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The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours.

Radiolabelled DNA-binding compounds can be used to increase the efficiency of radionuclide cancer therapy of disseminated disease. In this work, the aminoacridine compound N-[3-(acridine-9-ylamino)-propyl]-3-iodobenzamide (A3) labelled with the Auger-emitting nuclide 125I using Chloramine-T was studied. Optimal labelling conditions of 125I-A3 were investigated and the interaction with DNA was studied using a novel cell-free in vitro assay with naked human genomic DNA in agarose plugs. This novel assay showed to be simple and reliable. The results verify that 125I-A3 specifically binds DNA with low dissociation and is potent in causing double-strand breaks, yielding 1.0-1.4 breaks per decay. In conclusion, 125I-A3 is a most suitable DNA-binding compound for future therapeutic studies of Auger-electron emitters like 125I.

Objectives: To evaluate the effect of adjuvant chemotherapy in invasive bladder cancer.Methods: We conducted a systematic review and meta-analysis of updated individual patient data from all available randomised controlled trials comparing local treatment plus adjuvant chemotherapy versus the same local treatment alone.Results: Analyses were based on 491 patients from six trials, representing 90% of all patients randomised in cisplatin-based combination chemotherapy trials and 66% of patients from all eligible trials. The power of this meta-analysis is clearly limited. The overall hazard ratio for survival of 0.75 (95% CI 0.60-0.96, p = 0.019) suggests a 25% relative reduction in the risk of death for chemotherapy compared to that on control. Cox regression suggests that small imbalances in patient characteristics do not bias the results in favour of chemotherapy. However, the impact of trials that stopped early, of patients not receiving allocated treatments or not receiving salvage chemotherapy is less clear.Conclusions: This IPD meta-analysis provides the best evidence currently available on the role of adjuvant chemotherapy for invasive bladder cancer. However, at present there is insufficient evidence on which to reliably base treatment decisions. These results highlight the urgent need for further research into the use of adjuvant chemotherapy. The results of appropriately sized randomised trials, such as the ongoing EORTC-30994 trial are needed before any definitive conclusions can be drawn. (c) 2005 Elsevier B.V. All rights reserved.

Purpose: To study survival of cultured U-343MGaCl 2: 6 glioma cells after incubation with boron-containing liposomes targeting the epidermal growth factor receptor following neutron irradiation.Materials and methods: Epidermal growth factor-tagged liposomes were loaded with water-soluble boronated acridine developed for boron neutron capture therapy, (BNCT). Cellular uptake and distribution were studied. Further, cells were placed at 3 cm depth in a phantom and exposed to an epithermal neutron beam to study clonogenic cell survival.Results: The cellular uptake of boron reached 90 ppm and it was determined by subcellular fractionation that most of the cell-associated boron was located outside of the nucleus. For clonogenic survival, the cells were incubated with epidermal growth factor receptor-targeted liposomes for 4 hours resulting in a cellular concentration of 55 ppm boron (11 ppm B-10). At a fluence of 3 x 10(12) neutrons/cm(2) the cell killing effect of the boron-containing epidermal growth factor-liposomes was about ten times higher than for neutrons only. Furthermore, theoretical calculation of the survival by enriched compound (55 ppm B-10), using the parameters from non-enriched compound (11 ppm B-10), shows that the killing effect in this case would be approximately five orders of magnitude higher than for neutrons only.Conclusion: The results in this study show that epidermal growth factor-receptor targeted liposomes are suitable as tumor-cell delivery agents of boron for BNCT and support further studies to demonstrate their effectiveness in vivo.

