C.A. Hulsbergen-Van De Kaa

Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Background Colorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer. Methods Carriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue. Results Bladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology. Conclusion Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.

Value of 3-T multiparametric magnetic resonance imaging and magnetic resonance-guided biopsy for early risk restratification in active surveillance of low-risk prostate cancer: a prospective multicenter cohort study

ObjectivesThe objective of this study was to evaluate the role of 3-T multiparametric magnetic resonance imaging (MP-MRI) and magnetic resonance–guided biopsy (MRGB) in early risk restratification of patients on active surveillance at 3 and 12 months of follow-up. Materials and MethodsWithin 4 hospitals participating in a large active surveillance trial, a side study was initiated. Pelvic magnetic resonance imaging, prostate MP-MRI, and MRGB were performed at 3 and 12 months (latter prostate MP-MRI and MRGB only) after prostate cancer diagnosis in 1 of the 4 participating hospitals. Cancer-suspicious regions (CSRs) were defined on prostate MP-MRI using Prostate Imaging Reporting And Data System (PI-RADS) scores.Risk restratification criteria for active surveillance discontinuance were (1) histopathologically proven magnetic resonance imaging suspicion of node/bone metastases and/or (2) a Gleason growth pattern (GGP) 4 and/or 5 and/or cancer multifocality (≥3 foci) in MRGB specimens of a CSR on MP-MRI. ResultsFrom 2009 to 2012, a total of 64 of 82 patients were consecutively and prospectively included and underwent MP-MRI and a subsequent MRGB. At 3 and 12 months of follow-up, 14% (9/64) and 10% (3/30) of the patients were risk-restratified on the basis of MP-MRI and MRGB. An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% (38/45) for detection of any prostate cancer and 100% (45/45) for detection of a GGP 4 or 5 containing cancer upon MRGB, respectively. A CSR PI-RADS score of 4 or higher had a sensitivity of 92% (11/12) for detection of a GGP 4 or 5 containing cancer upon MRGB. ConclusionsApplication of MP-MRI and MRGB in active surveillance may contribute in early identification of patients with GGP 4 or 5 containing cancers at 3 months of follow-up. If, during further follow-up, a PI-RADS score of 1 or 2 continues to have a negative predictive value for GGP 4 or 5 containing cancers, a PI-RADS standardized reported MP-MRI may be a promising tool for the selection of prostate cancer patients suitable for active surveillance.

Comparison of surveillance and retroperitoneal lymph node dissection in Stage I nonseminomatous germ cell tumors

OBJECTIVES To compare retrospectively the treatment results of surveillance and primary retroperitoneal lymph node dissection (RPLND) of patients with clinical Stage I nonseminomatous germ cell tumors of the testis (NSGCT) in two institutions in The Netherlands. METHODS From 1982 to 1994, 90 consecutive patients with clinical Stage I NSGCT were prospectively entered in a surveillance protocol in Amsterdam (group 1). In the same period, 101 patients with clinical Stage I NSGCT underwent primary RPLND in Nijmegen (group 2). Both patient populations were comparable for patient age, presence of vascular invasion, and embryonal cell components in the primary tumor. All patients in group 1 with relapse, except for 2, were treated with cisplatin-based chemotherapy. All patients in group 2 with vital tumor in the RPLND specimen were treated with two adjuvant courses of combined chemotherapy (cisplatin, etoposide, and bleomycin). RESULTS In group 1, at a median follow-up of 7.7 years, 23 patients (26%) had relapse. The median time to relapse was 12 months. Relapses were located retroperitoneally (n = 18, 78%), in the lung (n = 3, 13%), scrotally (n = 1, 4%), and combined in the liver, lung, and pleura (n = 1, 4%). After treatment of relapses (chemotherapy in 21 and/or surgery in 11), only 1 patient died of disseminated disease. A disease-free survival rate of 98.5% was achieved at the median follow-up. The main toxicities consisted of short-lasting leukopenia, accompanied by infection (13%). Four patients reported cardiovascular and four neuropathy complaints. In group 2, the median follow-up was 6.9 years. In 31 patients (30.7%), vital tumor was found retroperitoneally; after two courses of combined chemotherapy, none of them had a relapse. Seven patients with pathologic Stage I disease (6.4%) had a pulmonary relapse within 1 year after surgery. No retroperitoneal relapses were found. After chemotherapy, 6 patients with relapse were salvaged, and 1 died of disseminated disease. The disease-specific survival rate in group 2 was 98% at the median follow-up. The most frequent surgical complications were lymphocele (n = 3), small bowel obstruction (n = 3), and abdominal pain (n = 3). The antegrade ejaculation rate was 94%. CONCLUSIONS Excellent treatment results in terms of disease-free survival can be achieved in Stage I NSGCT with both surveillance and primary RPLND. Patients with pathologic Stage II disease adjuvantly treated with chemotherapy did not have any relapse and consequently all survived. Most complications after both treatment strategies are reversible. The choice of treatment should be based on balanced information and not on dogmatic principles.

