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Biomedical subjects

R A Badalament

Publications and source records attributed to R A Badalament.

At least 19 recordsLinked to original sources
PubMed2001

Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial.

BACKGROUND: Intravesical chemotherapy (i.e., placement of the drug directly in the bladder) with mitomycin C is beneficial for patients with superficial bladder cancer who are at high risk of recurrence, but standard therapy is empirically based and patient response rates have been variable, in part because of inadequate drug delivery. We carried out a prospective, two-arm, randomized, multi-institutional phase III trial to test whether enhancing the drug's concentration in urine would improve its efficacy. METHODS: Patients with histologically proven transitional cell carcinoma and at high risk for recurrence were eligible for the trial. Patients in the optimized-treatment arm (n = 119) received a 40-mg dose of mitomycin C, pharmacokinetic manipulations to increase drug concentration by decreasing urine volume, and urine alkalinization to stabilize the drug. Patients in the standard-treatment arm (n = 111) received a 20-mg dose without pharmacokinetic manipulations or urine alkalinization. Both treatments were given weekly for 6 weeks. Primary endpoints were recurrence and time to recurrence. Treatment outcome was examined by use of Kaplan-Meier analysis with log-rank tests. Statistical tests were two-sided. RESULTS: Patients in the two arms did not differ in demographics or history of intravesical therapy. Dysuria occurred more frequently in the optimized arm but did not lead to more frequent treatment termination. In an intent-to-treat analysis, patients in the optimized arm showed a longer median time to recurrence (29.1 months; 95% confidence interval [CI] = 14.0 to 44.2 months) and a greater recurrence-free fraction (41.0%; 95% CI = 30.9% to 51.1%) at 5 years than patients in the standard arm (11.8 months; 95% CI = 7.2 to 16.4 months) and 24.6% (95% CI = 14.9% to 34.3%) (P =.005, log-rank test for time to recurrence). Improvements were found in all risk groups defined by tumor stage, grade, focality, and recurrence. CONCLUSIONS: This study identified a pharmacologically optimized intravesical mitomycin C treatment with statistically significantly enhanced efficacy.

Administration, Intravesical↗
PubMed2001

Distribution of DT-diaphorase and reduced nicotinamide adenine dinucleotide phosphate: cytochrome p450 oxidoreductase in bladder tissues and tumors.

PURPOSE: We previously showed that mitomycin C activity in human bladder tumors is inversely related to tumor stage and muscle invasive tumors are less sensitive than superficial tumors. Because DT-diaphorase and reduced nicotinamide adenine dinucleotide phosphate:cytochrome P450 oxidoreductase (P450R) have a role in mitomycin C bioactivation, we investigated the distribution of these enzymes as a function of depth in the bladder wall and in human bladder tumors located at different parts of the bladder. MATERIALS AND METHODS: Gene expression of DT-diaphorase and P450R relative to the expression of beta-actin was measured by reverse transcriptase-polymerase chain reaction in 4 dog and 8 human bladder tissue specimens, and in 46 human bladder tumors. DT-diaphorase activity was measured by enzymatic assay in dog and human bladders. RESULTS: Data showed decreasing expression of DT-diaphorase and P450R from urothelium to muscle layer in the normal bladder wall with higher interindividual variation in humans than in dogs (greater than 40-fold versus approximately 3-fold). The expression of DT-diaphorase and P450R in bladder tumors correlated inversely with tumor stage (p <0.05) and was significantly higher in superficial than in muscle invasive bladder disease. DT-diaphorase and P450R expression in bladder tumors was approximately 6-fold higher than in normal bladder tissue. In normal and tumor tissues DT-diaphorase expression correlated significantly with P450R (r2 = 0.33, p <0.01), while DT-diaphorase expression correlated with its enzyme activity (r2 = 0.84, p <0.01). CONCLUSIONS: Our results indicate a higher distribution of DT-diaphorase and P450R in superficial bladder tumors and tissues. Preferential enzyme distribution in superficial tumors may be a cause of the higher efficacy of intravesical mitomycin C therapy for superficial versus muscle invasive disease.