4591 Background: Current intravesical treatments of Ta-T1 urinary bladder cancer have shown good efficacy, but improvement is needed. We evaluated the efficacy and toxicity of 3 different dose regimens of gemcitabine administered intravesically to patients with urinary bladder cancer. Methods: Patients with histologically proven stage Ta, grade 1/2 urinary bladder cancer and a marker lesion diameter of 0.5 to 1 cm after transurethral resection were enrolled; they received gemcitabine 2000 mg that was instilled and kept in the bladder for 1 hour. Patients were randomized to one of the following regimens: 1 dose (group A); 2 doses/week for 3 weeks (group B); or 1 dose/week for 6 weeks (group C). Response was assessed via cystoscopy 9 weeks after the end of treatment. Results: Between January 2002 and March 2004, 32 patients were enrolled; 2 were excluded due to protocol violations (groups B and C). Of the 30 randomized patients (11, group A; 10, group B; 9, group C), 1 patient was not evaluable for efficacy (group A). Nine patients (31%) reported a complete response (1, group A; 4, group B; 4, group C); an additional 9 patients (31%) had no response; and 11 (38%) had a tumor increase. All 30 patients were evaluable for toxicity. No NCI-CTC grade 3/4 toxicity was observed. Grade 1/2 nausea was reported in 5 patients (17%), and grade 1/2 fever in 2 patients (7%). One patient (3%) had grade 1 thrombocytopenia, which was reversible, and 1 of the patients with fever had grade 1 anemia, which was also reversible. Instillations were discontinued due to toxicity for only 1 patient (nausea, fever). Ten patients (33%) were unable to retain the drug for the full hour. Conclusions: As an intravesical instillation, gemcitabine showed activity and was well tolerated. The single-dose regimen does not appear to be effective. Also, twice-weekly doses do not appear to be more effective than once-weekly doses. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly

This article discusses the development of international guidelines for the diagnosis, treatment, follow-up, and prevention of low-grade Ta urothelial carcinoma of the bladder. The authors, who are experts in this field from 3 continents and 7 countries, reviewed the English language literature through September 2004. The results of the authors' deliberations are presented here as a consensus document. The objective of this study was to determine the optimal diagnostic workup, treatment, follow-up, and prevention of low-grade, Ta urothelial carcinoma of the bladder. A consensus conference convened by the World Health Organization (WHO) and the Société Internationale d'Urologie (SIU) met to critically review the literature on the diagnosis and treatment of low-grade Ta urothelial carcinoma of the bladder. Research was conducted using Medline; this search engine also was used to identify additional works not detected at the initial search. Evidence-based recommendations for diagnosis and management of the disease were made with reference to a 4-point scale. Low-grade Ta urothelial carcinoma of the bladder is a well-studied subject with many level 1 and 2 evidence references that support clinical practice. Findings from 135 reviewed citations are summarized. Many grade A and B recommendations on the diagnostic workup and management of this disease can be given with level 1 and 2 evidence based on prospective randomized clinical trials of sufficient statistical power. This should improve the quality of the treatment of this disease.

OBJECTIVETo evaluate the expression of HER2 receptors (previously reported to be over‐expressed in malignant urothelium) in both primary tumours and metastases of transitional cell cancer, using two different staining methods and two different scoring techniques, considering the potential use of these receptors as targets for planned systemic anti‐HER2 nuclide‐based treatment.MATERIALS AND METHODSHER2 expression was evaluated with two different immunohistochemical methods in 90 patients with primary urinary bladder cancer tumours and corresponding metastases. Sections were first stained with the commercially available breast cancer test kit (HercepTest®, Dako, Glostrup, Denmark). Parallel sections were then stained with a modified HercepTest procedure. Two different evaluation criteria were compared; the HercepTest score that requires ≥ 10% stained tumour cells (as for breast cancer) and a proposed ‘Target score’ that requires >67% stained tumour cells. The latter score is assumed to be preferable for HER2‐targeted radionuclide therapy.RESULTSUsing the HercepTest kit, the Target score gave lower fractions of positive primary tumours and metastases than the HercepTest score. The modified HercepTest staining procedure and Target score gave high HER2 values in 80% of primary tumours and 62% of metastases, which is considerably more than that obtained with the HercepTest staining and score. There was a significant decrease in HER2 positivity with increasing distance from the primary tumour. In nine sentinel‐node metastases assessed, all but one were HER2‐positive. Considering all regional metastases, 74% were positive, and of distant metastases, 47%; 72% of the patients with positive primary tumours also expressed HER2 in their metastases.CONCLUSIONSWhen combining the modified HercepTest with customised evaluation criteria, more HER2‐positive tumours were diagnosed. The degree of HER2 down‐regulation was significantly higher in distant than in regional metastases. HER2‐targeted therapy may be an alternative or complementary to other methods in the future treatment of metastatic urinary bladder carcinoma.

