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J B deKernion

Publications and source records attributed to J B deKernion.

At least 37 records · Page 2Linked to original sources

Computer-generated graphical presentations: use of multimedia to enhance communication.

Personal computers may be used to create, store, and deliver graphical presentations. With computer-generated combinations of the five media (text, images, sound, video, and animation)--that is, multimedia presentations--the effectiveness of message delivery can be greatly increased. The basic tools are (1) a personal computer; (2) presentation software; and (3) a projector to enlarge the monitor images for audience viewing. Use of this new method has grown rapidly in the business-conference world, but has yet to gain widespread acceptance at medical meetings. We review herein the rationale for multimedia presentations in medicine (vis-à-vis traditional slide shows) as an improved means for increasing audience attention, comprehension, and retention. The evolution of multimedia is traced from earliest times to the present. The steps involved in making a multimedia presentation are summarized, emphasizing advances in technology that bring the new method within practical reach of busy physicians. Specific attention is given to software, digital image processing, storage devices, and delivery methods. Our development of a urology multimedia presentation--delivered May 4, 1996, before the Society for Urology and Engineering and now Internet-accessible at http://www.usrf.org--was the impetus for this work.

Communication↗

Three-dimensional ultrasound device for rapid determination of bladder volume.

OBJECTIVES: We sought to assess the accuracy, reliability, and clinical utility of the noninvasive determination of bladder volume using an automated, compact three-dimensional (3-D) ultrasound device. METHODS: We prospectively tested 249 adult outpatients for accuracy (n = 182), by comparing scan versus catheter volumes, or reliability (n = 67), by comparing the scan readings of two independent observers. Two models of the bladder scan device were tested (BVI-2500, 1994 and 1995 models). RESULTS: Scan and catheter volumes were correlated (y = 1.02x + 12.6, R2 = 0.90, P < 0.001) across a range of zero to 1015 cc, regardless of which machine model was used. Scan volume underestimated catheter volume by an average of 10 cc in men and 20 cc in women. If a scan-predicted volume of 100 cc or greater were used as a cutpoint for clinical importance, the device exhibited a sensitivity of 97%, a specificity of 91%, and an overall accuracy of 94%. These results were not affected by age, gender, height, weight, diagnosis, uterine presence/prostate size, or user experience. The two observers, one a graduate physician and the other a college student, achieved essentially the same volume determinations (y = 0.96x + 0.13, R2 = 0.90, P < 0.001). CONCLUSIONS: Volume determinations obtained with the bladder scan device are accurate and reliable in adult outpatients. A special technician is not required. These results may be attributable to use of automated planimetry and 3-D volumetry, rather than a fixed geometric formula, to custom measure each bladder shape.

Adult↗

Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia.

PURPOSE: We sought to quantify prostate tissue changes induced by finasteride and to identify a predictor of finasteride response in men with symptomatic benign prostatic hyperplasia (BPH) via a randomized, placebo controlled, double-blind clinical trial. MATERIALS AND METHODS: Men with symptomatic BPH (52 to 78 years old) were randomly assigned to 6 months of treatment with finasteride (26) or placebo (15). Outcome measures were clinical (urinary symptom score and flow rate), chemical (serum prostate specific antigen and dihydrotestosterone levels), volumetric (transrectal ultrasound, and magnetic resonance imaging for whole and zonal prostate volumes) and histological (morphometry of prostate sextant biopsies, separated into inner and outer gland segments, to measure the percent epithelium, stroma and glandular lumen). RESULTS: In the finasteride group we found a suggestion of decreasing symptom scores and increasing flow rates (not significant) with significant decreases (p < 0.01) in prostate specific antigen (48%), dihydrotestosterone (74%) and prostate volume (21%). Finasteride treatment induced a 55% decrease in inner gland epithelium (p < 0.01) with little effect on stroma or lumina. We also found a linear correlation between pretreatment inner gland epithelial content and prostate volume decrease induced by the drug (tau = 0.58, p = 0.01). CONCLUSIONS: Finasteride treatment results in a major suppression of prostate epithelium, which is most pronounced in the inner gland. Moreover, a finasteride induced prostate volume decrease was predictable by quantification of epithelial tissues of the inner gland. These data lend additional support to the emerging concept of transition zone primacy in symptomatic BPH.