Evaluation of diffusion-weighted MR imaging at inclusion in an active surveillance protocol for low-risk prostate cancer

PurposeWe aimed to determine whether diffusion-weighted magnetic resonance imaging, by means of the apparent diffusion coefficient (ADC), is able to guide magnetic resonance–guided biopsy in patients fit for active surveillance (AS) and identify patients harboring high-grade Gleason components not suitable for AS. Materials and MethodsOur study was approved by the institutional review board of all participating hospitals, and all patients signed informed consent at inclusion. Fifty-four consecutive patients with low-risk prostate cancer (PCa) underwent multiparametric magnetic resonance imaging (MP-MRI) at inclusion for AS. Cancer-suspicious regions (CSRs) upon 3-T MP-MRI were identified in all patients, and magnetic resonance–guided biopsy was performed in all CSRs to obtain histopathological verification. For all CSRs, a median ADC (mADC) was calculated. Wilcoxon signed ranks and Mann-Whitney tests was performed to detect differences between the groups. We used the area under the receiver operating characteristic curve to evaluate the accuracy of mADC to predict the presence of PCa in a CSR. Level of statistical significance was set at P < 0.05. ResultsMean mADC in the CSRs with PCa was 1.04 × 10−3 mm2/s (SD, 0.29), whereas the CSRs with no PCa displayed a mean mADC of 1.26 × 10−3 mm2/s (SD, 0.25; P < 0.001). Cancer-suspicious regions with a high-grade Gleason component displayed a mean mADC of 0.84 × 10−3 mm2/s (SD, 0.35) vs a mean mADC for the low-grade CSRs of 1.09 × 10−3 mm2/s (SD, 0.25; P < 0.05). A diagnostic accuracy of mADC for predicting the presence of PCa in a CSR with an area under the receiver operating characteristic curve of 0.73 was established (95% confidence interval, 0.61–0.84). ConclusionsMedian ADC is able to predict the presence and grade of PCa in CSRs identified by MP-MRI.

Three-dimensional grayscale ultrasound: evaluation of prostate cancer compared with benign prostatic hyperplasia.

OBJECTIVES To compare the accuracy of the detection, localization, and staging of prostate cancer using transrectal three-dimensional (3D) grayscale ultrasonography (3D-US) with conventional transrectal two-dimensional grayscale ultrasonography (2D-US). METHODS Fifty patients with clinical localized prostate cancer scheduled to undergo radical retropubic prostatectomy and 50 patients with clinical benign prostatic hyperplasia underwent transrectal ultrasound investigations (2D and 3D). The prostate images were retrospectively analyzed by two ultrasound experts unaware of the clinical findings. The images of the prostate cancer group were correlated with the whole-mount histologic specimens of the prostate. RESULTS All percentages are given for experts 1 and 2. The sensitivity, specificity, and accuracy for the detection of prostate cancer without considering the definitive localization of the tumor for 2D-US was 72% and 76%, 50% and 54%, and 63% and 64%, respectively; for 3D-US, the rates were 82% and 88%, 40% and 42%, and 61% and 65%. The sensitivity, specificity, and accuracy of the combination of 2D-US with 3D-US was 88% and 90%, 36% and 38%, and 62% and 64%, respectively. The sensitivity, specificity, and accuracy for the exact localization of the prostate tumor for 2D-US was 44% and 46%, 50% and 54%, and 47% and 50%, respectively; for 3D-US, they were 52% and 62%, 40% and 42%, and 46% and 52%. The staging of prostate cancer using 3D-US was correct in 49% (expert 1) and in 57% (expert 2) of patients. No difference was observed between 2D-US and 3D-US for accurate staging. Both experts judged the interpretation of 3D-US images as superior to that of 2D-US images. CONCLUSIONS Although 3D-US had statistically significant increased sensitivity in the detection of lesions and decreased specificity compared with 2D-US, 3D-US did not result in significant clinical improvement in the detection and staging of prostate cancer.

Isochromosome (12p) and Peritriploidy in a Highly Malignant Extrarenal Rhabdoid Tumor

Abstract Here we present a new case of i(12p) and peritriploidy in an extrarenal rhabdoid tumor.

