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Biomedical subjects

S B Malkowicz

Publications and source records attributed to S B Malkowicz.

106 records · Page 6Linked to original sources
PubMed1993

Characterization of chromosome 9 deletions in transitional cell carcinoma by microsatellite assay.

A panel of 18 superficial or invasive transitional cell carcinomas (TCCs) was analyzed for chromosome 9 deletions by performing a high-density loss of heterozygosity (LOH) analysis. Twenty-five microsatellite loci were assayed by the polymerase chain reaction (PCR) and 7 restriction fragment length polymorphism (RFLP) loci were analyzed by Southern blotting. Concordant results were obtained with these methods, including direct comparisons at 2 loci. Chromosome 9 LOH was observed in 13 (72%) of 18 informative cases, including 10 superficial lesions. In contrast, LOH on chromosomes 10, 15, 20 and 21 was < or = 8%. Evidence for missing copies of chromosome 9 was observed in 7 of 13 LOH cases. Comparison of cases with subchromosomal LOH implicated the region between the D9S55 locus on 9p12 and the argininosuccinate synthetase (ASS) locus on 9q34.1 as the location of a tumor suppressor gene relevant to TCC.

Argininosuccinate Synthase↗
PubMed1991

Regulatory pathways in tumor growth and invasion.

Human tumor cells constitutively produce a variety of growth factors, cytokines, chemoattractants, motility factors, and proteolytic enzymes and their inhibitors. Juxtaposed normal cells such as fibroblasts, endothelial cells, and monocytes are also potential producers of most of these factors but, in general, they require specific signals to trigger synthesis and/or to release biologically active factors. Growth stimulation of normal and malignant cells, angiogenesis, and stroma formation within malignant lesions, tissue degradation by invasive tumor cells, cell motility, detachment of tumor cells from lesions and/or attachment to basement membranes involve complex interactions between autocrine, paracrine, and endocrine factors. Despite the complexity of such interactions, preliminary regulatory pathways can now be proposed that may help to explain the role for both positive and negative regulators in tumor development, growth, and invasion.

Antigens, Neoplasm↗
PubMed1990

Development of upper tract carcinoma after cystectomy for bladder carcinoma.

Two hundred twenty patients who underwent a radical cystectomy and en bloc pelvic lymph node dissection with urinary diversion were reviewed to define the incidence of upper tract carcinoma developing after cystectomy. Each patient was followed for at least five years or until death. In 5 of 220 (2.4%) upper tract lesions developed, with a disease-free interval from cystectomy of twenty-two to fifty-four months. All patients died within two to twenty-seven months of diagnosis. Common pathologic features included the presence of high-grade multifocal lesions or carcinoma in situ (CIS) in the cystectomy specimen, tumor invasion of the intramural ureter, and positive findings on urethrectomy specimens. Although the incidence of this disease process is low, heightened surveillance of the upper urinary tracts would seem appropriate in patients displaying these pathologic features.

Aged↗
PubMed1990

The role of radical cystectomy in the management of high grade superficial bladder cancer (PA, P1, PIS and P2)

Between January 1979 and 1987, 411 consecutive patients were considered candidates for bilateral pelvic iliac lymph node dissection and radical cystectomy for the management of bladder cancer. From this group 160 were identified as having pathological stage P2 or less disease, including 11 who also had positive nodes. The 5-year actuarial survival rate for the respective stages at 95% confidence limits was 100% for stage P0/A, 80% for stage P1, 78% for stage P1 with stage PIS, 85% for pure stage PIS, 76% for stage P2 and 87% for stage P2 with stage PIS. Additionally, we identified a group of patients with stage P2 transitional cell carcinoma who were at significant risk for development of metastatic disease. Of 46 patients with stage P2 transitional cell carcinoma 18 had vascular space invasion resulting in 6 of 18 cancer-related deaths (33%). Our study demonstrates that radical cystectomy has been highly effective in curing patients with high grade superficial disease, including those with superficially invasive disease associated with nodal metastases.

Carcinoma, Transitional Cell↗
PubMed1989

Intravenous papaverine in constructing continent urinary reservoir.

The use of intravenous papaverine as an adjunct in the construction of a continent urinary reservoir is a safe and effective method to facilitate an important but sometimes restrictive portion of this procedure. Additionally, it does not seem unreasonable to extend this technique to other procedures which involve the use of small bowel.

Humans↗
PubMed1987

Comparison of calcium antagonist properties of antispasmotic agents.