T1 transitional cell cancer of the urinary bladder is associated with a significant risk of tumor progression when transurethral resection (TUR) is the only treatment. Additional intravesical immunotherapy can reduce this risk; however, long-term results of more than 15 years of follow-up indicate that almost half of the patients may lose their bladder or even die due to recurrent tumor. The alternative to TUR is cystectomy at either the initial presentation or time of first recurrence. However, although the results of this treatment strategy are encouraging, an unknown percentage of patients will lose their bladder and go on to experience all possible complications of urinary diversion unnecessarily. The central issue of conservative treatment but also the indication for cystectomy is the quality of TUR. From the present literature, it is evident that a 'textbook TUR' cannot be performed on every patient, i.e. macroscopical clearance of the bladder from tumor, separate thorough resection of the tumor base and separate biopsies of the borders of the resection area. Moreover, even in cases of a so-called 'correct TUR', a significant percentage of residual tumor is left behind and will be the source of local recurrence or progression. In addition, TUR specimens may be difficult to diagnose accurately, especially in respect to grade and stage. Recent publications demonstrate that the routinely performed second TUR detects residual tumors of similar or higher stage in a significant percentage of patients. The clinical implications of these findings can be considerable as the absence or presence of tumor may determine whether patients undergo conservative or aggressive treatment. Moreover, results of retrospective studies support this suggestion. Currently, there is no standard appropriate treatment of T1 tumors. However, we strongly recommend that future studies on the conservative treatment of T1 tumors include a second TUR within 2 to 4 weeks after the first one.

You have accessJournal of UrologyDiscussed Poster, Sunday, May 9, 2004, 8:00 am - 12:00 pm1 Apr 2004315: CT-Enhanced Lymphoscintigraphy in Detecting Sentinel Lymph Nodes of Invasive Bladder Cancer Amir Sherif, Ulrike Garske, Manuel De La Torre, Per-Uno Malmstrom, and Magnus Thorn Amir SherifAmir Sherif More articles by this author , Ulrike GarskeUlrike Garske More articles by this author , Manuel De La TorreManuel De La Torre More articles by this author , Per-Uno MalmstromPer-Uno Malmstrom More articles by this author , and Magnus ThornMagnus Thorn More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)37577-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "315: CT-Enhanced Lymphoscintigraphy in Detecting Sentinel Lymph Nodes of Invasive Bladder Cancer." The Journal of Urology, 171(4S), p. 83 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 171Issue 4SApril 2004Page: 83 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Amir Sherif More articles by this author Ulrike Garske More articles by this author Manuel De La Torre More articles by this author Per-Uno Malmstrom More articles by this author Magnus Thorn More articles by this author Expand All Advertisement PDF downloadLoading ...

