levels 8 (53%) had an initial decrease in PSA to undetectable levels but only 5 (33%) had a durable complete response (median followup 36 months, range 8 to 56). We conclude that patients with pathological stage C disease who are most likely to benefit from postoperative radiation therapy are those with initially undetectable postoperative PSA levels. We observed no striking difference in treatment outcome between early and delayed adjuvant radiation therapy.

Combined Modality Therapy↗