A real-time prostate cancer detection technique using needle insertion force and patient-specific criteria during percutaneous intervention.

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Tradeoff between sensitivity and specificity was obtained by varying the threshold value of the classifier, from which the receiver-operating characteristic (ROC) curve was generated. Sequential quadratic programming was used to optimize the CAD model by maximizing the area under the ROC curve (AUC) using a set of model-training patient data. When the CAD model was evaluated using an independent set of model-validation patient data, an AUC of 0.90 was achieved. The feasibility of cancer detection in real time during percutaneous interventions was established.

A real-time prostate cancer detection technique using needle insertion force and patient-specific criteria during percutaneous intervention.

In this article, the authors present a novel real-time cancer detection technique by using needle insertion forces in conjunction with patient-specific criteria during percutaneous interventions. Needle insertion experiments and pathological analysis were performed for developing a computer-aided detection (CAD) model. Backward stepwise regression method was performed to identify the statistically significant patient-specific factors. A baseline force model was then developed using these significant factors. The threshold force model that estimated the lower bound of the cancerous tissue forces was formulated by adding an adjustable classifier to the baseline force model. Trade-off between sensitivity and specificity was obtained by varying the threshold value of the classifier, from which the receiver-operating characteristic (ROC) curve was generated. Sequential quadratic programming was used to optimize the CAD model by maximizing the area under the ROC curve (AUC) using a set of model-training patient data. When the CAD model was evaluated using an independent set of model-validation patient data, an AUC of 0.90 was achieved. The feasibility of cancer detection in real time during percutaneous interventions was established.

Robotic system for prostate brachytherapy.

In contemporary brachytherapy procedures, needle placement at the desired target is challenging for a variety of reasons. A robot-assisted brachytherapy system can potentially improve needle placement and seed delivery, resulting in enhanced therapeutic outcome. In this paper we present a robotic system with 16 degrees of freedom (DOF) (9 DOF for the positioning module and 7 DOF for the surgery module) that has been developed and fabricated for prostate brachytherapy. Strategies to reduce needle deflection and target movement were incorporated after extensive experimental validation. Provision for needle motion and force feedback was included in the system to improve robot control and seed delivery. Preliminary experimental results reveal that the prototype system is sufficiently accurate in placing brachytherapy needles.

Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma.

To evaluate the distribution and density of epidermal growth factor (EGF) receptors (EGF-Rs) on urothelium, immunohistological studies using a monoclonal antibody to the binding portion of the human EGF-R were performed on frozen specimens of normal urothelium (N = 20), urothelium from patients with nonurothelial urological malignancies (N = 15) and inflammatory diseases (N = 8), low grade superficial transitional cell carcinomas (TCC) (N = 13), high grade superficial or invasive TCC (N = 28), and endoscopically normal appearing urothelium from patients with low grade superficial (N = 5) or high grade (N = 21) TCC elsewhere in the bladder (or ipsilateral renal pelvis/ureter). EGF-Rs are found only on the basal layer of epithelial cells (with scattered representation on intermediate cells) in 95% of normal urothelial specimens and 100% of pathological specimens without urothelial malignancy. Alternatively, 92.3% of specimens of low grade superficial TCC and 100% of high grade TCCs had EGF-Rs richly expressed on the superficial as well as the deeper layers of urothelium. This "malignant" distribution of EGF-Rs was also found on all specimens of endoscopically normal appearing urothelium in patients with TCC elsewhere. The density of EGF-Rs correlated closely with tumor grade on both "premalignant" and frankly neoplastic urothelium. We conclude that the expression of EGF-Rs on urothelium favors the interaction of premalignant and malignant tissue with urinary EGF. To determine if altering the physiochemical environment of urine could interfere with this interaction, the effects of pH on the binding of and growth responses to EGF were assessed on four human TCC cell lines. Scatchard plots demonstrated that varying pH from 5.0 to 7.5 did not significantly change the total number of receptors, but EGF-R affinity was reduced approximately 20-fold as pH decreased from 7.5 to 5 in each TCC target. Similarly, significant growth stimulation by EGF at pH 7.5 was abrogated at pH less than or equal to 7.0 while growth rates in the absence of EGF remained unchanged at lower pHs. It thus appears that urinary acidification may hold promise in the management and prevention of recurrent bladder cancer.

Normal and malignant human urothelium: in vitro effects of epidermal growth factor.