You have accessJournal of UrologyDiscussed Poster, Sunday, May 9, 2004, 8:00 am - 12:00 pm1 Apr 2004277: Long Term Follow Up of a Randomised Study of BCG Versus Mitomycin-C in High Risk Superficial Bladder Cancer Truls Gårdmark, Per-Uno Malmstrom, Peter Wiklund, Staffan Jahnson, Hans Wijkström, and Rolf Wahlquist Truls GårdmarkTruls Gårdmark More articles by this author , Per-Uno MalmstromPer-Uno Malmstrom More articles by this author , Peter WiklundPeter Wiklund More articles by this author , Staffan JahnsonStaffan Jahnson More articles by this author , Hans WijkströmHans Wijkström More articles by this author , and Rolf WahlquistRolf Wahlquist More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)37539-6AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "277: Long Term Follow Up of a Randomised Study of BCG Versus Mitomycin-C in High Risk Superficial Bladder Cancer." The Journal of Urology, 171(4S), p. 73 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 171Issue 4SApril 2004Page: 73 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Truls Gårdmark More articles by this author Per-Uno Malmstrom More articles by this author Peter Wiklund More articles by this author Staffan Jahnson More articles by this author Hans Wijkström More articles by this author Rolf Wahlquist More articles by this author Expand All Advertisement Loading ...

The incidence of lung cancer is increasing throughout the world and is the most common cause of cancer-related death. Early detection followed by surgery has a reasonable, curative potential, but 30-50% of patients experience relapses. The immunohistochemical expressions of HER-2, EGFR and COX-2 were investigated in 53 resected non-small cell lung carcinomas and correlated to microvessel density and clinical data. HER-2, EGFR and COX-2 overexpressions were demonstrated in 15%, 30% and 40% of the tumours, respectively. In adenocarcinomas, HER-2 and COX-2 overexpression were more common, whereas in squamous cell carcinomas, EGFR overexpression was more common. COX-2 expression correlated with HER-2 expression (p = 0.002), and demonstrated a trend towards a correlation with microvessel density (p = 0.10). None of the markers alone had any impact on survival. However, HER-2+/EGFR- tumours proved to have a poor prognosis. In conclusion, adjuvant treatment with HER-2 antagonists might be a future treatment option in resected non-small cell lung cancer patients, especially when HER-2 is overexpressed without a concomitant overexpression of EGFR.

You have accessJournal of UrologyDiscussed Poster, Sunday, May 9, 2004, 8:00 am - 12:00 pm1 Apr 2004327: Downstaging Analysis Following Neoadjuvant Cisplatinum Based Combination Chemotherapy for Invasive Bladder Carcinoma.Evaluation of Two Combined Prospective Nordic Trials Amir Sherif, Erkki Rintala, Oddvar Mestad, Lars Holmberg, Jonas Nilsson, Sten Nilsson, and Per-Uno Malmstrom Amir SherifAmir Sherif More articles by this author , Erkki RintalaErkki Rintala More articles by this author , Oddvar MestadOddvar Mestad More articles by this author , Lars HolmbergLars Holmberg More articles by this author , Jonas NilssonJonas Nilsson More articles by this author , Sten NilssonSten Nilsson More articles by this author , and Per-Uno MalmstromPer-Uno Malmstrom More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(18)37589-XAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "327: Downstaging Analysis Following Neoadjuvant Cisplatinum Based Combination Chemotherapy for Invasive Bladder Carcinoma.Evaluation of Two Combined Prospective Nordic Trials." The Journal of Urology, 171(4S), p. 86 © 2016 by American Urological AssociationFiguresReferencesRelatedDetails Volume 171Issue 4SApril 2004Page: 86 Advertisement Copyright & Permissions© 2016 by American Urological AssociationMetricsAuthor Information Amir Sherif More articles by this author Erkki Rintala More articles by this author Oddvar Mestad More articles by this author Lars Holmberg More articles by this author Jonas Nilsson More articles by this author Sten Nilsson More articles by this author Per-Uno Malmstrom More articles by this author Expand All Advertisement PDF downloadLoading ...