Aged↗

In vitro modulation of tumor progression-associated properties of hormone refractory prostate carcinoma cell lines by cytokines.

BACKGROUND: Cytokines exert cytostatic and immunomodulatory effects on carcinoma cells. Growth inhibition of human prostate carcinoma by cytokines has been demonstrated both in vitro and in vivo, whereas the cellular and molecular changes in prostate carcinoma properties after cytokine treatment have never been characterized. We have thus investigated whether the intrinsic properties of prostate carcinoma cells that are associated with tumor development and progression can be altered by direct cytokine treatment. METHODS: LNCaP, DU-145, and PC-3 cell lines were treated with tumor necrosis factor-alpha (TNF-alpha) (200 U/mL), interferon-gamma (IFN-gamma) (500 U/mL), human leukocyte interferon (IFN-alpha) (500 U/mL), and interleukin-2 (IL-2) (400 U/mL). The expression of (prostate-specific antigen [PSA] and prostate-specific membrane [PSM]), androgen receptor (AR), growth factors, oncogenes, collagenase, cell adhesion molecules, HLA antigens, cell adhesion to human bone marrow stroma, and cell growth were determined by quantitative polymerase chain reaction (PCR) analysis, fluorescence-activated cell sorter (FACS) analysis, and cell attachment and proliferation assays, and were compared with non-treated cells. RESULTS: PCR analysis indicated that only LNCaP cells expressed PSA, PSM, and AR mRNA. Cytokine treatment did not alter PSM mRNA expression, whereas a 15-fold decrease in PSA and a 5-fold reduction in AR mRNA expression was detected in TNF-alpha-treated cells. The down regulation of PSA production was also demonstrated at the protein level in a dose-dependent fashion. A fivefold decrease in PSA mRNA was also detected in IL-2-treated LNCaP cells but without a reduction in AR. Down regulated epidermal growth factor receptor (EGF-R) and basic fibroblast growth factor (b-FGF) mRNA expressions were detected in TNF-alpha- and IFN-alpha-treated DU-145 and PC-3 cells, whereas, only reduced EGF-R expression was observed in LNCaP cells. IFN-gamma and IL-2 treatment down regulated the expression of collagenase Type IV mRNA in DU-145 and PC-3 cells, whereas tumor transforming growth factor-beta (TGF-beta) and IL-6 mRNA expressions did not exhibit any essential changes after cytokine treatment. A reduction in c-myc mRNA expression was observed in TNF-alpha- and IFN-alpha-treated cells, whereas no change in HER-2 expression was noted in any cytokine treated cells. Up regulated P-cadherin, but not E-cadherin, mRNA expression was detected in TNF-alpha- and IFN-gamma-treated PC-3 cells. FACS analysis revealed that all but IL-2-treated cells had enhanced HLA Class I expression, with the maximum effect seen in TNF-alpha-treated LNCaP cells (threefold increase). Up regulated HLA Class II expression was seen only in IFN-gamma-treated cells. All cytokine-treated DU-145 and PC-3 cells expressed reduced levels of alpha3, but not beta1, integrin. Up regulated of ICAM-1 expression was seen in all cytokine treated DU-145 and PC-3 cells, whereas no change in CD44 occurred. Cytokine treatment reduced the binding affinity of LNCaP and DU-145, but not of PC-3 cells, to human bone marrow stromal cells, and all cytokines but IL-2 showed a mild to moderate growth inhibition to prostate cancer cells, with a marked inhibition only observed in TNF-alpha-treated LNCaP cells. CONCLUSIONS: Cytokine treatment can effectively alter several prostate carcinoma properties that are closely associated with tumor invasion and a metastatic phenotype, suggesting that immunotherapy via the local delivery of cytokines may have a potentially therapeutic role in the treatment of hormone-refractory prostate cancer through both direct and indirect antitumor mechanisms.

Antigens, Neoplasm↗

Prostate cancer.

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Androgen Antagonists↗

Natural immune reactivity-associated therapeutic response in patients with metastatic renal cell carcinoma receiving tumor-infiltrating lymphocytes and interleukin-2-based therapy.