Cultures of human normal urothelial (HU) cells and transitional cell carcinoma (TCC) cell lines were tested for their ability to specifically bind and respond to epidermal growth factor (EGF). The criteria of response investigated were stimulation of growth and induction of ornithine decarboxylase (ODC) activity. All four human TCC cell lines tested were stimulated to grow by EGF (1-100 ng/ml) in a dose related fashion while only one of four HU cell cultures was similarly stimulated, and growth stimulation of this cell line occurred only at early passage. TCC and HU cells bound EGF to similar degrees with Kds of 0.86 nM for TCC and 2.54 nM for HU (P greater than 0.05) and 91637 +/- 9816 (SD) (high affinity) receptors/cell for TCC and 124275 +/- 16841 for HU (P greater than 0.10). Baseline ODC activity was statistically similar in the two TCC and the three HU cell cultures tested. However, EGF induced dose related ODC activity only in the TCC cell lines and not in any of the HU cell cultures. Thus, while both malignant and normal urothelium bind EGF equally well in vitro, only TCC responds to EGF in two parameters relevant to neoplasia: growth and induction of ODC activity.

Normal and malignant human urothelium: in vitro response to blockade of polyamine synthesis and interconversion.

To assess the effect of polyamine blockade on urinary epithelium, growth of normal human urothelial cell cultures and human transitional cell carcinoma (TCC) cell lines in the presence of various inhibitors of polyamine synthesis was evaluated. All four human TCC cell lines tested were quite sensitive to the specific inhibitor of ornithine decarboxylase, alpha-difluoromethylornithine (DFMO), requiring less than or equal to 1.0 mM DFMO to double generation time. Alternatively, all three human urothelial cultures tested required 5-20-fold higher DFMO concentrations to achieve similar growth inhibition. The inhibitory effect of DFMO on TCC was found to act synergistically with that of the inhibitor of S-adenosylmethionine decarboxylase, methylglyoxal bis(guanylhydrazone), and additively with that of recombinant beta-serine interferon. Addition of individual polyamines entirely prevented the inhibitory effects of DFMO and/or methylglyoxal bis(guanylhydrazone) but not that of beta-serine interferon. It appears that inhibition of polyamine synthesis and/or interconversion holds promise in the management of TCC and that the in vitro model described will be of value in investigating such clinical applications.

Serum-free medium for the in vitro growth of normal and malignant urinary bladder epithelial cells.

A serum-free medium, DH-S1, is described which is valuable for the establishment of primary cultures of normal and malignant transitional epithelium (transitional cell carcinoma of the bladder). Growth of epithelial cells in DH-S1 is facilitated but that of fibroblasts is suppressed. Another established human transitional cell carcinoma cell line, 647V, has grown continually in DH-S1 for over 36 passages. Morphological and antigenic studies comparing 647V cells growing in serum-containing and serum-free medium reveal differences which are pronounced at low cell density but which almost disappear at higher densities. A new human transitional cell carcinoma cell line, LA-B1, is described whose initial growth was supported by this serum-free medium.

Prostate-specific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer.

PURPOSE: A study of preradiation and postradiation, serial serum prostate-specific antigen (PSA) levels was performed in patients who had clinically localized prostate cancer. The prognostic value of the PSA in pretreatment evaluation and posttreatment follow-up was assessed. PATIENTS AND METHODS: Sixty-three patients who presented with clinically localized prostate cancer and who were treated with external-beam radiation therapy were followed-up for a median of 25 months. A serum PSA and physical examination were performed at 3-month intervals, and a bone scan was done yearly. An increase in PSA triggered an additional metastatic workup. Prostate rebiopsy was performed for new, palpable nodules or for a serial increase in PSA in the context of a negative metastatic workup. RESULTS: Forty-one patients remained recurrence-free and 22 recurred clinically, 15 distantly and seven locally. The PSA was the strongest, independent, pretreatment prognostic indicator (P = .019) among pretreatment PSA, stage, and grade, but lost significance when the serum prostatic acid phosphatase (PAP) status was included. The initial rate of the PSA decrease after radiation (median half-life, 2.6 months) failed to predict outcome. Recurrence-free patients reached postradiation PSA levels that were equivalent to those reported in disease-free male populations; failure of the PSA to reach such normal levels was a multivariate predictor of subsequent failure (P less than .037). All clinicopathologic documentations of failure were preceded by an increase in PSA levels during follow-up. Delayed versus early PSA increase was associated with clinically localized versus metastatic first recurrence. CONCLUSIONS: The serum PSA is an independent pretreatment and posttreatment predictor of outcome. Additionally, for a median follow-up of 25 months, delayed PSA failure is associated with clinically localized rather than metastatic recurrence, a relationship that may help in selection for local salvage therapy.

