Christoph von Klot

Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone: A Multicentre Analysis

BACKGROUND The degree of antitumour activity of enzalutamide following disease progression on docetaxel and abiraterone remains controversial. OBJECTIVE To examine the effect of enzalutamide in patients progressing following taxane-based chemotherapy and abiraterone. DESIGN, SETTING, AND PARTICIPANTS Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS We identified 137 patients who prior to enzalutamide had progressed following a median of eight cycles of docetaxel and seven courses of abiraterone. The median time on enzalutamide was 3.2 mo; median OS from the time patients started enzalutamide was 8.3 mo (95% confidence interval, 6.8-9.8). Only 45 (38%) and 22 (18%) patients had PSA declines (unconfirmed) >30% and 50%, respectively. Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS Median OS on enzalutamide following disease progression on taxane-based chemotherapy and abiraterone was modest, but patients who experience a PSA decline >30% or 50%, respectively, with enzalutamide in this setting had longer survival. PATIENT SUMMARY Enzalutamide produces modest prostate-specific antigen (PSA) responses in patients progressing following chemotherapy and abiraterone. Despite a modest PSA response, survival may still be improved.

Urinary tract injuries in patients with multiple trauma

This article mainly reviews urinary tract injuries in patients with multiple trauma. Approximately 10% of all traumatic injuries resulting from an external force will involve the genitourinary system. The article discusses mechanisms of injury, diagnosis, and therapeutical approaches for renal, ureteral, bladder, and urethral trauma. Due to the complexity of such injuries—despite several attempts to provide a standard strategy in trauma patients with urinary tract involvement—an individual and patient-specific-therapeutic approach is mandatory in most cases. However, the availability of classified guidelines may help the surgeon to reach the most accurate decision. Because of the similarity of American and European guidelines on urological trauma, this article adapts injury severity scales and classification from the American Association for the Surgery of Trauma.

Apoptosis gene polymorphisms and risk of prostate cancer: A hospital-based study of German patients treated with brachytherapy

BACKGROUND AND OBJECTIVES Prostate cancer has a genetic component, and single nucleotide polymorphisms (SNPs) can contribute to the risk. We aimed to investigate the role of polymorphisms in 10 candidate genes with a key function in apoptosis. METHODS AND MATERIALS Eight coding SNPs were chosen in ATM (Ser49Cys), BID (Ser56Cys), CASP8 (Asp302His), CASP10 (Val410Ile), LGALS3 (Pro64His), RASSF1 (Ser133Ala), TP53 (Arg72Pro), and TP53AIP1 (Ala7Val), and two non-coding SNPs were selected in BCL2 (-938C/A) and HDM2 (SNP309). A hospital-based case-control series of 510 prostate cancer patients and 490 healthy males from Northern Germany were genotyped for these polymorphisms. RESULTS SNP rs4644 in LGALS3 showed evidence for a protective effect of the minor allele, encoding the His64 variant (OR 0.82, 95% CI 0.69;0.99, P = 0.04). Carriers were underrepresented among cases under a dominant model (OR 0.71; 95% CI 0.54;0.92; P = 0.01), and the effect appeared more pronounced in patients diagnosed before the age of 60 years (OR 0.52; 95% CI 0.31;0.85, P = 0.01). The other nine polymorphisms did not vary significantly between cases and controls, though subtle trends were noted for BCL2 (P = 0.07) and CASP10 (P = 0.08). The Asp302His variant of CASP8 tended to associate with a protective effect in the group with higher Gleason score under a dominant model (P = 0.03). Carriers of either the CASP8 or the CASP10 variants were underrepresented in the prostate cancer series (P = 0.02). CONCLUSIONS These results provide first evidence to implicate the functional Pro64His variant of galectin-3 (LGALS3) in the genetic susceptibility towards prostate cancer. The potential role of polymorphisms in BCL2, CASP8, and CASP10 merits further investigation.

No Androgen Withdrawal Syndrome for Enzalutamide: A Report of Disease Dynamics in the Postchemotherapy Setting

durable effect of the treatment. Unfortunately, our study design did not include any invasive procedures such as biopsies of the sphincter to check what happened in these patients at the cellular level. Patients who failed in the short term or mildly improved have rapidly become incontinent again, suggesting that delayed improvement cannot be expected for this therapy. Our longitudinal follow-up could not explain more precisely the reasons for failure that have occurred after the first results had been published [5], but even in these particularly complex cases, further treatment was still possible, and no complication occurred in the long term. These long-term follow-up data provide unique insight into the results of autologous myoblast injection therapy after 6 yr. The take-home message, which should be considered with caution because of the small study sample, is that this technique applied to complex cases with an objective of salvage therapy (1) provides sustainable results in patients cured after 1 yr of follow-up; (2) is associated with SUI recurrence in the long term when not completely effective in the short term; and, in case of failure, (3) does not compromise the results of further other antiincontinence surgeries. Other limitations of the present work include the lack of urodynamics, imaging, and anatomical data to document more precisely the long-term modifications of the sphincter. Our results should be confronted with larger series and encourage other teams involved in regenerative therapies for female SUI to publish comparable long-term data, which are critically lacking in the field.