Combination therapy with systemically administered interleukin-2 (IL-2) and tumor infiltrating lymphocytes (TIL) demonstrates significant clinical activity in some patients with metastatic renal cell carcinoma (RCC). The objective of this study was to identify predictors of therapeutic response in patients with IL-2- and TIL-based immunotherapy. We characterized and compared immunologic properties of tumors, TILs, peripheral blood lymphocytes (PBLs) and sera of responding (R, n = 8) with nonresponding patients (NR, n = 9). Before undergoing nephrectomy, responding patients exhibited a higher percentage of circulating natural killer (NK) cells (CD56+ CD3-) (43 +/- 20%) as compared with nonresponders (18 +/- 16%) (p < 0.01). After nephrectomy, the CD56+ CD3-/CD56- CD3+ ratio in responding patients (pre: 2.60 +/- 2.24; post: 0.28 +/- 0.19; p < 0.05) significantly decreased and was similar to that of patients not responding to therapy (0.42 +/- 0.36). Sera from patients responding to immunotherapy, obtained before and after completion of therapy, contained natural killer (NK)-enhancing factor(s) that significantly enhanced the proliferation (3.2 x 10(3) +/- 25%/ 3.6 x 10(3) +/- 13% counts/min) and cytotoxicity [17.6 +/- 4.0/18.0 +/- 1.9 lytic units (LU)] of fresh PBLs as compared with normal serum (1.8 x 10(3) +/- 8% counts/min; 13.4 +/- 2.5 LU) or sera from nonresponders (1.6 x 10(3) +/- 25%/1.5 x 10(3) +/- 20% counts/min; 8.3 +/- 5.9/6.8 +/- 4.8 LU). In contrast to noncultured tumor suspension, IL-2 cultivation induced TIL growth, cytotoxicity, and multicytokine synthesis, and a complete clearance of tumor cells. No significant differences were observed between responders and nonresponders in the in vitro characteristics of tumor/TIL, which include the degree of intratumoral lymphocytic infiltrate, TIL expansion, specific lysis of autologous tumor, phenotype, expansion time, quantity of TIL infused, cytokine release, and degree of tumor aggressiveness. We conclude that clinical response to TIL and IL-2-based immunotherapy is associated with patients' baseline natural immune status. The percentage of circulating NK cells and the presence of serum NK-cell-enhancing factors may serve as potential predictors of response in patients with advanced RCC. The in vitro study of RCC-TIL suggests that activated TIL may provide a synergistic effect to that of administered IL-2 on activation of cellular immune response in situ, rendering a tumor eradication, while the clinical outcome is largely dependent on the pretreatment immune status of patient.

Adult↗

Cost-efficient radical prostatectomy with a clinical care path.

PURPOSE: We assessed changes in hospital costs and resource use among patients undergoing radical prostatectomy following implementation of a clinical care path. MATERIALS AND METHODS: A standardized clinical care path for patient management before and after radical prostatectomy was developed and implemented at a large academic medical center in California. All 577 consecutive patients undergoing radical prostatectomy during the 3 years before and 1 year after implementation of the care path were included in the study. Each patient was entered prospectively into a hospital-wide financial data base, which served as the source for observations on hospital costs, hospital charges and length of stay. RESULTS: After implementation of the radical prostatectomy care path hospital costs decreased by 12% ($7,916 versus $6,934, p < 0.001), hospital charges decreased by 20% ($17,005 versus $13,524, p < 0.0001) and length of stay decreased by 28% (5 versus 3.6 days, p < 0.0001). Decreases were noted in all categories of the hospital patient financial profile, except operating room charges. CONCLUSIONS: By standardizing preoperative and postoperative management for patients undergoing radical prostatectomy, significant savings can be achieved over and above existing trends toward shorter hospital stays and lower hospital costs.

Aged↗

Serum prostate specific antigen levels after transurethral resection of prostate: a longitudinal characterization in men with benign prostatic hyperplasia.

