Guidance of adjuvant instillation in intermediate-risk non-muscle invasive bladder cancer by drug screens in patient derived organoids: a single center, open-label, phase II trial.

BACKGROUND: In intermediate-risk non-muscle invasive bladder cancer (NMIBC) clinical guidelines suggest an adjuvant instillation with a chemotherapeutic agent. However, the agent and regimen are not clearly defined. Worldwide, less than 15% of patients receive this adjuvant chemotherapeutic instillation. We recently developed a pipeline for the generation of patient derived organoids (PDO) in NMIBC. In this phase II trial, we aim to use our in vitro pipeline to select the most effective drug for chemotherapeutic instillation in NMIBC patients. METHODS: Patients with first diagnosis of intermediate-risk NMIBC that are directed to transurethral resection of bladder tumor (TURBT) are enrolled. During TURBT, tumor is sampled, and specimens are directed to generate PDO. Once the PDO are formed, drug screens on them for Epirubicin, Mitomycin C, Gemcitabine and Docetaxel are performed. The drug with the highest antitumor activity in vitro will then be selected for 6 adjuvant intravesical instillations once weekly. Thereafter, patients are followed according to clinical guidelines by cystoscopy. DISCUSSION: The aim of this trial is to use drug screens in PDO to precise treatment selection for adjuvant instillation therapies in patients with intermediate-risk NMIBC. The ultimate goal of this trial is to reduce the risk of cancer recurrence. In the future, we aim to conduct clinical multicenter trials with an increased sample size, a broader panel of compounds and a focus on the reduction of cancer recurrence by precision delivery of care. Trial registration NCT05024734.

A longitudinal study evaluating interim assessment of neoadjuvant chemotherapy for bladder cancer.

OBJECTIVES: To evaluate the usefulness of radiological re-staging after two and four cycles of neoadjuvant chemotherapy (NAC), the impact of re-staging on further patient management, and the correlation between clinical and final pathological tumour stage at radical cystectomy (RC). PATIENTS AND METHODS: We conducted a longitudinal, single-centre, cohort study of prospectively collected consecutive patients who underwent NAC and RC for urothelial muscle-invasive bladder cancer between July 2001 and December 2017. Patients underwent repeated computed tomography scans for re-staging after two cycles of NAC and after completion of NAC before RC. RESULTS: Of 180 patients, 110 had ≥four cycles of NAC and had complete imaging available. In the entire cohort, further patient management was only changed in 2/180 patients (1.1%) after two cycles of NAC based on radiological findings. Patients who were stable after two cycles but then downstaged after at least four cycles of NAC had a similarly lowered risk of death (hazard ratio [HR] 0.53). Only one patient downstaged after two cycles was subsequently upstaged after four cycles. Clinical downstaging was observed in 51 patients (46%), 55 patients (50%) had no change in clinical stage and four patients (3.6%) were clinically upstaged. Patients clinically downstaged after four cycles of NAC had a lower risk of death (HR 0.49, 95% confidence interval 0.25-0.94; P = 0.033) compared to those with no change or upstaged after completion of NAC. CONCLUSIONS: Re-staging of muscle-invasive bladder cancer after two cycles of NAC offers little additional information, rarely changes patient management, and may therefore be omitted, whereas re-staging after completion of NAC by CT is a strong predictor of overall survival.

Seminal Vesical Sparing Cystectomy for Bladder Cancer is Feasible with Good Functional Results without Impairing Oncological Outcomes: A Longitudinal Long-Term Propensity-Matched Single Center Study.

