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1.
Surgery ; 115(6): 745-50, 1994 Jun.
Article in English | MEDLINE | ID: mdl-7515197

ABSTRACT

BACKGROUND: The purpose of this study was to determine the incidence and mortality rate of prostate cancer in men without a rectum at a single institution. The usefulness of serum prostate specific antigen (PSA) to screen for prostate cancer in men without a rectum was defined. Improved biopsy techniques and therapeutic options were developed in those with elevated levels. METHODS: We undertook a retrospective review of 65 men who underwent an abdominoperineal resection. Twenty-five of these men underwent serum PSA determinations (mean age, 68 years). RESULTS: Four (16%) of 25 patients had elevated PSA levels. Three of these four men and two additional patients (one before the availability of PSA and one with normal serum PSA level) were found to have biopsy-proven prostate cancer. Two men (3% of the 65 patient population) died of metastatic prostate cancer. CONCLUSIONS: We believe that men about to undergo an abdominoperineal resection should have a preoperative serum PSA measurement. Moreover, we recommend that men older than 49 years of age (older than 39 years for those with positive family histories) without a rectum should have annual serum PSA determinations as if recommended for the general male population at large. If an elevated serum PSA level is discovered, the transperineal ultrasonogram-guided biopsy technique offers an effective method to detect peripheral zone prostate cancers.


Subject(s)
Adenocarcinoma/diagnosis , Neoplasms, Second Primary/diagnosis , Prostate-Specific Antigen/blood , Prostate/pathology , Prostatic Neoplasms/diagnosis , Rectum/surgery , Adenocarcinoma/diagnostic imaging , Adenocarcinoma/surgery , Aged , Aged, 80 and over , Biopsy , Humans , Male , Middle Aged , Neoplasms, Second Primary/diagnostic imaging , Neoplasms, Second Primary/surgery , Pilot Projects , Prostate/diagnostic imaging , Prostatectomy , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/surgery , Rectal Neoplasms/surgery , Retrospective Studies , Ultrasonography
2.
J Urol ; 147(5): 1411-5, 1992 May.
Article in English | MEDLINE | ID: mdl-1569697

ABSTRACT

An electromyographic technique is presented that has been developed in an effort to quantitate the number of motor units in the urinary sphincter. Sphincter contraction was provoked by electrical stimulation and recorded with a catheter mounted electrode. Incremental stimulation produced corresponding increments of sphincter contraction that were recorded as the magnitude of the sphincter electromyogram. Estimates of the number of motor units in the sphincter were made by analysis of variance of a Poisson distribution. Using this method, the mean number of motor units in the sphincter of five dogs was estimated to be 129 with values ranging from 80 to 182. Anatomical correlation was sought by infiltrating this sphincter with horseradish peroxidase, which is taken up by axonal transport to stain the motor neurons in the spinal cord. The mean number of motor neurons was 229 with values ranging from 116 to 358. There are technical and physiologic explanations for the observed differences between the predicted and the actual number of motor neurons stained and this is addressed in the discussion.


Subject(s)
Cell Count/methods , Motor Neurons/cytology , Urethra/cytology , Animals , Dogs , Female
3.
J Urol ; 145(3): 535-7, 1991 Mar.
Article in English | MEDLINE | ID: mdl-1997704

ABSTRACT

Bladder dysfunction in myelodysplasia may present a significant hazard to the upper tract and a threat to kidney function. Urodynamic features of high leak pressure and detrusor-sphincter dyssynergia have been associated with an increased risk. We have developed an objective score to describe urodynamic findings in myelodysplasia. The score includes consideration of bladder compliance, detrusor contractility and reflux, in addition to leak pressure and sphincter behavior. In 171 myelodysplastic patients a significant correlation was demonstrated between the score and upper tract studies at the time of urodynamics and the score and the management decision. Of 73 myelodysplasia patients with normal upper tracts at the first urodynamics study hydronephrosis later developed in 14. The score was a potent predictor of outcome (p = 0.0006).


Subject(s)
Hydronephrosis/epidemiology , Neural Tube Defects/physiopathology , Urinary Bladder, Neurogenic/physiopathology , Urinary Bladder/physiopathology , Urodynamics/physiology , Child, Preschool , Female , Humans , Hydronephrosis/physiopathology , Male , Predictive Value of Tests , Risk Factors , Vesico-Ureteral Reflux/physiopathology
4.
Urology ; 36(3): 280-2, 1990 Sep.
Article in English | MEDLINE | ID: mdl-2392819

ABSTRACT

Duplication of the urethra with an accessory phallic urethra in females is a rare anomaly usually discovered early in life because of associated genitourinary anomalies. We report on a thirty-three-year-old female with this anomaly who presented with double urinary stream and recurrent urinary tract infections. The nature of this anomaly, its diagnosis, and management are reviewed.