PURPOSE: We studied the long-term effects of adenomectomy on serum levels of prostate specific antigen (PSA) in men with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A consecutive series of 82 men undergoing adenomectomy for BPH between 1990 and 1992 was studied. PSA levels were determined before and serially after operation for as long as 5 years. RESULTS: Mean PSA decreased from 4.6 ng/ml. preoperatively to 0.7 ng./ml. 6 months postoperatively. These low levels were maintained throughout the 5-year observation period. The PSA decrease correlated with grams of tissue removed (r = 0.54, p < 0.001) and averaged 0.11 ng./ml./gm. Postoperatively mean PSA velocity was 0.01 ng./ml. per year, that is essentially flat, and it was not influenced by patient age, race, type of operation, grams of tissue removed, baseline PSA, PSA density of T1a lesions (7). One to 5 years after adenomectomy 6 of the 82 men had invasive prostatic carcinoma, and PSA levels and velocities remained low. CONCLUSIONS: These data support the concept of transition zone primacy in determining serum PSA. Furthermore, they suggest a possible need for a modified reference range when using PSA to screen for prostatic carcinoma in the estimated 3 million men alive in the United States who previously underwent adenomectomy for BPH.

Adult↗

The effects of granulocyte-macrophage colony-stimulating factor on tumour-infiltrating lymphocytes from renal cell carcinoma.

It has been shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) can induce specific and non-specific anti-tumour cytotoxicity and also stimulates the proliferation and function of peripheral lymphocytes and thymocytes. GM-CSF and interleukin 2 (IL-2) act synergistically on peripheral lymphocytes for the induction of a highly effective cytotoxic cell population. Thus, the goal of our investigation was to study the effects of GM-CSF upon expansion, proliferation and in vitro killing activity of tumour-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC). TILs from seven consecutive tumours were cultured with GM-CSF (500 or 1000 nmol ml-1) without IL-2 supplementation, with suboptimal doses of IL-2 (8 and 40 U ml-1) plus GM-CSF (1000 nmol ml-1), and with a dose of IL-2 (400 U ml-1) which sufficed alone to induce TIL development plus GM-CSF (500 or 1000 nmol ml-1). GM-CSF alone or together with suboptimal doses of IL-2 was not able to induce or facilitate TIL development in these cultures. When GM-CSF at both concentrations studied was added to optimal doses of IL-2 the resulting TIL populations proliferated significantly better and faster (+66%), resulting in a higher cell yield (+24%) at the time of maximal expansion of the TIL cultures. The length of the culture periods of TILs was not affected by GM-CSF when compared with the control cultures supplemented with IL-2 alone. In vitro killing activity of TIL populations stimulated with IL-2 and GM-CSF remained unspecific, but lysis of the autologous tumour targets as well as the allogeneic renal tumour targets was significantly enhanced (+138%) as compared with the corresponding control TILs stimulated with IL-2 alone. Lysis of the natural killer (NK)-sensitive control cell line K562 and the NK-resistant Daudi cell line remained unchanged even though FACS analysis of TILs cultured with IL-2 and 1000 nmol of GM-CSF demonstrated a significantly higher proportion of cells expressing the CD56 molecule (+50%). Specific receptors for GM-CSF could not be demonstrated on TILs from RCC. Our data demonstrate that GM-CSF alters the biological behaviour of IL-2-activated TILs from renal cell carcinoma in terms of proliferation, in vitro killing activity and cell-surface molecule expression.(ABSTRACT TRUNCATED AT 400 WORDS)

Carcinoma, Renal Cell↗

Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study.

A total of 65 patients with von Hippel-Lindau disease underwent surgery for renal cell carcinoma (54 bilaterally and 11 unilaterally) at 8 medical centers. Only 1 patient presented with metastatic disease. Radical nephrectomy and nephron sparing surgery were performed in 16 and 49 patients, respectively. Mean posttreatment followup was 68 months. The 5 and 10-year cancer-specific survival rates for all patients were 95% and 77%, respectively. The corresponding rates for patients treated with nephron sparing surgery were 100% and 81%, respectively. Of the latter patients 25 (51%) had postoperative local tumor recurrence but only 2 had concomitant metastatic disease. Survival free of local recurrence was 71% at 5 years but only 15% at 10 years. End stage renal failure occurred in 15 patients (23%): 6 underwent renal transplantation (5 are alive with satisfactory renal function and no evidence of malignancy) and 9 were treated with chronic dialysis (6 are free of tumor). Our results indicate that nephron sparing surgery can provide effective initial treatment for patients with renal cell carcinoma and von Hippel-Lindau disease. These patients must be followed closely, since most will eventually have locally recurrent renal cell carcinoma. When removal of all renal tissue is necessary to achieve control of malignancy, renal transplantation can provide satisfactory replacement therapy for end stage renal disease.