PURPOSE: Seminal vesicle-sparing radical cystectomy has been reported to improve short-term functional results without compromising oncological outcomes. However, there is still a lack of data on long-term outcomes after seminal vesicle-sparing radical cystectomy. The aim of this study was to compare oncological and functional outcomes in patients after seminal vesicle-sparing vs nonseminal vesicle-sparing radical cystectomy. MATERIALS AND METHODS: Oncological and functional outcomes of 470 consecutive patients after radical cystectomy and orthotopic ileal reservoir from 2000 to 2017 were evaluated. They were stratified into 6 groups according to nerve-sparing and seminal vesicle-sparing status as attempted during surgery: no sparing at all (55), unilateral nerve sparing (159), bilateral nerve sparing (132), unilateral seminal vesicle-sparing and unilateral nerve sparing (30), unilateral seminal vesicle sparing and bilateral nerve sparing (45), and bilateral seminal vesicle sparing (49) and used propensity modeling to adjust for preoperative differences. RESULTS: Median followup among the entire cohort was 64 months. Among the 6 groups, our analysis showed no difference in local recurrence-free survival (p=0.173). However, progression-free, cancer-specific and overall survival were more favorable in patients with seminal vesicle-sparing radical cystectomy (p <0.001, p=0.006 and p <0.001, respectively). Proportions of patients with erectile function recovery were higher in the seminal vesicle-sparing groups at all time points in all analyses, respectively, with pronounced earlier recovery in patients with bilateral seminal vesicle sparing. Importantly, patients with seminal vesicle sparing were significantly less in need of erectile aids to achieve erection and intercourse. Over the whole period, daytime urinary-continence was significantly better in the seminal vesicle sparing groups (OR 2.64 to 5.21). CONCLUSIONS: In a highly selected group of patients, seminal vesicle sparing radical cystectomy is oncologically safe and results in excellent functional outcomes that are reached at an earlier time point after surgery and remain superior over a longer period of time.

Genomic Subtyping in Bladder Cancer.

PURPOSE OF REVIEW: Molecular characterization of cancer allows us to understand oncogenesis and clinical prognosis as well as facilitates development of biomarkers and treatment. Our aim was to review the current literature on genomic characterization of bladder cancer, and how far we are in implementing genomics into clinical practice. RECENT FINDINGS: Bladder cancers are molecularly diverse tumors with a high mutational rate. On molecular level, bladder cancer can be categorized into at least six subtypes called luminal-papillary, luminal-unstable, luminal non-specified, basal-squamous, neuroendocrine-like, and stroma-rich. These subtypes have characteristic genomic and transcriptomic profiles and appear to have different prognoses. Several molecular subtypes have been identified in bladder cancer. Prospective trials are underway to validate the applicability of genomic subtypes for clinical decision making. Further integrative analyses of genomic alterations, gene expression, epigenetics, and proteomics need to be performed before genomic subtyping can be attained in clinical practice.

Correction to: Genomic Subtyping in Bladder Cancer.

The original version of this article contained a mistake. The included Conflict of Interest statement was incorrect.

Evolution of Urothelial Bladder Cancer in the Context of Molecular Classifications.

Bladder cancer is a heterogeneous disease that is not depicted by current classification systems. It was originally classified into non-muscle invasive and muscle invasive. However, clinically and genetically variable tumors are summarized within both classes. A definition of three groups may better account for the divergence in prognosis and probably also choice of treatment. The first group represents mostly non-invasive tumors that reoccur but do not progress. Contrarily, the second group represent non-muscle invasive tumors that likely progress to the third group, the muscle invasive tumors. High throughput tumor profiling improved our understanding of the biology of bladder cancer. It allows the identification of molecular subtypes, at least three for non-muscle invasive bladder cancer (Class I, Class II and Class III) and six for muscle-invasive bladder cancer (luminal papillary, luminal non-specified, luminal unstable, stroma-rich, basal/squamous and neuroendocrine-like) with distinct clinical and molecular phenotypes. Molecular subtypes can be potentially used to predict the response to treatment (e.g., neoadjuvant chemotherapy and immune checkpoint inhibitors). Moreover, they may allow to characterize the evolution of bladder cancer through different pathways. However, to move towards precision medicine, the understanding of the biological meaning of these molecular subtypes and differences in the composition of cell subpopulations will be mandatory.

Forty years of cisplatin-based chemotherapy in muscle-invasive bladder cancer: are we understanding how, who and when?

PURPOSE: For 40 years cisplatin-based chemotherapy has been administered to patients with muscle-invasive bladder cancer (MIBC). The best evidence of its efficacy is found in the context of neoadjuvant chemotherapy (NAC). However, the benefit to the patient is modest, with an improvement in 5-year overall survival of only 5-8%. Approximately 60% of patients still have muscle-invasive disease at cystectomy despite NAC. Selecting patients based on the likelihood of response appears to be a promising strategy to improve on this modest benefit. To realize this promise, researchers are investigating biomarkers for identifying responders and non-responders prior to NAC. METHODS: In this review, we discuss a number of tissue- and liquid-based biomarkers associated with the response to NAC. RESULTS AND CONCLUSIONS: We elaborate biomarkers at the methylation, DNA, RNA and protein levels and give their current status in clinical trials and/or their implementation in daily clinical practice. In particular, detection of alterations in DNA damage repair pathways as well as molecular subtypes seems to be a promising method for identifying responders to NAC. Furthermore, we illustrate liquid-based biomarkers. Circulating tumor DNA (ctDNA) in patient blood and urine appear to offer an elegant way for biological characterization of MIBC. Recent data show that the presence of ctDNA is limited in patients with localized MIBC being considered for NAC. At this disease stage, ctDNA in patient urine may be more promising for the genomic characterization of MIBC. However, ctDNA in blood or urine has not yet been rigorously investigated in this clinical context.