Several agents commonly employed for the treatment of detrusor hyperreflexia or instability are characterized as antispasmotics. Their mechanism of action is not completely understood but it has been proposed that their actions are dependent on anticholinergic activity, CNS mediated relaxation, or local anesthetic properties. The purpose of this study was to determine if imipramine, flavoxate HCl, or oxybutynin HCl possess any calcium antagonist properties. This was accomplished by determining the ability of these agents to inhibit a standard cholinergic stimulus (200 uM bethanechol) over a range of extracellular calcium concentrations (0.5 to 10.0 mM). In-vitro isolated smooth muscle strips of rabbit bladder dome were utilized. Control tissues displayed a reproducible response to bethanechol stimulation at different calcium concentrations with an ED50 of 0.4 mM calcium and a peak response of 5.0+/-0.4 grams tension. Flavoxate (2.5 mM), oxybutynin (2.5 uM), and imipramine 25 uM) all significantly reduced peak tension generation. The ED 50's for extracellular calcium in the presence of flavoxate and oxybutynin were not significantly different from controls. Imipramine at both 3 and 25 uM significantly increased the ED50 for calcium. The above data demonstrate that imipramine possesses competitive calcium antagonism. The relative contribution of calcium antagonism toward the inhibitory effects of imipramine is unknown but may play a significant role in its clinical activity.

Animals↗
PubMed1986

Acute biochemical and functional alterations in the partially obstructed rabbit urinary bladder.

Rapid structural and functional alterations have been noted in several models of partial outlet obstruction. To better characterize the rapid progression of alterations, the partially obstructed urinary bladders of mature NZW male rabbits were studied at 1, 3, 5, 7 and 14 days of outlet obstruction with respect to muscarinic receptor density, DNA, RNA, lipid and hydroxyproline content. Functional characteristics were assessed by measuring the in vitro response of the whole bladder to cholinergic and field stimulation. Wet weight increased eight-fold by day 7, decreasing to four-fold at day 14. Receptor density decreased by 50% by day 1 and remained low throughout. Although DNA concentration varied only slightly from controls, RNA increased four-fold by day 7. Hydroxyproline concentration per mg. tissue decreased in the obstructed bladder, yet total hydroxyproline content of the obstructed bladder significantly increased. Total lipids increased significantly during day 3 through 7 and decreased by day 14. Cystometry revealed a large capacity low pressure system at day 1 which rapidly changed to a low compliance system of lesser volume by day 14. Bladder emptying was significantly impaired in all obstructed specimens. Additionally, electrical field stimulation was significantly less effective than cholinergic stimulation in effecting bladder emptying. The above findings suggest that rapid changes in biochemical parameters occur during the early stage of acute obstruction which may in part be secondary to metabolic or inflammatory alterations in the detrusor. It additionally suggests that the myogenic alterations in partial outlet obstruction are rapid and partially adaptive, while neurogenic alterations appear degenerative and display a lesser degree of short term adaptation.

Animals↗
PubMed1985

Recovery from short-term obstruction of the rabbit urinary bladder.

Partial bladder outlet obstruction is a commonly encountered pathophysiologic state. Recently we have reported on the rapid nature of the contractile and functional changes that occur in the rabbit urinary bladder within one week of chronic partial obstruction. The purpose of this present study is to investigate the ability of the bladder to recover from one week of partial obstruction. Twenty-six mature male white New Zealand rabbits were separated into 3 groups. Each rabbit was anesthetized with ketamine-xylazine and a partial obstruction of the bladder established by gently securing a 2.0 silk suture around the temporarily catheterized bladder neck. The rabbits in group 1 were sacrificed following one week of partial obstruction. For groups 2 and 3, the obstructing suture was surgically removed after one week of obstruction adn the rabbit was allowed to recover for either two or four weeks. At the end of one week of obstruction the bladder displayed a 9-fold increase in tissue mass, 50 per cent reduction in contractile response to bethanechol and a 76 per cent reduction in the ability of the bladder to expel saline. After the two week recovery period, the bladder mass was reduced to approximately twice the control mass, the contractile and pressure responses to bethanechol were returned to control levels, and the ability of the bladder to expel saline recovered to approximately 75 per cent of control levels. No further improvements were observed following the four week recovery period. It appears that although the contractile response recovers completely following the one week obstruction period, the ability of the bladder to empty remains partially impaired.

Adenosine Triphosphate↗
PubMed1985

The effect of parasympathetic decentralization on the feline urinary bladder.