High-dose ketoconazole in advanced hormone-refractory prostate cancer: endocrinologic and clinical effects.

High-dose ketoconazole (400 mg orally three times a day) and physiologic replacement doses of glucocorticoids (hydrocortisone, 20 mg 8 AM, 10 mg 4 PM, and 8 PM) were administered to 38 patients with advanced prostatic cancer, refractory to at least initial testicular androgen deprivation. Thirty patients were completely evaluable; six were withdrawn due to possible ketoconazole-related toxicity and were considered drug failures. Two patients were unevaluable due to intercurrent therapy or inability to maintain follow-up. Ketoconazole was generally well tolerated. Mild or moderate nausea and vomiting occurred in 37% of patients, but required dose modification or discontinuation in only three patients; no hepatic damage was seen. Five of 36 patients (14%) responded to ketoconazole as determined by palpable or radiographic tumor mass reduction of 50% or greater and normalization of acid phosphatase or bone scan. Fifty percent of patients entered were stable at 90 days. Plasma androstenedione and dehydroepiandrosterone sulfate (DHEAS) were reduced markedly in almost all patients. Plasma testosterone (T) levels were low and remained unchanged, while gonadotropins were persistently elevated. Mean plasma ketoconazole content was 6.6 micrograms/mL after 28 days of therapy. While ketoconazole with hydrocortisone does suppress plasma androgens in advanced prostatic cancer patients, this infrequently causes regression of cancer that has progressed despite adequate testicular androgen ablation.

Relationship between in vivo acetylator phenotypes and cytosolic N-acetyltransferase and O-acetyltransferase activities in human uroepithelial cells.

The in vivo acetylator phenotype as well as N-acetyltransferase (NAT) and O-acetyltransferase (OAT) activities in cytosols from cultured uroepithelia were determined in 25 urological patients. In vivo acetylator phenotypes were categorized by determining the amounts of 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 1-methylxanthine in urine after the administration of a 200 mg dose of caffeine. Subjects were grouped according to the AFMU/AFMU + 1-methylxanthine ratio as "slow" (< 0.41) or "rapid" (> or = 0.41) acetylators. The uroepithelia were obtained from these subjects, cultured in vitro, and the cytosols were prepared. NAT and OAT activities were determined using 4-aminobiphenyl (ABP) and [3H]N-hydroxy-4-aminobiphenyl (N-OH-ABP) as substrates, respectively. In vivo phenotyping resulted in 18 patients being slow acetylators and seven rapid. The mean NAT and OAT activities for these different subsets were: 3.58 nmol/mg protein/min and 409 pmol/mg tRNA/mg protein for the slow; and 3.38 nmol/mg protein/min and 428 pmol/mg tRNA/mg protein for the rapid, respectively. Furthermore, in individual samples, NAT and OAT activities tended to parallel each other, implying that the same enzyme might catalyze both NAT and OAT activities in uroepithelia. The N-acetylation of ABP was inhibited by N-OH-ABP and also by p-aminobenzoic acid, a substrate which is preferred by the monomorphic NAT enzyme. Similarly, OAT-mediated binding of [3H]N-OH-ABP to tRNA was inhibited in a dose-dependent manner by ABP and p-aminobenzoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Toxicity evaluation of difluoromethylornithine: doses for chemoprevention trials.

This intergroup trial was developed to determine the toxicity of relatively low doses of difluoromethylornithine (DFMO) administered to humans for 1 year. The goal was to find an appropriate DFMO dose for use in human chemoprevention trials. Patients with resected superficial bladder cancers were studied. Following stratification, they were randomized to daily DFMO doses of 0.125, 0.25, 0.5, or 1.0 g/day for a planned period of 1 year. Patients were followed closely for evidence of drug toxicity. Seventy-six patients were evenly randomized (19 per group) to receive each dose of DFMO. Forty-nine patients received DFMO for more than 200 days while 35 received the drug for > or = 350 days. No substantial drug-related toxicity was observed at any dose. DFMO doses of > or = 1 g/day for periods up to 1 year appear to be without significant toxicity in most patients. This dose range may be appropriate for use in future human cancer chemoprevention trials.

Intraoperative optimized inverse planning for prostate brachytherapy: early experience.