Adolescent↗

In vitro modulation of the invasive and metastatic potentials of human renal cell carcinoma by interleukin-2 and/or interferon-alpha gene transfer.

BACKGROUND: Continuous local delivery of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) via gene transfer appears to be more effective than systemic therapy in preventing the growth of human renal cell carcinoma (RCC) in vitro and in vivo. To understand further if cytokine-gene transfection of RCC could alter certain cellular properties that are associated with the invasive and metastatic potentials of tumor, the authors characterized six cell lines that produce IL-2 and/or IFN-alpha in their expression of intercellular adhesion molecule-1 (ICAM-1) and CD44; binding affinity to extracellular matrix (ECM) components (fibronectin, laminin, type IV collagen, and vitronectin); and preference in forming homotypic aggregation and mRNA levels of c-myc, epidermal growth factor receptor (EGF-R), tumor transforming growth factor-beta (TGF-beta) and type IV collagenase. These six lines were compared with control vector transfected parental R11 line. METHODS: The expression of ICAM-1 and CD44 was determined by fluorescence-activated cell sorter (FACS) analysis, the tumor cell binding affinity to ECM components was measured by cell attachment assay, the degree of homotypic aggregation was quantified by cell aggregation assay, and the mRNA levels of c-myc, EGF-R, TGF-beta, and collagenase were analyzed by a quantitative polymerase chain reaction analysis. RESULTS: Both IL-2-gene- and IFN-alpha-gene-modified R11 exhibited enhanced expression of ICAM-1, suppression of CD44, and decreased binding affinity to ECM components, when compared with the R11-control vector. All cytokine-producing tumor lines showed a decreased preference to form homotypic aggregation. Interferon-alpha gene transfer downregulated c-myc, EGF-R, and type IV collagenase mRNA expression, whereas only the higher producers of IL-2 downregulated TGF-beta mRNA expression. Exogenous IL-2 and/or IFN-alpha treatment of a IFN-alpha-resistant RCC enhanced both HLA class I antigen and ICAM-1 expression and suppressed CD44 expression, but had no effect on tumor growth rate. CONCLUSIONS: The local production of high concentrations of IL-2 and IFN-a at the tumor site may directly alter tumor properties associated with invasive and metastatic phenotypes of RCC. Interleukin-2 and/or IFN-alpha gene therapy may be an effective strategy for treatment of patients with advanced renal cancer.

Base Sequence↗

Comparison of prostate specific antigen concentration versus prostate specific antigen density in the early detection of prostate cancer: receiver operating characteristic curves.

We present the results of a prospective multicenter clinical trial of nearly 5,000 men in which prostate specific antigen (PSA) density was compared to the serum PSA concentration alone for early detection of prostate cancer. All men were evaluated with PSA and digital rectal examination. If PSA was elevated (greater than 4 ng./ml., Hybritech Tandem assay) or digital rectal examination was suspicious, transrectal ultrasound guided biopsies were recommended. Prostate volume was estimated by transrectal ultrasound measurements using a prolate ellipse volume calculation and PSA density was calculated by dividing serum PSA concentration by gland volume. Using a PSA density cutoff of 0.15 as recommended in the literature enhanced specificity but at the cost of missing half of the tumors. Of the organ confined neoplasms 47% were detected by a PSA of greater than 4.0 ng./ml. but they were missed by a PSA density of more than 0.15. PSA density may not be predictive for cancer because accurate estimation of transrectal ultrasound volume is difficult (r = 0.61 for estimated transrectal ultrasound volume versus pathological prostate weight). However, a relationship does exist among transrectal ultrasound volume, PSA and positive predictive value for cancer. PSA concentrations of less than 4.0 ng./ml. did not indicate a need for biopsy (positive predictive value 12 to 17%) unless the digital rectal examination findings were suspicious for cancer. A high percentage of patients with a PSA of more than 10 ng./ml. had cancer (30 to 75%), regardless of gland size. Patients with intermediate PSA concentrations (4.1 to 9.9 ng./ml.) and a gland size of 50 cc or less had a 35 to 51% positive predictive value, while those with intermediate PSA concentrations and a large gland (more than 50 cc) had a 15% positive predictive value. We conclude that in men with a PSA level of 4.1 to 9.9 ng./ml., and normal digital rectal examination and transrectal ultrasound findings, the use of a PSA density cutoff of more than 0.15 for biopsy results in half of the tumors being missed. Thus, we recommend that men in this group undergo biopsy based upon serum PSA concentration rather than PSA density.