To examine the pharmacologic nature of parasympathetic decentralization on feline vesical smooth muscle, male cats were subjected to bilateral ventral rhizotomy from levels lumbar 7 to coccygeal 1 and studied at 1 and 3 months. By employing manual bladder decompression twice daily, compensatory bladder hypertrophy was absent or minimal in all specimens. In vitro muscle bath studies of bladder body demonstrated no significant end organ pharmacologic supersensitivity to cholinergic or alpha and beta adrenergic stimulation. Membrane receptor assays displayed a rise in muscarinic cholinergic and beta adrenergic receptors at 1 month which decreased at 3 months. The cholinergic receptor data parallels ultrastructural studies which demonstrate early cholinergic nerve terminal degeneration after motor decentralization followed by subsequent regrowth of cholinergic axons. Alpha 1 and alpha 2 adrenergic receptor densities remained constant in control, 1 month, and 3 month preparations. This lack of classic end organ denervation supersensitivity in the decentralized urinary bladder suggests that other mechanisms may be responsible for eliciting a positive response with the clinical denervation supersensitivity test.

Animals↗
PubMed1985

Effect of diltiazem on in vitro rabbit bladder function.

The relationship between extracellular calcium and urinary bladder function was investigated by studying the effect of the specific calcium antagonist diltiazem on the functional ability of the in vitro whole rabbit urinary bladder to empty in response to pharmacological stimulation. The bladder was found to require an extracellular calcium concentration of 4.5 X 10(-4) M to elicit near complete cholinergic-mediated emptying. Diltiazem (1 X 10(-6) - 1 X 10(-4) M) inhibition of bladder function was competitively antagonized by increasing the extracellular calcium concentration (0.45 X 10(-4) - 3.6 X 10(-4) M). In the absence of diltiazem, alterations in the extracellular calcium concentration between 0.45 X 10(-4) and 3.6 X 10(-4) M had no significant effects on bladder response to bethanechol. KCl-mediated bladder emptying was significantly more sensitive to diltiazem inhibition than was bethanechol-stimulated emptying. Even at the intermediate diltiazem concentration of 1 X 10(-5) M, increasing the extracellular calcium concentration did not completely reverse the inhibitory effect of diltiazem on bladder response to KC1. These findings are consistent with the hypothesis that diltiazem at low concentrations may inhibit extracellular calcium influx while at higher concentrations translocation of intracellular stores of calcium may be inhibited as well. The study also suggests that diltiazem is capable of inhibiting urinary bladder function and deserves further consideration as a possible therapeutic agent in certain forms of urinary bladder dysfunction.

Animals↗
PubMed1981

The ontogeny of the autonomic innervation and contractile response of the rabbit urinary bladder.

Although there has been considerable research on urinary bladder innervation, physiology and response to pharmacological agent, very little information is available concerning the ontogeny of bladder innervation and the contractile response to autonomic agents. The developmental aspects of urinary bladder innervation and function have been studied in the rabbit utilizing the following techniques: histochemical methodology to demonstrate autonomic innervation; in vitro responses to autonomic agents to demonstrate contractile responses; and ratio-ligand binding assays to determine specific receptor densities. The results of these studies can be summarized as follows: 1) at birth, the density of adrenergic fibers in the rabbit urinary bladder is very sparse, whereas there is a dense cholinergic innervation present. Over the first 6 weeks of postnatal development, there is a rapid progressive increase in the density of adrenergic fibers, whereas there is no significant change in the cholinergic innervation; 2) at birth, isolated strips of bladder respond poorly to methoxamine (alpha adrenergic agonist) and isoproterenol (beta-adrenergic agonist), but well to bethanechol (muscarinic cholinergic) and ATP (purinergic); 3) at birth, the density of adrenergic alpha and beta receptors is low; over the first 6 weeks of postnatal development, the density increases progressively to adult levels. The muscarinic receptor density is high at birth and does not change significantly over the first 6 weeks of postnatal development.

Animals↗
PubMedDate not supplied

The use of clinical parameters in an interactive statistical package to predict pathological features associated with local failure after radical prostatectomy for prostate cancer.

The capability of an interactive statistical package (ISP) to predict the patients whose pathologic findings at the time of radical prostatectomy for prostate cancer would require postoperative radiation therapy to prevent local failure is investigated. A retrospective review of the clinical pretreatment factors and pathologic findings of 174 patients with adenocarcinoma of the prostate treated from 1989 to 1993 with radical retropubic prostatectomy was performed and served as a knowledge base of the ISP. The pathologic findings of seminal vesicle involvement, gross transcapsular disease, and positive surgical margins are defined as outcomes associated with a high risk of local failure after radical prostatectomy and, thereby, requiring postoperative radiation therapy to decrease this risk. By using the pretreatment clinical factors including prostate-specific antigen (PSA), Gleason score, clinical stage, and endorectal magnetic resonance imaging (MRI) findings as input to the ISP, patients are identified from a test group of 50 cases with known pathologic outcome who would require postoperative radiotherapy to decrease local failure. Low- (0% to 33%), intermediate- (34% to 67%), and high-risk groups (68% to 100%) for pathologic features associated with local failure were predicted accurately (r > .95) by the ISP for the 50 test cases. Factors identified on univariate analysis by the ISP as significant predictors of local failure postoperatively include PSA > 20 (p < .001), clinical stage (p < .001), MRI finding of gross transcapsular disease (p < .001), MRI finding of seminal vesicle involvement (p < .001), and Gleason score (p < .003).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMedDate not supplied