Subject(s)
Urethra/abnormalities , Adult , Female , Humans , Radiography , Recurrence , Urethra/diagnostic imaging , Urethra/surgery , Urinary Bladder/diagnostic imaging , Urinary Tract Infections/etiology
5.
J Urol ; 144(1): 106-8; discussion 108-9, 1990 Jul.
Article in English | MEDLINE | ID: mdl-2359155

ABSTRACT

Preoperative urodynamic and radiographic evaluation identified features of bladder neck and urethral weakness in 62 women undergoing cystourethropexy for the correction of anatomical stress urinary incontinence. Despite the coexistence of anatomical and outlet factors persistent stress incontinence due to intrinsic urethral weakness occurred in only 2 patients (3%), neither of whom was identifiable by preoperative urethral function evaluation. Preoperative coexisting urgency symptoms had no impact on the surgical outcome, resolving in the majority of patients with sensory urgency and responding to alternate postoperative management in those with bladder instability. We conclude that anatomical correction by cystourethropexy is appropriate for women with mixed etiology incontinence in whom urethrovesical hypermobility is present.


Subject(s)
Urethra/surgery , Urinary Bladder/surgery , Urinary Incontinence, Stress/surgery , Adult , Aged , Aged, 80 and over , Female , Humans , Methods , Middle Aged , Postoperative Complications , Recurrence , Urethra/physiopathology , Urinary Incontinence, Stress/etiology , Urinary Incontinence, Stress/physiopathology , Urodynamics
6.
Cancer Res ; 45(11 Pt 1): 5270-80, 1985 Nov.
Article in English | MEDLINE | ID: mdl-2932216

ABSTRACT

5-Trifluoromethyl-2'-deoxycytidine (F3methyl-dCyd), when coadministered with tetrahydrouridine (H4Urd), surpasses the efficacy of 5-trifluorothymidine and 5-trifluoromethyl-2'-deoxycytidine when administered alone as demonstrated with adenocarcinoma 755 and Lewis lung carcinoma as solid tumors implanted in C57BL X DBA/2 F1 mice. It appears that the reason for the heightened efficacy of F3methyl-dCyd, when coadministered with low concentrations of H4Urd, is decreased systemic deamination and subsequent systemic catabolism by pyrimidine nucleoside phosphorylases, which do not act on deoxycytidine and its analogues. Furthermore, the elevated levels of cytidine deaminase in these mouse tumors may result in selective conversion of F3methyl-dCyd to 5-trifluorothymidine at the tumor site. This suggests an approach to the treatment of human tumors possessing elevated levels of cytidine deaminase such as certain leukemias, bronchogenic carcinoma of the lung, adenocarcinomas of the colon and rectum, astrocytomas, and certain tumors which are refractory to chemotherapy with 1-beta-D-arabinofuranosylcytosine. In contrast to fluorinated pyrimidines in current use, F3methyl-dCyd + H4Urd potentially allows an exclusive DNA-, rather than both a DNA- and RNA-, directed approach. The major mechanism of the antitumor activity of F3methyl-dCyd appears to be via inhibition by 5-trifluorothymidine-5'-monophosphate of thymidylate synthetase, the target enzyme of fluoropyrimidine analogues in current use. However, the established and potential differences in the mode of action, anabolism, nature of incorporation into DNA, repair and cofactor requirements of F3methyl-dCyd and its anabolites, compared to that of the commonly utilized fluorinated pyrimidines, indicate that F3methyl-dCyd + H4Urd is a novel combination of agents. In comparative studies with Lewis lung carcinoma, F3methyl-dCyd (+ H4Urd) was shown to surpass the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine and to be essentially equal in efficacy to 5-fluorodeoxycytidine (+ H4Urd). The optimum established protocol against Lewis lung carcinoma is F3methyl-dCyd, 175 mg/kg, + H4Urd, 25 mg/kg, once per day for 7 days. Studies utilizing high concentrations of H4Urd coadministered with F3methyl-dCyd indicate that the major pathway of tumor inhibition is via conversion of F3methyl-dCyd to 5-trifluorothymidine in view of the fact that tumor inhibition diminishes at doses of H4Urd which result in extensive (93%) inhibition of tumor cytidine deaminase.(ABSTRACT TRUNCATED AT 400 WORDS)


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cytidine Deaminase/analysis , DNA/metabolism , Deoxycytidine/administration & dosage , Neoplasms, Experimental/drug therapy , Nucleoside Deaminases/analysis , Tetrahydrouridine/administration & dosage , Uridine/analogs & derivatives , Animals , Cells, Cultured , Cytidine Deaminase/antagonists & inhibitors , Deoxycytidine/metabolism , Female , Floxuridine/therapeutic use , Fluorouracil/therapeutic use , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Neoplasms, Experimental/metabolism , Thymidylate Synthase/antagonists & inhibitors , Trifluridine/metabolism , Trifluridine/therapeutic use
7.
Int J Radiat Oncol Biol Phys ; 10(8): 1453-8, 1984 Aug.
Article in English | MEDLINE | ID: mdl-6236189