Animals↗
PubMed2000

Patient-reported complications after cryoablation therapy for prostate cancer.

To define the patient-reported complications after cryoablation therapy for prostate cancer and to compare these results to previously published patient-reported complications for radical prostatectomy and external beam irradiation. A questionnaire similar to previously published patient-reported complication studies was sent to the first 290 patients treated by cryoablation therapy at our Institution. The questionnaire was returned by 267 patients. Forty-four patients were excluded from analysis because of prior irradiation, transurethral prostatectomy, or cryoablation, resulting in a study group of 223 patients. Of the 208 patients with good urinary control preoperatively, 9 (4.3%) patients used incontinence pads after cryoablation. Seven of the 8 patients who used one pad daily reported leakage of only a few drops. Impotency, defined as an inability to obtain erections adequate for vaginal penetration, occurred in 85% of men who were potent preoperatively. Urethrorectal fistula occurred in 1 patient (0.4%). Bladder outlet obstruction caused by stricture of sloughed necrotic prostatic tissue required dilation or transurethral resection in 10% of patients. Scrotal swelling, penile tingling, and pelvic pain occurred in 18, 15, and 12% of patients, respectively; typically, these resolved spontaneously within 3 months. Patient-reported complications for cryoblation compared favorably to those reported for radical prostatectomy and external beam irradiation. Patient satisfaction was high; 96% of patients reported that they would choose cryosurgery as a treatment option again.

Aged↗
PubMed1999

Cryosurgery for prostate cancer: improved glandular ablation by use of 6 to 8 cryoprobes.

OBJECTIVES: To describe and assess the efficacy for increased glandular destruction by using 6 to 8 cryoprobes in place of the traditional 5 probes. METHODS: In April 1996, a revised method for cryosurgery was begun that uses 6 to 8 cryoprobes, and by July 1997, 81 men had been treated. This group was compared retrospectively to our last 82 cases done before April 1996 using 5 cryoprobes. All cases were consecutive. To ensure that the groups were similar, comparison was performed of entrance prostate-specific antigen (PSA), clinical stage, and Gleason score. Six months after cryosurgery, PSA and residual epithelial acini were compared between the two groups. RESULTS: The two groups were comparable for all the above parameters (P >0.05). The degree of overall glandular kill was greater for the 6 to 8-probe method (P = 0.023). Complete glandular ablation for the 5-probe and 6 to 8-probe methods was 39% and 53%, respectively, and the difference was not significant (P = 0.072). However, when one combined the complete glandular ablation group with the none to few residual acini group, 67.5% for the 5-probe method and 88.9% for the 6 to 8-probe method, a significant difference was found (P = 0.001). The odds of having many remaining acini versus having none to few were 3.5 times greater in the 5-probe group than in the 6 to 8-probe group. The mean and median PSA for the 5- and 6 to 8-probe groups were 0.19 and 0.1 versus 0.11 and 0.07 ng/mL, respectively, a significant difference (P = 0.02). No difference was found in rates of tumor persistence or complications. CONCLUSIONS: A revised method for cryosurgery using 6 to 8 cryoprobes has proved to be more effective for near-glandular ablation than the traditional 5-probe method. It was easily applied, had a wide margin of safety, and even shortened learning time. These innovations have permitted a closer approach to the goal of complete glandular destruction.

Cryosurgery↗
PubMed1999

Patient-reported complications after cryoablation therapy for prostate cancer.