Curcumin as Treatment for Bladder Cancer: A Preclinical Study of Cyclodextrin-Curcumin Complex and BCG as Intravesical Treatment in an Orthotopic Bladder Cancer Rat Model

Objective To evaluate the antitumor effect of cyclodextrin-curcumin complex (CDC) on human and rat urothelial carcinoma cells in vitro and to evaluate the effect of intravesical instillations of CDC, BCG, and the combination in vivo in the AY-F344 orthotopic bladder cancer rat model. Curcumin has anticarcinogenic activity on urothelial carcinoma and is therefore under investigation for the treatment of non-muscle invasive bladder cancer. Curcumin and BCG share immunomodulating pathways against urothelial carcinoma. Methods Curcumin was complexed with cyclodextrin to improve solubility. Four human urothelial carcinoma cell lines and the AY-27 rat cell line were exposed to various concentrations of CDC in vitro. For the in vivo experiment, the AY-27 orthotopic bladder cancer F344 rat model was used. Rats were treated with consecutive intravesical instillations of CDC, BCG, the combination of CDC+BCG, or NaCl as control. Results CDC showed a dose-dependent antiproliferative effect on all human urothelial carcinoma cell lines tested and the rat AY-27 urothelial carcinoma cell line. Moreover, intravesical treatment with CDC and CDC+BCG results in a lower percentage of tumors (60% and 68%, respectively) compared to BCG (75%) or control (85%). This difference with placebo was not statistically significant (p=0.078 and 0.199, respectively). However, tumors present in the placebo and BCG-treated rats were generally of higher stage. Conclusions Cyclodextrin-curcumin complex showed an antiproliferative effect on human and rat urothelial carcinoma cell lines in vitro. In the aggressive orthotopic bladder cancer rat model, we observed a promising effect of CDC treatment and CDC in combination with BCG.

2 De waarde van herhaalde 3T multiparametrische MRI en MR-geleide biopten vs. herhaalde echogeleide biopten in een active surveillanceprotocol voor prostaatkanker: resultaten na 1 jaar follow-up

Introductie Castratieresistente prostaatkanker (CRPC) kenmerkt zich onder andere door een stijgend PSA, wat duidt op activiteit van de androgeenreceptor (AR), ondanks lage serumtestosteronwaarden. Twee mogelijke verklaringen voor deze AR-activatie zijn: 1) de-novohormoonsynthese en 2) conversie van bijnierandrogenen naar DHT in prostaatkanker (PC) cellen. We hebben in een in-vitrostudie deze hypothesen getest door de groei in hormoonnaïeve (HNPC-) en CRPC-cellijnen te stimuleren met de substraten voor de-novosynthese (de hormoonprecursors progesteron en pregnenolon) of met de bijnierandrogenen DHEA en androsteendion. Daarnaast hebben we een cocultuurmodel ontwikkeld om groeistimulatie van PC door de bijnier en behandeling met de bijnierandrogeen-syntheseremmer orteronel te testen.

Waarde van 3 Tesla MRI met endorectale spoel bij de lokale stadiëring van prostaatkanker

SamenvattingDoel:De nauwkeurigheid bepalen van multiparametrische 3 Tesla (3T) MRI met endorectale spoel (inclusief T2-gewogen, diffusiegewogen en dynamische contrastversterkende opnamen) bij de stadiëring van prostaatkanker in een prospectieve setting.Materiaal en methode:Van januari 2007 tot januari 2010 ondergingen 123 opeenvolgende patiënten een radicale prostatectomie. Hiervan ondergingen 83 patiënten preoperatief een multiparametrische 3T MRI met endorectale spoel (zonder voorafgaande hormoon- of radiotherapie). De radiologische stadiëring, bepaald middels prospectieve MRI-verslagen gemaakt door 2 ervaren radiologen, werd vergeleken met het pathologische tumorstadium. Nauwkeurigheid van de detectie van extraprostatische doorgroei (EPE) werd bepaald.Resultaten:In de prostatectomiepreparaten was bij 53% (44/83) van de patiënten EPE aanwezig. Nauwkeurigheid, sensitiviteit en specificiteit voor de detectie van EPE met de MRI waren respectievelijk 72% (60/83), 54% (21/39) en 89% (39/44).Conclusie:In een prospectieve klinische setting is de multiparametrische 3T-MRI met endorectale spoel een accurate techniek bij de stadiëring van prostaatkanker voorafgaand aan radicale prostatectomie.SummaryValue of 3 Tesla Endorectal Coil Magnetic Resonance Imaging in Local Staging of Prostate CancerObjective:To prospectively evaluate the accuracy of 3 Tesla (3T) multiparametric endorectal coil MRI (including. T2- weighted, diffusion-weighted and dynamic contrast enhanced imaging) for local staging of prostate cancer in a clinical setting.Materials and methods:From Januray 2007 until January 2010, 123 consecutive patients underwent radical prostatectomy. Of these, 83 received a preoperative multiparametric 3T endorectal coil MRI (with no prior hormone or radiotherapy). Staging outcomes in prospective MRI reports made by two experienced radiologists were compared to pathologic tumour stage. Pooled accuracy rates of detection of extraprostatic extension (EPE) were determined.Results:On prostatectomy specimens, EPE was evident in 53% (44/83) of all patients. Overall accuracy, sensitivity and specificity for MR detection of EPE was 72% (60/83), 54% (21/39) and 89% (39/44), respectively.Conclusions:In a prospective clinical setting, multiparametric 3T MR imaging using the endorectal coil is an accurate technique in local staging of prostate cancer prior to radical prostatectomy.