Update of the ICUD-SIU International Consultation on Bladder Cancer 2018: urinary diversion.

PURPOSE: To provide a comprehensive overview and update of the joint consultation of the International Consultation on Urological Diseases (ICUD) and Société Internationale d'Urologie on Bladder Cancer Urinary Diversion (UD). METHODS: A detailed analysis of the literature was conducted reporting on the different modalities of UD. For this updated publication, an exhaustive search was conducted in PubMed for recent relevant papers published between October 2013 and August 2018. Via this search, a total of 438 references were identified and 52 of them were finally eligible for analysis. An international, multidisciplinary expert committee evaluated and graded the data according to the Oxford System of Evidence-based Medicine. RESULTS: The incidence of early complications has been reported retrospectively in the range of 20-57%. Unfortunately, only a few randomized controlled studies exist within the field of UD. Consequently, almost all studies used in this report are of level 3-4 evidence including expert opinion based on "first principles" research. CONCLUSIONS: Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Complications can occur up to 20 years after surgery, emphasizing the need for lifelong follow-up. Progress has been made to prevent complications implementing robotic surgery and fast track protocols. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good results.

Perioperative chemotherapy in upper tract urothelial carcinoma: a comprehensive review.

PURPOSE: To evaluate the role of neoadjuvant (NAC) and adjuvant chemotherapy (AC) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). METHODS: A comprehensive review of the current literature was performed searching for all studies investigating NAC and AC in UTUC in MEDLINE and https://clinicaltrials.gov , prior to April 2016. The following keywords were used: "ureteral neoplasms," "urothelium," "ureter," "upper tract urothelial," "chemotherapy," "adjuvant," "neoadjuvant" and relevant variants. RESULTS: No randomized trials investigated the role of AC or NAC for UTUC. There was one prospective study with n = 36 patients investigating AC with carboplatin-paclitaxel. We included 14 retrospective studies (four in the NAC and ten in the AC setting), with a total of 694 patients receiving cisplatin-based or non-cisplatin-based AC after RNU and 1437 patients undergoing RNU alone. We found that the current literature, mainly based on retrospective studies, suggests significant overall and cancer-specific survival benefits for AC in UTUC. NAC appears promising, with favorable pathologic response rates up to 14%. CONCLUSIONS: Evidence is scarce for both NAC and AC use in UTUC. This comprehensive review suggests promising response rates for NAC and a survival benefit for patients treated with AC. Prospective randomized trials are needed to establish the role of AC and NAC in UTUC.

Recent progress with next-generation biomarkers in muscle-invasive bladder cancer.

Muscle-invasive bladder cancer is a heterogeneous disease with different clinical phenotypes. Histomorphological variants, variable mutation rates and aberrant protein expression, along with the recently identified molecular subtypes, have been linked to prognosis and response to therapy. Complete response to chemotherapy and outcome after radical cystectomy are difficult to predict. To date, no validated pathological or clinical test exists to predict response. Advances in high-throughput, next-generation, genomic techniques to study the molecular pathways that govern the disease have led to novel strategies for the identification of such biomarkers relevant to muscle-invasive bladder cancer. Progress has been made not only in tissue-based biomarkers, but also in the liquid biopsy field. Liquid biopsies represent an opportunity to obtain patient samples non-invasively at multiple time-points during their treatment course without the need for biopsy. Especially in the metastatic setting, this will allow monitoring of the molecular evolution of the tumor under treatment, which should inform subsequent therapeutic decisions.

Neuroendocrine Differentiation in Metastatic Conventional Prostate Cancer Is Significantly Increased in Lymph Node Metastases Compared to the Primary Tumors.