OBJECTIVES: To define the patient-reported complications after cryoablation therapy for prostate cancer and to compare these results to previously published patient-reported complications for radical prostatectomy and external beam irradiation. METHODS: A questionnaire similar to previously published patient-reported complication studies was sent to the first 290 patients treated by cryoablation therapy at our institution. The questionnaire was returned by 267 patients. Forty-four patients were excluded from analysis because of prior irradiation, transurethral prostatectomy, or cryoablation, resulting in a study group of 223 patients. RESULTS: Of the 208 patients with good urinary control preoperatively, 9 (4.3%) patients used incontinence pads after cryoablation. Seven of the 8 patients who used one pad daily reported leakage of only a few drops. Impotency, defined as an inability to obtain erections adequate for vaginal penetration, occurred in 85% of men who were potent preoperatively. Urethrorectal fistula occurred in 1 patient (0.4%). Bladder outlet obstruction caused by stricture or sloughed necrotic prostatic tissue required dilation or transurethral resection in 10% of patients. Scrotal swelling, penile tingling, and pelvic pain occurred in 18%, 15%, and 12% of patients, respectively; typically, these resolved spontaneously within 3 months. CONCLUSIONS: Patient-reported complications for cryoablation compared favorably to those reported for radical prostatectomy and external beam irradiation. Patient satisfaction was high; 96% of patients reported that they would choose cryosurgery as a treatment option again.

Aged↗
PubMed1998

Multicenter radioimmunoscintigraphic evaluation of patients with prostate carcinoma using indium-111 capromab pendetide.

BACKGROUND: Optimum therapy for prostate carcinoma patients requires accurate staging, but computed tomography (CT) and magnetic resonance imaging (MRI) have limitations as methods for detecting soft tissue metastases. In this study, radioimmunoscintigraphy (RIS) was evaluated for its ability to identify sites of metastatic disease in lymph nodes. METHODS: RIS was evaluated in 51 prostate carcinoma patients at high risk for metastatic disease. An intravenous infusion of indium-111 capromab pendetide was given, followed by nuclear medicine imaging on two separate dates. Bilateral, open pelvic lymph node dissection was performed with additional exploration and biopsy of scan positive extraprostatic regions. Histologic evaluation of removed tissue confirmed the accuracy of RIS. In addition, results were compared with other standard methods for diagnosing patients prior to surgery. RESULTS: Nineteen patients (37%) had evidence of lymph node involvement with RIS. Fifteen of the 19 positive patients had pathologic evidence of cancer in the biopsied lymph nodes. Sensitivity, specificity, accuracy, and the positive predictive value for detection of extraprostatic disease were 75%, 86%, 81%, and 79%, respectively. CT, MRI, and ultrasound of the pelvis demonstrated a combined accuracy of only 48% in detecting lymph node disease. Twenty-five previously undetected sites were deemed positive with RIS. Fourteen of these were biopsy-proven tumor sites, seven were probable tumor sites, and four were assumed to be false-positive. CONCLUSIONS: RIS had an impact on patient management through its detection of occult disease in more than 50% of prostate carcinoma patients studied, and it provided information concerning the likelihood that lymph node metastases would be found during surgery.

Antibodies, Monoclonal↗
PubMed1998

Bladder tissue uptake of mitomycin C during intravesical therapy is linear with drug concentration in urine.

The design of an ongoing Phase III study of intravesical mitomycin C therapy to treat bladder cancer is partly based on the assumption that drug penetration into bladder tissue is linearly related to drug concentration. The present study was designed to (a) test this assumption and (b) to compare drug concentrations in tumor and adjacent normal tissues in human bladders. We previously reported the uptake kinetics of a 20-mg dose in dog and human bladders (M. G. Wientjes et al., Cancer Res., 51: 4347-4354, 1991, and Cancer Res., 53: 3314-3320, 1993). The present study used a 40 mg/20 ml dose. Serial blood and urine samples were taken from dogs during the 120-min instillation. Bladder tissues were harvested from dogs and patients at the end of instillation. A comparison of the results of the present and previous studies indicates identical tissue penetration kinetic parameters in dogs for the two doses, i.e., a approximately 30-fold concentration drop across the urothelium and a half-width of approximately 500 microns. In addition, the average tissue concentration in dog and human bladders attained with the 40-mg dose (8.77 micrograms/g in dogs and 7.55 micrograms/g in humans) was about twice that achieved with the 20-mg dose (4.33 micrograms/g in dogs and 3.91 micrograms/g in humans). In dogs, the plasma concentration of MMC reached a steady state within 10 min; the mean maximal plasma concentration was 8.5 ng/ml. This plasma concentration is indistinguishable from the concentration derived from the 20-mg dose and indicates a minimal systemic exposure even at the higher dose. The average MMC concentration in tumor-bearing tissues was about 40% higher than the concentration in adjacent normal tissues (P = 0.01). In conclusion, the linear relationship between drug uptake in bladder tissues and drug concentration in urine supports the assumption used in the design of the ongoing Phase III clinical trial.