PURPOSE: To demonstrate the feasibility of an intraoperative inverse planning technique with advanced optimization for prostate seed implantation. METHODS AND MATERIALS: We have implemented a method for optimized inverse planning of prostate seed implantation in the operating room (OR), based on the genetic algorithm (GA) driven Prostate Implant Planning Engine for Radiotherapy (PIPER). An integrated treatment planning system was deployed, which includes real-time ultrasound image acquisition, treatment volume segmentation, GA optimization, real-time decision making and sensitivity analysis, isodose and DVH evaluation, and virtual reality navigation and surgical guidance. Ten consecutive patients previously scheduled for implantation were included in the series. RESULTS: The feasibility of the technique was established by careful monitoring of each step in the OR and comparison with conventional preplanned implants. The median elapsed time for complete image capture, segmentation, GA optimization, and plan evaluation was 4, 10, 2.2, and 2 min, respectively. The dosimetric quality of the OR-based plan was shown to be equivalent to the corresponding preplan. CONCLUSION: An intraoperative optimized inverse planning technique was developed for prostate brachytherapy. The feasibility of the method was demonstrated through an early clinical experience.

Automated treatment planning engine for prostate seed implant brachytherapy.

PURPOSE: To develop a computer-intelligent planning engine for automated treatment planning and optimization of ultrasound- and template-guided prostate seed implants. METHODS AND MATERIALS: The genetic algorithm was modified to reflect the 2D nature of the implantation template. A multi-objective decision scheme was used to rank competing solutions, taking into account dose uniformity and conformity to the planning target volume (PTV), dose-sparing of the urethra and the rectum, and the sensitivity of the resulting dosimetry to seed misplacement. Optimized treatment plans were evaluated using selected dosimetric quantifiers, dose-volume histogram (DVH), and sensitivity analysis based on simulated seed placement errors. These dosimetric planning components were integrated into the Prostate Implant Planning Engine for Radiotherapy (PIPER). RESULTS: PIPER has been used to produce a variety of plans for prostate seed implants. In general, maximization of the minimum peripheral dose (mPD) for given implanted total source strength tended to produce peripherally weighted seed patterns. Minimization of the urethral dose further reduced the loading in the central region of the PTV. Isodose conformity to the PTV was achieved when the set of objectives did not reflect seed positioning uncertainties; the corresponding optimal plan generally required fewer seeds and higher source strength per seed compared to the manual planning experience. When seed placement uncertainties were introduced into the set of treatment planning objectives, the optimal plan tended to reach a compromise between the preplanned outcome and the likelihood of retaining the preferred outcome after implantation. The reduction in the volatility of such seed configurations optimized under uncertainty was verified by sensitivity studies. CONCLUSION: An automated treatment planning engine incorporating real-time sensitivity analysis was found to be a useful tool in dosimetric planning for prostate brachytherapy.

Proliferation-independent growth factor modulation of the radiation sensitivity of human prostate cells.

The survival of human prostatic epithelial cells irradiated in different physiological states is reported. Exponentially growing cells and contact-inhibited cells grown and irradiated in the presence of the growth factors epidermal growth factor (EGF) and bovine pituitary extract (bPE) had overlapping radiation dose-cell survival curves. However, when EGF and bPE were removed from exponentially growing cells before irradiation, an increase in radiosensitivity was observed if the cells were replated into medium containing growth factors (EGF and bPE) immediately after irradiation. Treating cells with the nonspecific growth factor receptor antagonist suramin had similar effects as did growth factor deprivation. In contrast, when growth factor-deprived cells were maintained in this same medium for 12 h postirradiation, an increase in radiation survival was observed. This increase in survival is attributed to the repair of potentially lethal damage (PLD). Both the increase in radiosensitivity induced by deprivation of growth factor before irradiation and the repair of PLD caused by deprivation of growth factor after irradiation were independent of changes in cellular proliferation.

The diagnosis of interstitial cystitis.

The diagnosis of interstitial cystitis can be firmly established by evaluating symptoms and history carefully, ruling out other diseases which can mimic its clinical picture, and performing the necessary cystoscopic examination (almost always under anesthesia). We also advocate that biopsy be performed in all individuals; although, since no pathognomonic abnormalities are demonstrable, it is unclear if the diagnosis of interstitial cystitis can be established or excluded by biopsy alone (unless, of course, another disease is encountered). While urodynamic studies are primarily useful to rule out interstitial cystitis, they may, in addition, have a role in subsequent management and/or in assessment of therapeutic response and thus, at least simple cystometry should probably also be performed. However, more complex urodynamic (e.g., electromyography, urethral pressure profilometry, etc.), radiographic (e.g., intravenous urography, voiding cystourethrography, or computerized axial tomography), laboratory or surgical (e.g., laparoscopy, prostate biopsy) studies are of minimal value in diagnosing interstitial cystitis and should only be done in the face of clinical evidence indicating their appropriateness.