Neuroendocrine serum markers released from prostate cancers have been proposed for monitoring disease and predicting survival. However, neuroendocrine differentiation (NED) in various tissue compartments of metastatic prostate cancer is poorly described and its correlation with specific tumor features is unclear. NED was determined by Chromogranin A expression on immunostains from a tissue microarray of 119 nodal positive, hormone treatment-naïve prostate cancer patients who underwent radical prostatectomy and extended lymphadenectomy. NED in the primary cancer and in the metastases was correlated with tumor features and survival. The mean percentage of NED cells increased significantly (p < 0.001) from normal prostate glands (0.4%), to primary prostate cancer (1.0%) and nodal metastases (2.6%). In primary tumors and nodal metastases, tumor areas with higher Gleason patterns tended to display a higher NED, although no significance was reached. The same was observed in patients with a larger primary tumor volume and higher total size and number of metastases. NED neither in the primary tumors nor in the metastases predicted outcome significantly. Our data suggest that (a) increasing levels of neuroendocrine serum markers in the course of prostate cancer might primarily derive from a poorly differentiated metastatic tumor component; and (b) NED in conventional hormone-naïve prostate cancers is not significantly linked to adverse tumor features.

Prediction of Lymph Node Metastasis in Patients with Bladder Cancer Using Whole Transcriptome Gene Expression Signatures.

PURPOSE: Clinical staging in patients with muscle invasive bladder cancer misses up to 25% of lymph node metastasis. These patients are at high risk for disease recurrence and improved clinical staging is critical to guide management. MATERIALS AND METHODS: Whole transcriptome expression profiles were generated in 199 patients who underwent radical cystectomy and extended pelvic lymph node dissection. The cohort was divided randomly into a discovery set of 133 patients and a validation set of 66. In the discovery set features were identified and modeled in a KNN51 (K-nearest neighbor classifier 51) to predict pathological lymph node metastases. Two previously described bladder cancer gene signatures, including RF15 (15-gene cancer recurrence signature) and LN20 (20-gene lymph node signature), were also modeled in the discovery set for comparison. The AUC and the OR were used to compare the performance of these signatures. RESULTS: In the validation set KNN51 achieved an AUC of 0.82 (range 0.71-0.93) to predict lymph node positive cases. It significantly outperformed RF15 and LN20, which had an AUC of 0.62 (range 0.47-0.76) and 0.46 (range 0.32-0.60), respectively. Only KNN51 showed significant odds of predicting LN metastasis with an OR of 2.65 (range 1.68-4.67) for every 10% increase in score (p <0.001). RF15 and LN20 had a nonsignificant OR of 1.21 (range 0.97-1.54) and 1.39 (range 0.52-3.77), respectively. CONCLUSIONS: The new KNN51 signature was superior to previously described gene signatures for predicting lymph node metastasis. If validated prospectively in transurethral resection of bladder tumor samples, KNN51 could be used to guide patients at high risk to early multimodal therapy.

Complications and Short-Term Explantation Rate Following Artificial Urinary Sphincter Implantation: Results from a Large Middle European Multi-Institutional Case Series.

UNLABELLED: Background/Aims/Objectives: To analyze perioperative complication and short-term explantation rates after perineal or penoscrotal single-cuff and double-cuff artificial urinary sphincter (AUS) implantation in a large middle European multi-institutional patient cohort. METHODS: 467 male patients with stress urinary incontinence underwent implantation of a perineal single-cuff (n = 152), penoscrotal single-cuff (n = 99), or perineal double-cuff (n = 216) AUS between 2010 and 2012. Postoperative complications and 6-month explantation rates were assessed. For statistical analysis, Fisher's exact test and Kruskal-Wallis rank sum test, and a multiple logistic regression model were used (p < 0.05). RESULTS: Compared to perineal single-cuff AUS, penoscrotal single-cuff implantation led to significantly increased short-term explantation rates (8.6% (perineal) vs. 19.2% (penoscrotal), p = 0.019). The postoperative infection rate was significantly higher after double-cuff compared to single-cuff implantation (6.0% (single-cuff) vs. 13.9% (double-cuff), p = 0.019). The short-term explantation rate after primary double-cuff placement was 6.5% (p = 0.543 vs. perineal single-cuff). In multivariate analysis, the penoscrotal approach (p = 0.004), intraoperative complications (p = 0.005), postoperative bleeding (p = 0.011), and perioperative infection (p < 0.001) were independent risk factors for short-term explantation. CONCLUSIONS: Providing data from a large contemporary multi-institutional patient cohort from high-volume and low-volume institutions, our results reflect the current standard of care in middle Europe. We indicate that the penoscrotal approach is an independent risk factor for increased short-term explantation rates.