Administration, Intravesical↗
PubMed1996

Penetration of intravesical doxorubicin in human bladders.

The bladder wall penetration kinetics of intravesical doxorubicin were examined in radical cystectomy patients, to provide insight into drug concentrations at target tumor sites. The dosing solution (40 mg/20 ml) was instilled just prior to the start of surgery and maintained for 60-115 min until just prior to bladder excision. The data showed considerable inter-patient variability in the peak plasma concentration (24-fold), urine concentration (7- fold), and tissue concentration (28-fold). The urine concentration at the time of tissue harvest was about 17% of the concentration in the dosing solution. This was due to the dilution by post-catheterization residual urine and urine produced during treatment. The doxorubicin concentration dropped by 32-fold across the urothelium, and declined semi-logarithmically with respect to depth in the capillary-perfused tissues beneath the urothelium with a 50% decrease over about 500 micromole. In three of six patients from whom tumor tissue was obtained, the doxorubicin concentration was higher than the adjacent non-tumor-bearing tissues of comparable tissue depth, whereas the reverse was seen in the remaining three tumors. The plasma concentrations were 0.02, 0.03, 0.05, 0.27, and 0.69% of the concentrations in the tumors, urothelium, lamina propria, superficial and deep muscle layers, respectively. These data indicate: (a) a considerable intra- and inter-patient variability in bladder tissue concentrations, in part due to the variability in the urine concentration; (b) the urothelium is an effective barrier to doxorubicin penetration; and (c) a targeting advantage of intravesical therapy for the treatment of superficial bladder cancer yielding superficial bladder tissue concentrations at least 2000-fold higher than in the systemic circulation. A comparison of the data of doxorubicin with our previously published data on mitomycin C shows similar bladder tissue pharmacokinetics for the two drugs, suggesting that there is no pharmacokinetic preference for either drug.

Administration, Intravesical↗
PubMed1996

Bladder cancer. Current diagnostic methods and treatment options.

The incidence of bladder cancer has grown over the years, presumably in part because of increasing exposure to carcinogenic agents in modern-day life. Drs Badalament and Schervish outline the latest diagnostic and staging methods for the disease and summarize treatment options for superficial, invasive, and metastatic cancers, including discussion of various methods for urinary diversion following cystectomy.

Humans↗
PubMed1996

An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies with prostate specific antigen level.

PURPOSE: We determined the enhanced ability to predict nonorgan confined prostate cancer using several histopathological and quantitative nuclear imaging parameters combined with serum prostate specific antigen (PSA). MATERIALS AND METHODS: Several independent pathological and quantitative image analysis variables obtained from sextant biopsy specimens, as well as preoperative PSA were used. The study population included 210 patients with pathologically staged disease (192 with PSA). All variables were examined by univariate and multivariate logistic regression analyses to assess ability to predict disease organ confinement status. RESULTS: Univariate logistic regression analysis demonstrated that, in decreasing order, quantitative nuclear grade, preoperative PSA, total percent tumor involvement, number of positive sextant cores, preoperative Gleason score and involvement of more than 5% of a base and/or apex biopsy were significant (p < or = 0.006) for prediction of disease organ confinement status. Backward stepwise logistic regression was applied to these univariately significant variables, including deoxyribonucleic acid ploidy, to calculate a multivariate model for prediction of disease organ confinement status. This algorithm had a sensitivity of 85.7%, specificity 71.3%, positive predictive value 72.9%, negative predictive value 84.7% and area under the receiver operating characteristic curve 85.9%. CONCLUSIONS: Information from pathological study of sextant prostate biopsies, preoperative PSA blood test and a new image analysis variable termed quantitative nuclear grade can be combined to create a multivariate algorithm that can predict more accurately nonorgan confined prostate cancer compared to previously reported methods.

Aged↗
PubMed1996

Pharmacodynamics of doxorubicin in human bladder tumors.