Complication of Clorpactin WCS90 therapy for interstitial cystitis.

A case of ureteral fibrosis complicating Clorpactin WCS90 treatment for interstitial cystitis in a patient with vesicoureteral reflux is presented. The results of a laboratory experiment designed to study the effects of Clorpactin WCS90 on refluxing ureters are discussed.

Interstitial cystitis: early diagnosis, pathology, and treatment.

In a retrospective review, 52 patients with interstitial cystitis have been studied. Patients with persistent lower tract irritative symptoms, repeatedly sterile urine, and negative urine cytology must be suspected of having interstitial cystitis, and a diagnosis of urethral syndrome in such patients is highly questionable until cystoscopy under anesthesia has been performed. We believe that the finding of multiple petechia-like hemorrhages (glomerulations) on the second distention of the bladder is the hallmark of interstitial cystitis, and that a reduced bladder capacity and a Hunner's ulcer represent a different (classic) stage of this disease. In all stages, the characteristic histologic finidng is submucosal edema and vasodilation. The presence of eosinophils and mast cells is variable, and even in the classic disease the muscularis often appears to be normal. Immuno fluorescent studies and laboratory tests, including the fluorescent antinuclear antibody test (FANA), have not helped us to diagnose (or investigate) interstitial cystitis. Bladder instillations with a 0.4 per cent solution of oxychlorosene sodium (Clorpactin WCS-90) have provided remarkable relief for many patients with this disease, particulary those with the classic form.

Redo retroperitoneal lymphadenectomy for germ cell tumor.

Redo retroperitoneal lymph node dissection (RPLND) for the treatment of germ cell tumors (GCTs) is an uncommonly performed procedure. We report on 9 patients who underwent redo RPLND at the University of Wisconsin (UW) between January 1988 and December 1990. Indications for redo RPLND include: residual retroperitoneal mass after initial RPLND and chemotherapy, normal alpha-fetoprotein (AFP) and beta subunit of human chorionic gonadotropin (B-HCG), otherwise negative metastatic workup, and evidence that the mass is resectable. Overall, 6 of 9 patients are alive with no evidence of disease at a mean follow-up of thirty-two months. Preoperative evaluation, histopathology, morbidity, and technical aspects of this procedure, which is a critical part of the management of GCT, are reviewed.

Role of lymphadenectomy in the treatment of renal cell carcinoma.

We evaluated the role of lymphadenectomy (LND) in the prevention of local recurrence following radical nephrectomy for renal cell carcinoma (RCC) by two retrospective studies. In one, the relative importance of various tumor characteristics to the subsequent development of local recurrence was investigated in 37 patients who underwent radical nephrectomy and later progressed. In 29 evaluable patients, only nodal metastasis was predictive of local recurrence, which developed in 6 of 7 node-positive patients. In our second study the records of 69 consecutive patients with RCC who underwent radical nephrectomy with or without simultaneous LND (N = 42 and 27, respectively) were reviewed. Local control after LND was excellent in node-positive disease; in no node-positive patient with unilateral RCC has a local recurrence developed (N = 5). LND did not extend hospitalization or add to the morbidity of radical nephrectomy.

Recovery of epidermal growth factor in voided urine of patients with bladder cancer.

Epidermal growth factor (EGF), a potent mitogen and tumor promoter, is excreted in urine permitting it to incubate with urothelial cells. We have previously shown that the distribution of receptors for EGF (EGF-Rs) on malignant urothelium changes to favor contact between EGF-Rs and intraluminal EGF. OBJECTIVES. To determine if concentrations of EGF in voided urine are different in patients with transitional cell carcinoma (TCC) of the bladder than in those without this condition. METHODS. EGF was measured by radioimmunoassay in the urine of 54 patients with newly diagnosed TCC (16 with grade 1, Stage Ta lesions, and 38 with grade 3, Stage T > or = 2 lesions) and 66 pathologic and normal controls without TCC. Subjects were matched for age and good renal function. RESULTS. EGF concentrations were significantly reduced in patients with TCC compared with controls either when uncorrected (p < 0.0001) or corrected (p < 0.000000002) for urinary creatinine excretion. CONCLUSIONS. The reduced concentration of EGF in voided urine supports previous evidence that the urinary EGF/urothelial EGF-R interaction is important for TCC development and growth, and has the potential to serve as a marker of tumor persistence, recurrence, and therapeutic response.