ABSTRACT

Our approach to overcome the problem of rapid catabolism and general toxicity encountered with 5-halogenated analogues of deoxyuridine (5-bromo, chloro or iododeoxyuridine), which has limited their use as tumor radiosensitizers, is to utilize 5-chlorodeoxycytidine (CldC) with tetrahydrouridine (H4U). We propose that CldC, coadministered with H4U, is metabolized in the following manner: CldC----CldCMP----CldUMP---- ----CldUTP----DNA. All the enzymes of this pathway are elevated in many human malignant tumors and in HEp-2 cells. In X irradiation studies with HEp-2 cells, limited to 1 or 2 radiation doses, we have obtained 3.0 to 3.8 apparent dose enhancement ratios (these represent upper limits) when cells are preincubated with inhibitors of pyrimidine biosynthesis: N-(Phosphonacetyl)-L-aspartate (PALA) and 5-fluorodeoxyuridine (FdU) or 5-fluorodeoxycytidine (FdC) + H4U. Optimum conditions for radiosensitization are: PALA (0.1 mg/ml) 18-20 hr prior to FdU (0.1 microM) or FdC (0.02 microM) + H4U (0.1 mM) followed 6 hr later by CldC (0.1-0.2 mM) + H4U (0.1 mM) for 56-68 hr. Viabilities of 10 +/- 4% to 15 +/- 1% (+/- S.E.) were obtained for drug-treated unirradiated cells. Enzymatic studies indicate that this toxicity may be tumor selective. CldC + H4U alone (at these concentrations) results in 20% substitution of CldU for thymidine in DNA (determined by HPLC analysis). Preliminary toxicity studies indicate that mice will tolerate treatment protocols involving a single dose of PALA (200 mg/kg) followed by a dose of FdU (50 mg/kg) and 3 cycles of CldC (500 mg/kg) + H4U (100 mg/kg) at 10 hour intervals, with marginal weight loss (4%). In this approach we seek to obtain preferential conversion of CldC to CldUTP at the tumor site by taking advantage of quantitative differences in enzyme levels between tumors and normal tissues.


Subject(s)
Aspartic Acid/analogs & derivatives , Deoxycytidine/analogs & derivatives , Floxuridine/pharmacology , Organophosphorus Compounds/pharmacology , Phosphonoacetic Acid/pharmacology , Radiation-Sensitizing Agents/pharmacology , Tetrahydrouridine/pharmacology , Uridine/analogs & derivatives , Animals , Aspartic Acid/pharmacology , Carcinoma, Squamous Cell , Cell Line , Cell Survival/drug effects , Cell Survival/radiation effects , Deoxycytidine/pharmacology , Dose-Response Relationship, Radiation , Humans , Laryngeal Neoplasms , Mice , Phosphonoacetic Acid/analogs & derivatives , Radiation-Sensitizing Agents/toxicity
8.
Cancer Res ; 44(6): 2551-60, 1984 Jun.
Article in English | MEDLINE | ID: mdl-6539164