Intravesical doxorubicin treatment delivers high drug concentrations to the bladder wall, yet the treatment produces only a variable and incomplete response in superficial bladder cancer and insignificant activity in muscle-invading disease. This study evaluated the pharmacological basis for the clinical observations and potential prognostic indicators of tumor sensitivity to doxorubicin. The pharmacodynamics of doxorubicin were studied using histocultures of surgical specimens of seven superficial (Ta and T1) and nine invasive (T2-T4) tumors. After a 2-h exposure, drug treatment caused a concentration-dependent inhibition of proliferation, as measured by bromodeoxyuridine incorporation into DNA. Extensive cell death was observed at high concentrations (>10 micrometer) in sensitive tumors. The IC50 values ranged from 0.14 to 5.2 micrometer for superficial tumors and from 1.4 to >100 micrometer for invasive tumors. A comparison of the IC50 and IC90 values with the drug concentrations previously determined in human bladder walls showed that IC50 was achieved in all Ta tumors, 67-100% of T1 tumors, and one of the nine invasive tumors, whereas IC90 was achieved in all Ta tumors but none of the other tumors. To determine the biological basis of variable doxorubicin sensitivity among different tumors, we examined the relationship of chemosensitivity with tumor pathology and with expression of multidrug resistance p-glycoprotein (Pgp) and p53 protein. The invasive, high-grade, highly proliferative, p53- and Pgp-positive tumors were more resistant than the superficial, lower-grade, p53- and Pgp-negative tumors. All tumors were negative for bcl-2. The rank order of these factors was p53 expression > tumor stage > grade > bromodeoxyuridine labeling index > Pgp. Statistical analysis using the Akaike Information Criterion indicates that the two-parameter combination of p53 expression with stage further improved the predictive value. The present study shows that: (a) there was a >700-fold difference in doxorubicin sensitivity among superficial and invasive tumors; (b) the variable and incomplete response of superficial bladder cancer to intravesical doxorubicin therapy is likely due to the 35-fold variability in tumor chemosensitivity and, to a lesser degree, the 4-fold variability in tissue pharmacokinetics; (c) the lack of response of invasive cancer to intravesical doxorubicin therapy is likely the result of the inadequate drug concentrations presented to the deep muscle layers and the low chemosensitivity of the more aggressive tumors; and (d) the combination of p53 expression and high stage was the most significant predictor of doxorubicin sensitivity, whereas Pgp expression was the least important.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Sextant prostate biopsies. A histopathologic correlation with radical prostatectomy specimens.

BACKGROUND: Among patients with clinically localized prostate cancer, preoperative prediction of tumor volume and pathologic stage has been unreliable. This study examines the application of transrectal ultrasound-guided sextant biopsies to predict the extent of disease. METHODS: One hundred and two patients with clinically resectable prostate cancer were evaluated by systematic sextant biopsies. Radical prostatectomy specimens were embedded totally as whole mounts, tumor areas were outlined, and volume was measured using a digital scanner. The number of positive sextant biopsies was compared with age, race, preoperative prostate specific antigen (PSA), PSA density, DNA ploidy, pathologic stage, capsular and seminal vesicle involvement, prostate and tumor volume, and Gleason score. Stepwise logistic regression was used to determine if pathologic stage or tumor size could be predicted by these parameters. RESULTS: The number of positive sextant biopsies correlated with traditional prognostic indicators. When patients with three or fewer positive biopsies were compared with those with four or more positive sextant biopsies, significant differences were identified relative to preoperative PSA (P < 0.001), tumor volume (P < 0.001), pathologic stage (P < 0.001), Gleason score (P < 0.001), seminal vesicle involvement (P < 0.001), and capsular penetration (P < 0.001). There were no significant differences based on age, race, DNA ploidy, and overall prostate volume. Logistic regression showed that patients with four or more positive sextant biopsies and high Gleason score had a greater likelihood of pT3 classification. Likewise, the probabilities of a tumor volume less than 0.5 ml could be predicted by the number of positive sextant biopsies and PSA alone. The number of positive sextant biopsies was the only factor that could predict a tumor volume greater than 4.0 ml. CONCLUSION: The number of positive sextant biopsies appears to be an important prognostic indicator of pathologic (pT) classification and tumor volume. This information is valuable in selecting the treatment strategy for patients with prostate cancer.