Neoadjuvant androgen deprivation prior to transperineal prostate brachytherapy: smaller volumes, less morbidity.

PURPOSE: Prostate brachytherapy is becoming increasingly utilized in the definitive treatment of men with early-stage prostate cancer. Others have reported a close relation between total dose to the gland and genitourinary and gastrointestinal toxicity. We tested the hypothesis that 3 months of hormone deprivation would decrease gland size and decrease radioactivity implanted, which would result in less morbidity. Here, we report the toxicity associated with this novel treatment strategy. METHODS: One hundred fifty-five prostate cancer patients underwent ultrasound-guided transperineal implantation of palladium-103 at the Hospital of the University of Pennsylvania between January 1994 and July 1998. All men received at least 3 months of neoadjuvant luteinizing hormone-releasing hormone (LHRH) agonist therapy and were registered in the study. This group of men were compared with 55 men treated at the Hospital of the University of Pennsylvania with brachytherapy alone between December 1991 and December 1993. RESULTS: Compared with men treated with implant alone, men who received LHRH agonist therapy had significantly smaller glands at the time of implant (27.7 cm3 vs 36.3 cm3), required fewer seeds (47.9 vs 83.2), and had significantly less radioactivity implanted (76.3 mCi vs 117 mCi). The genitourinary and gastrointestinal morbidity in the men receiving hormone deprivation was minimal, with long-term side effects occurring in only three patients. In addition, potency was preserved in 83% of men. DISCUSSION: Three months or more of neoadjuvant LHRH agonist therapy before transperineal brachytherapy is safe, significantly reduces the amount of radioactivity implanted, and is associated with very low rates of genitourinary and gastrointestinal toxicity. In addition, potency preservation after combined-modality therapy is excellent and is similar to that of implantation alone. Further studies of this treatment approach are warranted.

Aged↗
PubMedDate not supplied

Role of percent positive biopsies and endorectal coil MRI in predicting prognosis in intermediate-risk prostate cancer patients.

PURPOSE: This study was performed to determine the clinical factors that can optimize preoperative staging for clinically localized intermediate-risk prostate cancer patients. MATERIALS AND METHODS: Logistic and Cox regression multivariable analyses were performed on 480 prostate cancer patients whose disease was confined to the prostate to evaluate the ability of clinical stage, prostate-specific antigen (PSA), biopsy Gleason sum, percent positive biopsies, and endorectal coil magnetic resonance imaging (MRI) results to predict pathologic established extracapsular extension, seminal vesicle invasion, and time to postoperative PSA failure in patients with clinically localized prostate cancer. Intermediate risk was defined as PSA 4-10 ng/mL and Gleason sum 5-7; PSA 10-20 ng/mL and Gleason sum < or = 7. RESULTS: Intermediate-risk patients with at least 50%, 67%, 83%, or 100% positive biopsies have disease pathologically confined to the prostate at least 45% of the time; however, if an endorectal coil MRI is positive for either capsular penetration or seminal vesicle invasion, no more than 29% of patients have pathologically determined organ-confined disease. No intermediate-risk patient with both a positive MRI and at least 50% positive biopsies had pathologically determined organ-confined disease. Intermediate-risk patients with less than 50% positive biopsies had pathologically determined organ-confined disease in at least 77% of the cases. CONCLUSIONS: Intermediate-risk patients with an endorectal coil MRI showing extracapsular extension or seminal vesticle invasion are at high risk for early postoperative PSA failure. The concomitant presence of at least 50% positive biopsies increases this risk to unity. Therefore, these patients are not good candidates for surgery alone because of their high risk of extraprostatic disease and should be considered for entry onto phase III trials examining the effect of adding androgen-deprivation therapy to definitive local therapy (external-beam radiation therapy or surgery) on overall survival. The subgroup of intermediate-risk patients likely to benefit from an endorectal coil MRI are those patients with PSA > 10-20 ng/mL; biopsy Gleason score < or = 7, and at least 50% positive biopsies representing approximately 7.5% of the total patient population.

Biopsy↗