ABSTRACT

In view of the 20- to 80-fold elevation of deoxycytidine-5'-phosphate (dCMP) deaminase in many human malignant tumors, we have utilized 5-fluorodeoxycytidine ( FdCyd ) coadministered with tetrahydrouridine ( H4Urd ) as a combination of antitumor agents against two murine solid tumors which possess high levels of dCMP deaminase. This approach is based on our past studies in which we demonstrated that FdCyd is an excellent substrate for mammalian 2'-deoxycytidine kinase, and that H4Urd increases the toxicity of FdCyd in the mouse. Cell culture studies utilizing 2'- deoxytetrahydrouridine which inhibits cytidine deaminase and as 2'- deoxytetrahydrouridine -5'-monophosphate inhibits dCMP deaminase, provide indirect evidence for the pathway that we had proposed in the past, 2'- Deoxytetrahydrouridine antagonized the toxicity of FdCyd to a greater extent than did H4Urd and showed marked antagonism in cytidine deaminase-deficient cells. Cell lines lacking both cytidine and 2'-deoxycytidine-5'-monophosphate deaminase were markedly resistant to FdCyd . Thymidine and deoxyuridine antagonized toxicity in a manner consistent with the proposed pathway of anabolism of FdCyd and consistent with its resulting in the inhibition of thymidylate synthetase. We have established the efficacy of FdCyd + H4Urd chemotherapy utilizing adenocarcinoma 755 and Lewis lung carcinoma in C57BL X DBA/2 F1 mice. An example of an optimum schedule versus Lewis lung carcinoma is FdCyd , 10 to 12 mg/kg, plus H4Urd , 25 mg/kg, coadministered simultaneously, once per day on Days 1 to 7 after tumor implantation. Tumor inhibitions on Days 12, 14, and 16 were 95, 90, and 80%, respectively, with 8% maximum weight loss. Comparative studies were undertaken only with Lewis lung carcinoma and it was established that FdCyd + H4Urd surpasses the efficacies of 5-fluorouracil and 5-fluorodeoxyuridine as well as FdCyd when administered without H4Urd . We propose that the administration of FdCyd with H4Urd can result in preferential, tumor-directed conversion of a nontoxic nucleoside analogue to a toxic antimetabolite by an enzyme that is markedly elevated in human tumor tissue. The analogues of deoxycytidine are resistant to catabolism and are anabolized by a different subset of enzymes than are 5-fluorouracil or 5-fluorodeoxyuridine; therefore, it is a novel approach. Not only are there intrinsic selectivity, metabolic stability, and the advantages that accrue from prodrug therapy in this strategy, but in addition, the potential for an exclusively DNA-directed effect exists. This is in contrast to approaches with 5-fluorouracil and 5-fluorodeoxyuridine, in which, in addition to DNA effects, parallel effe


Subject(s)
DCMP Deaminase/metabolism , DNA Replication/drug effects , Deoxycytidine/analogs & derivatives , Nucleotide Deaminases/metabolism , Tetrahydrouridine/toxicity , Uridine/analogs & derivatives , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Ehrlich Tumor/drug therapy , Carcinoma, Squamous Cell , Cell Line , Cell Survival/drug effects , Cricetinae , Cricetulus , Deoxycytidine/toxicity , Drug Evaluation, Preclinical , Female , Humans , Leukemia L1210/drug therapy , Leukemia, Experimental/drug therapy , Lung Neoplasms/drug therapy , Mammary Neoplasms, Experimental/drug therapy , Mice , Ovary
9.
Antimicrob Agents Chemother ; 22(3): 431-41, 1982 Sep.
Article in English | MEDLINE | ID: mdl-6291452

ABSTRACT

Enzyme kinetic studies from this laboratory (M. Dobersen and S. Greer, Biochemistry 17:920-928, 1978) suggested that deoxycytidine could antagonize the toxicity of 5-halogenated analogs of deoxycytidine without interfering with their antiviral activity. Antagonism by deoxycytidine of the toxicity of 5-chlorodeoxycytidine without impairing its anti-herpes simplex virus type 2 activity is demonstrated in the present studies. Tetrahydrouridine, an inhibitor of cytidine deaminase, was utilized. The high Km for deoxycytidine (0.6 mM) with respect to the herpes pyrimidine nucleoside kinase as compared with the low Km for 5-chlorodeoxycytidine (1.1 microM) accounts for the absence of antagonism of the antiviral activity. The high Km for 5-chlorodeoxycytidine (56 microM) as compared with the low Km of deoxycytidine (2 microM) with respect to mammalian deoxycytidine kinase accounts, in great part, for the antagonism of toxicity. In addition, antagonism of toxicity by deoxycytidine is the result of factors other than the kinetic parameters of nucleoside kinases, as indicated by its antagonism of the cytotoxicity of 5-chlorodeoxyuridine. This may be attributed to replenishment of low dCTP pools, diminished because of effector inhibition of ribonucleoside diphosphate reductase by Cl-dUTP. Resistance of the herpes-encoded enzymes to effector control may also play a role in the selective antagonism. Cell culture studies with high concentrations of tetrahydrouridine and 2'-deoxytetrahydrouridine suggest that competition by deoxycytidine for deaminases may not play a major role. The fact that deoxycytidine antagonizes the toxicity of chlorodeoxyuridine also argues against competition for the deaminases as a major reason for its effect. Limited studies with a topical herpes simplex virus type 2 infection system indicate heightened efficacy of 5-chlorodeoxycytidine (and tetrahydrouridine) when deoxycytidine is coadministered. The concepts of selective antagonism of a chemotherapeutic agent derived from these studies may be applied to other approaches that extent beyond viral chemotherapy.


Subject(s)
Antiviral Agents/pharmacology , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Simplexvirus/drug effects , Animals , Antiviral Agents/toxicity , Cell Cycle/drug effects , Cytidine Deaminase/antagonists & inhibitors , DNA, Viral/metabolism , Deoxyuridine/analogs & derivatives , Deoxyuridine/pharmacology , Herpes Simplex/drug therapy , Kinetics , Mice , Virus Replication/drug effects
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