Age Factors↗
PubMed1995

Histocultures of human prostate tissues for pharmacologic evaluation.

This study evaluated the growth of human prostate tumors in histoculture, an in vitro culture technique that maintains three-dimensional tissue structure and organization. Eighty-six percent of 50 tumor specimens from 50 patients were successfully cultured. The histocultures showed proliferation of epithelial tumor cells and stromal cells. Prostate specific antigen (PSA) and prostatic acid phosphatase (PAP) were detectable by immunohistochemistry for at least 8 weeks. Synthesis of PSA was further confirmed by its presence in medium. The mean thymidine labeling index (LI) of the neoplastic cells was 62%. There was no correlation between thymidine LI and tumor grade. The explants maintained their characteristics for at least 8 weeks as indicated by unchanged thymidine LI, PSA and PAP immunohistochemistry after 2 and 8 weeks in culture. A 24 to 48 hour delay in processing the tissues for culture did not reduce the thymidine LI. The thymidine LI and PSA and PAP staining in tumors cultured in a Minimal Essential Medium (MEM)-based or a PFMR-4-based culture medium were similar, suggesting an insignificant effect of the medium on cell proliferation. Migration of neoplastic cells from the tissue fragments into the collagen gel matrix was noted in 1 of 10 samples cultured in MEM-based medium versus 8 of 10 samples cultured in PFMR-4 medium (p < 0.01). Exposure of 13 patient tumors to suramin, doxorubicin and 5-fluorouracil at clinically relevant concentrations and duration showed tumor sensitivity in 23%, 31% and 15% of the specimens. These values approximate the historical clinical response rates. These data suggest that the histoculture system holds promise for short-term culture of human patient prostate tumor specimens for biologic and pharmacologic studies.

Acid Phosphatase↗
PubMed1994

Correlation of human bladder tumor histoculture proliferation and sensitivity to mitomycin C with tumor pathobiology.

This study examined the in vitro proliferation and mitomycin C (MMC) sensitivity of patient bladder tumors as a function of the tumor pathobiology. Surgical specimens of transitional cell carcinoma of the bladder were maintained as histocultures on collagen gels. The thymidine labeling index (LI) was determined by autoradiography and the labeling for proliferating cell nuclear antigen (PCNA) by immunohistochemistry. There was a linear correlation between the thymidine LI and the PCNA LI, but the PCNA LI were quantitatively lower than the thymidine LI. The mean thymidine LI were 30.9, 32.4 and 51.5% for the grade I, II and III tumors, 33.6 and 56.3% for the superficial (Tis, Ta and T1) and invasive (T2-T4) tumors, and 28.9 and 50.9% for the diploid and aneuploid tumors. Analysis of variance indicates that these differences were statistically significant. These data indicate that the proliferation of tumor histocultures paralleled the tumor aggressiveness in vivo. The tumor sensitivity to MMC, measured by the inhibition of the thymidine LI of tumor cells, was studied in 31 tumors. At a 2 hour exposure, as is currently used in intravesical therapy, the MMC concentrations required for 50% inhibition of thymidine LI (IC50) showed a 120-fold intertumor variation (0.102 to 12.4 micrograms./ml.). The sensitivity to MMC inversely correlated with tumor aggressiveness. The IC50 increased with tumor LI (p < 0.05). The mean IC50 were 2.61 and 5.79 micrograms./ml. for superficial and invasive tumors (p < 0.05), 1.06, 3.05 and 4.49 micrograms./ml. for grade I, II and III tumors (p < 0.05), and 2.53 and 4.31 micrograms./ml. for diploid and aneuploid tumors (p = 0.14). These data indicate a large difference in sensitivity of human bladder tumors to MMC, with greater sensitivity for well-differentiated superficial tumors and lesser sensitivity for undifferentiated, invasive tumors.

Autoradiography↗