Aged↗

The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy.

A total of 601 patients who underwent radical retropubic prostatectomy for localized prostate cancer at our institution was followed with serial prostatic specific antigen (PSA) determinations. Three separate groups were delineated by pathological stage: 293 patients with organ confined disease, 215 with involvement of the capsule or positive margins and 93 with extension to the seminal vesicles. Followup ranged from 12 to 237 months (median 34). Five and 10-year disease-free survival rates for the 601 patients were 86 +/- 2% and 78 +/- 3%, respectively. The rate of detectable PSA (greater than 0.4 ng./ml.), used as an indicator of cancer progression, revealed 5 and 10-year disease-free rates of 69 +/- 2% and 47 +/- 3%, respectively. When comparing the patients from an earlier series to those who underwent surgery after 1986, an improvement in the 5-year clinical disease-free rate was noted (78 +/- 2% versus 93 +/- 2%, respectively). Similarly, an improvement in the 5-year disease-free survival rate with nondetectable PSA level was demonstrated in our contemporary series (80 +/- 3%) compared to our historical series. Of the 601 patients 123 had a detectable post-prostatectomy PSA level with or without clinical evidence of metastasis. A PSA doubling time before onset of adjuvant therapy was determined in 94 patients. Post-prostatectomy PSA doubling times were significantly different when comparing the patients who ultimately had progression to distant metastases (median 4.3 months) to those with either clinical local recurrence or a PSA elevation as the sole indicator of recurrence (median 11.7 months). Radical retropubic prostatectomy, whether assessed by clinical or biochemical means, has demonstrated excellent disease-free survival rates, especially since the advent of PSA and anatomical radical prostatectomy.

Adult↗

Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands.

OBJECTIVES: Morphometry, or quantitative image analysis, offers great promise in characterizing the various histologic types of benign prostatic hyperplasia (BPH), but to date, a systematic study of the tissue components is lacking. Thus we employed morphometry to examine the distribution of primary BPH tissues throughout whole human prostates. METHODS: The prostate glands of 20 men with BPH were removed for low-volume carcinoma and subjected to a uniform, comprehensive, systematic quantification of the primary BPH tissue components using the technique of digitization and point-count morphometry. RESULTS: We found the following average volumes among the 20 glands: epithelium, 19.9% (S.D. 5.1%, range 11.7% to 30.8%); fibromuscular stroma, 50.4% (S.D. 9.4%, range 32.2% to 74.4%); glandular lumina, 29.7% (S.D. 8.9%, range 11.9% to 47.5%). Within the individual prostates, we found symmetry in primary BPH tissue distribution, except that the outer prostate was on average 25% richer in epithelium than the inner prostate (p < 0.05). When tissue composition was determined in simulated biopsy specimens, corrected for radial (ie, inner vs outer gland) orientation, the correlation with whole-organ composition was statistically significant for "percentage epithelium" (r = 0.72, p < 0.01) and for "stromal/epithelial ratio" (r = 0.63, p < 0.01). CONCLUSIONS: Major differences in primary tissue composition may separate different hyperplastic prostates. Primary BPH tissues are rather symmetrically distributed within individual prostates. Quantitative histologic differences between prostates, potentially important in clinical decision-making may be accurately diagnosed by morphometry of radially oriented biopsy specimens.

Aged↗

Ischemia of neobladder. Clinical manifestations and management.

Substitution enterocystoplasty is becoming more common in a selected group of patients. Acute or chronic ischemia is an exceptional event. We describe the clinical manifestations and management of chronic ischemia of a neobladder that occurred weeks after a successful initial operation. The possible mechanisms responsible for this complication are reviewed.

Chronic Disease↗