Optimization of Extracorporeal Shock Wave Lithotripsy Delivery Rates Achieves Excellent Outcomes for Ureteral Stones: Results of a Prospective Randomized Trial.

PURPOSE: Management of ureteral stones remains controversial. To determine whether optimizing the extracorporeal shock wave lithotripsy delivery rate would improve the treatment of solitary ureteral stones we compared the outcomes of 2 delivery rates in a prospective randomized trial. MATERIALS AND METHODS: From July 2010 to October 2012, 254 consecutive patients were randomized to extracorporeal shock wave lithotripsy at a shock wave delivery rate of 60 and 90 pulses per minute in 130 and 124, respectively. The primary study end point was the stone-free rate at 3-month followup. Secondary end points were stone disintegration, treatment time, complications and the rate of secondary treatments. Descriptive statistics were used to compare end points between the 2 groups. The adjusted OR and 95% CI were calculated to assess predictors of success. RESULTS: The stone-free rate at 3 months was significantly higher in patients who underwent extracorporeal shock wave lithotripsy at a shock wave delivery rate of 90 pulses per minute than in those who received 60 pulses per minute (91% vs 80%, p = 0.01). Patients with proximal (100% vs 83%, p = 0.005) and mid ureteral stones (96% vs 73%, p = 0.03) accounted for the observed difference but not those with distal ureteral stones (81% vs 80%, p = 0.9, respectively). Treatment time, complications and the rate of secondary treatments were comparable between the 2 groups. On multivariable analysis the shock wave delivery rate of 90 pulses per minute, proximal stone location, stone density, stone size and an absent indwelling Double-J® stent were independent predictors of success. CONCLUSIONS: Optimizing the extracorporeal shock wave lithotripsy delivery rate can achieve excellent results for ureteral stones.

Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer.

PURPOSE: Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS: We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS: RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS: T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer.

FGFR3 expression in primary invasive bladder cancers and matched lymph node metastases.

PURPOSE: FGFR3 is considered a good therapeutic target for bladder cancer. However, to our knowledge it is unknown whether the FGFR3 status of primary tumors is a surrogate for related metastases, which must be targeted by FGFR targeted systemic therapies. We assessed FGFR3 protein expression in primary bladder tumors and matched nodal metastases. MATERIALS AND METHODS: We examined matched primary tumor and nodal metastases from 150 patients with bladder cancer clinically staged as N0M0. Four samples per patient were incorporated into a tissue microarray and FGFR3 expression was assessed by immunohistochemistry. FGFR3 expression was tested for an association with categorical clinical data using the Fisher exact test, and with overall and recurrence-free survival by Kaplan-Meier analysis. RESULTS: Duplicate spots from primary tumors and lymph node metastases were highly concordant (OR 8.6 and 16.7, respectively, each p <0.001). Overall FGFR protein expression levels did not differ between primary and metastatic lesions (p = 0.78). Up-regulated expression was recorded in 53 of 106 evaluable primary tumor spots and 56 matched metastases. Concordance of FGFR3 expression levels in 79 matched primary tumor and metastasis specimens was high (OR 8.45, p <0.001). In 15 and 12 patients expression was up-regulated in only metastasis and in only the primary tumor, respectively. Overall and recurrence-free survival was not related to FGFR3 expression. CONCLUSIONS: FGFR3 expression in matched primary and metastasized bladder cancer specimens showed good but not absolute concordance. Thus, in most patients primary tumor FGFR3 status can guide the selection of FGFR targeted therapy.

Prevalence and prognostic significance of TMPRSS2-ERG gene fusion in lymph node positive prostate cancers.