OBJECTIVES:To evaluate whether, in patients with carcinoma in situ (CIS) of the urinary bladder, alternating instillation therapy with mitomycin C (MMC) and bacillus Calmette-Guerin (BCG) was more effective and less toxic than conventional BCG monotherapy. METHODS:Patients were stratified prospectively for primary, secondary, and concomitant CIS and randomized to one of two regimens. Patients in the alternating group received six weekly intravesical instillations of MMC 40 mg, followed by alternating monthly instillations of BCG 120 mg and MMC for one year. In the monotherapy group, only BCG was instilled on the same schedule. RESULTS:Of 323 enrolled patients, 304 were eligible for analysis. After an overall median follow-up of 56 months, the Kaplan-Meier disease-free estimate for BCG monotherapy was significantly better than that for alternating therapy (p=0.03; log rank test). Risk for progression appeared lower in the BCG monotherapy group (p=0.07), but no differences existed in survival. Besides the regimen, CIS category also predicted outcome to some extent. BCG monotherapy caused significantly more local side-effects and premature cessation of instillation treatment than did the alternating therapy. However, no differences were observed in the number of serious side-effects. CONCLUSION:One-year BCG monotherapy was more effective than the alternating therapy for reducing recurrence and compared well with the best regimens reported from substantially smaller series. The alternating therapy was better tolerated.

PURPOSE:Transitional cell carcinoma (TCC) of the prostate/prostatic urethra is a risk factor for urethral recurrence after radical cystoprostatectomy for TCC. Using conventional sectioning techniques, prostate involvement (prostatic urethra, acini, ducts and/or stroma) has been detected in a range of 10-20% of the patients, whereas transversal whole mount sectioning has revealed 43 % prostate involvement in two reported series. Due to different mechanisms of prostate involvement (intraurethral, extravesical and direct overgrowth into the prostatic stroma), preoperative transurethral biopsies of the prostate might not accurately determine such involvement. In this study we examine the prostate using a longitudinal whole mount sectioning technique, correlate TCC of the prostate with the characteristics of the bladder tumour and, thus, validate the preoperative transurethral resection biopsies.MATERIAL AND METHODS:Patients scheduled for cystoprostatectomy or cystoprostatourethrectomy were investigated by preoperative resection biopsies from the prostatic urethra and mapping of the bladder. The cystectomy specimen was fixated with the bladder filled with formalin, and the prostate and bladder neck examined using longitudinal whole mount sectioning.RESULTS:In 13 of the 43 (30%), patients TCC was identified in the prostate. Of these 13 patients, 9 had been identified in the preoperative resection biopsies from the prostatic urethra. Of the patients with prostatic involvement, 46% had carcinoma in situ (Cis) in the bladder neck/trigone and 38% had multifocal Cis in the bladder. Comparing this to the group of patients without prostatic involvement, the respectively figures are 20% and 23%. A tumour in the trigone, either invasive or Cis, was detected in 5/13 patients with prostatic involvement as compared to one patient (3%) without TCC of the prostate. Multiple bladder tumours were more common in patients with prostatic involvement and were larger (3.2 cm compared to 2.2 cm).CONCLUSIONS:Preoperative resection biopsies from the prostatic urethra do not always detect TCC in the prostate. Cis in the bladder neck/trigone or multifocal and multiple bladder tumours could be risk factors for prostate involvement of TCC.

Background Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment 06 survival in patients with this disease.Methods We analysed updated data for 2688 individual patients from ten available randomised trials.Findings Platinum-based combination chemotherapy showed a significant benefit to overall survival (combined hazard ratio [HR] 0.87 [95% Cl 0.78-0.98, p=0.016]; 13% reduction in risk of death; 5% absolute benefit at 5 years [1-7]; overall survival increased from 45% to 50%). This effect was observed irrespective of the type of local treatment, and did not vary between subgroups of patients. The HR for all trials, including those using single-agent cisplatin, tended to favour neoadjuvant chemotherapy (HR=0.91, 95% Cl 0.83-1.01) although this tendency was not significant (p=0.084). Although platinum based combination chemotherapy was beneficial, there was no evidence to support the use of single-agent platinum; indeed, there was a significant difference in the effect between these groups of trials (p=0.044).Interpretation This improvement in survival encourages the use of platinum-based combination chemotherapy for patients with invasive bladder cancer.