BACKGROUND: TMPRSS2-ERG gene fusion is the most frequent genetic alteration in prostate cancer. However, information about its distribution in lymph node positive prostate cancers and the prognostic significance in these advanced tumors is unknown. METHODS: Gene fusion status was determined by fluorescence in situ hybridization on a tissue-microarray constructed from 119 hormone-naïve nodal positive, surgically treated prostate cancers containing samples from the primary tumors and corresponding lymph node metastases. Data were correlated with various tumor features (Gleason score, stage, cancer volume, nodal tumor burden) and biochemical recurrence-free, disease-specific, and overall survival. RESULTS: TMPRSS2-ERG fusion was detected in 43.5% of the primary tumors. Conversely, only 29.9% of the metastasizing components showed the fusion. Concordance in TMPRSS2-ERG status between primary tumors and metastases was 70.9% (Kappa 0.39); 20.9% and 8.1% of the patients showed the mutation solely in their primary tumors and metastases, respectively. TMPRSS2-ERG fusion was not correlated with specific histopathological tumor features but predicted favorable biochemical recurrence-free, disease-specific and overall survival independently when present in the primary tumor (P < 0.05 each). CONCLUSION: TMPRSS2-ERG fusion is more frequent in primary prostate cancer than in corresponding metastases suggesting no selection of fusion-positive cells in the metastatic process. The gene fusion in primary tumors independently predicts favorable outcome.

CCND1/CyclinD1 status in metastasizing bladder cancer: a prognosticator and predictor of chemotherapeutic response.

The CCND1 gene encodes the protein CyclinD1, which is an important promoter of the cell cycle and a prognostic and predictive factor in different cancers. CCND1 is amplified to a substantial proportion in various tumors, and this may contribute to CyclinD1 overexpression. In bladder cancer, information about the clinical relevance of CCND1/CyclinD1 alterations is limited. In the present study, amplification status of CCND1 and expression of CyclinD1 were evaluated by fluorescence in situ hybridization and immunohistochemistry on tissue microarrays from 152 lymph node-positive urothelial bladder cancers (one sample each from the center and invasion front of the primary tumors, two samples per corresponding lymph node metastasis) treated by cystectomy and lymphadenectomy. CCND1 amplification status and the percentage of immunostained cancer cells were correlated with histopathological tumor characteristics, cancer-specific survival and response to adjuvant chemotherapy. CCND1 amplification in primary tumors was homogeneous in 15% and heterogeneous in 6% (metastases: 22 and 2%). Median nuclear CyclinD1 expression in amplified samples was similar in all tumor compartments (60-70% immunostained tumor nuclei) and significantly higher than in non-amplified samples (5-20% immunostained tumor nuclei; P<0.05). CCND1 status and CyclinD1 expression were not associated with primary tumor stage or lymph node tumor burden. CCND1 amplification in primary tumors (P=0.001) and metastases (P=0.02) and high nuclear CyclinD1 in metastases (P=0.01) predicted early cancer-related death independently. Subgroup analyses showed that chemotherapy was particularly beneficial in patients with high nuclear CyclinD1 expression in the metastases, whereas expression in primary tumors and CCND1 status did not predict chemotherapeutic response. In conclusion, CCND1 amplification status and CyclinD1 expression are independent risk factors in metastasizing bladder cancer. High nuclear CyclinD1 expression in lymph node metastases predicts favorable response to chemotherapy. This information may help to personalize prognostication and administration of adjuvant chemotherapy.

Removal of limited nodal disease in patients undergoing radical prostatectomy: long-term results confirm a chance for cure.

PURPOSE: In 2003 we reported on the outcomes of 88 patients with node positive disease who underwent radical prostatectomy and pelvic lymph node dissection (median 21 nodes) between 1989 and 1999. Patients with limited nodal disease appeared to have a good chance of long-term survival, even without immediate adjuvant therapy (androgen deprivation therapy and/or radiotherapy). In this study we update the followup in these patients and verify the reported projected probability of survival. MATERIALS AND METHODS: The projected 10-year cancer specific survival probability after the initially reported followup of 3.2 years was 60% for these patients with node positive disease. The outcome has been updated after a median followup of 15.6 years. RESULTS: Of the 39 patients with 1 positive node 7 (18%) remained biochemically relapse-free, 11 (28%) showed biochemical relapse only and 21 (54%) experienced clinical progression. Of these 39 patients 22 (57%) never required deferred androgen deprivation therapy and 12 (31%) died of prostate cancer. All patients with 2 (20) or more than 2 (29) positive nodes experienced biochemical relapse and only 5 (10%) of these 49 experienced no clinical progression. Of these 49 patients 39 (80%) received deferred androgen deprivation therapy. CONCLUSIONS: Biochemical relapse is likely in patients with limited nodal disease after radical prostatectomy and pelvic lymph node dissection, but for 46% of patients this does not imply death from prostate cancer. Patients with 1 positive node have a good (75%) 10-year cancer specific survival probability and a 20% chance of remaining biochemical relapse-free even without immediate adjuvant therapy.