Initial Experience with Volumetric 68Ga-PSMA I&T PET/CT for Assessment of Whole-body Tumor Burden as a Quantitative Imaging Biomarker in Patients with Prostate Cancer

A quantitative imaging biomarker is desirable to provide a comprehensive measure of whole-body tumor burden in patients with metastatic prostate cancer, and to standardize the evaluation of treatment-related changes. Therefore, we evaluated whether prostate-specific membrane antigen (PSMA) ligand PET/CT may be applied to provide PSMA-derived volumetric parameters for quantification of whole-body tumor burden. Methods: One hundred one patients who underwent 68Ga-PSMA I&T PET/CT because of increasing prostate-specific antigen (PSA) levels after radical prostatectomy were included in this retrospective analysis. Tracer uptake was quantified using SUVs. Volumetric parameters, that is, PSMA-derived tumor volume (PSMA-TV) and total lesion PSMA (TL-PSMA), were calculated for each patient using a 3-dimensional segmentation and computerized volumetry technique and compared with serum PSA levels. In a group of 10 patients, volumetric parameters were applied for treatment monitoring. Results: Volumetric parameters, that is, whole-body PSMA-TV and whole-body TL-PSMA, demonstrated a statistically significant correlation with PSA levels (P < 0.0001) as a surrogate marker of tumor burden, whereas SUVmax (P = 0.22) or SUVmean (P = 0.45) did not. Treatment response and treatment failure were paralleled by concordant changes in both whole-body PSMA-TV and whole-body TL-PSMA (P = 0.02), whereas neither the change in SUVmax (P = 1.0) nor the change in SUVmean (P = 1.0) concordantly paralleled changes in PSA levels. Conclusion: PSMA-derived volumetric parameters provide a quantitative imaging biomarker for whole-body tumor burden, capable of standardizing quantitative changes in PET imaging of patients with metastatic prostate cancer and of facilitating therapy monitoring.

Androgen deprivation therapy as backbone therapy in the management of prostate cancer

Androgen deprivation therapy (ADT) is well established as a backbone therapy for metastatic prostate cancer (mPCa), and both European and American guidelines emphasize the importance of maintaining ADT after progression to metastatic castration-resistant prostate cancer (CRPC). However, the use of ADT varies widely in clinical practice despite these recommendations. Both research and development of increasingly precise assay technologies have improved our understanding of androgen production and signaling, and the recent data have suggested that a new serum testosterone cutoff value of <0.7 nmol/L should be employed. Most clinical trials to date have used the historical 1.7 nmol/L cutoff, but the <0.7 nmol/L cutoff has been associated with improved patient outcomes. Combining agents with different mechanisms of action to achieve intense androgen blockade may improve survival both before and after progression to CRPC. Data suggest that this intensive approach to androgen deprivation could delay the transition to CPRC and hence improve survival dramatically. Various combinations of backbone ADT with chemotherapy or radiotherapy are under investigation. Administration of ADT is established in patients with intermediate or high-risk localized prostate cancer (PCa) receiving radiotherapy with curative intent. This article reviews the current and potential role of ADT as backbone therapy in both hormone-sensitive PCa and CRPC with a focus on mPCa.

Decreased GATA5 mRNA expression associates with CpG island methylation and shortened recurrence-free survival in clear cell renal cell carcinoma

BackgroundGATA-5, a zinc-finger transcription factor and member of the GATA family proteins 1–6, is known to be involved in cellular differentiation. We recently found that tumor-specific hypermethylation of the GATA5 CpG island (CGI) occurs in renal cell carcinoma (RCC) and is associated with an adverse clinical outcome. In this study, we investigated whether epigenetic GATA5 alterations may result in changes in GATA5 mRNA expression levels and correlate with the observed prognostic impact of epigenetic changes in GATA5 in RCC.MethodsQuantitative real-time reverse-transcribed polymerase chain reaction was applied to measure relative GATA5 mRNA expression levels in 135 kidney tissue samples, including 77 clear cell RCC (ccRCC) tissues and 58 paired adjacent normal renal tissue samples. Relative GATA5 expression levels were determined using the ΔΔCt method and detection of three endogenous control genes then compared to previously measured values of relative methylation.ResultsThe mean relative GATA5 mRNA expression level exhibited an approximately 31-fold reduction in tumor specimens compared with corresponding normal tissues (p < 0.001, paired t-test). Decreased GATA5 mRNA expression was inversely correlated with increased GATA5 CGI methylation (p < 0.001) and was associated with shortened recurrence-free survival in ccRCC patients (p = 0.023, hazard ratio = 0.25).ConclusionGATA5 mRNA expression is decreased in ccRCC, likely due to gene silencing by methylation of the GATA5 CGI. Moreover, reduced GATA5 mRNA levels were associated with a poor clinical outcome, indicating a possible role of GATA5 for the development of aggressive ccRCC phenotypes.

Insertion Sheaths Prevent Breakage of Flexible Ureteroscopes Due to Laser Fiber Passage: A Video-Endoluminal Study of the Working Channel

BACKGROUND It has been postulated that laser insertion sheaths prevent mechanical damage to the inside of working channels of flexible ureteroscopes. The presented study, for the first time, aims at confirming this hypothesis and visualized the damage of the endoscopic working channel by video-endoluminal observation after a series of laser fiber passages with or without the protection of a laser fiber insertion sheath. MATERIALS AND METHODS Four nonassembled working channels of two different manufacturers (Olympus™, Wolf™) were tested in a deflection model (50° and 180°). Flexifib™ laser fibers (LISA laser products) with an optical core diameter of 273 μm were inserted through 0.9% NaCl irrigated working channels in cycles of 10 insertions either with or without protection of the Flexgard™ insertion sheath. After 30 insertions, the examination cycle was reduced to 5 insertions each cycle until breakage. Test cycles were followed by endoluminal video examination of the working channel with the 2.4F flexible fiber scope by Polydiagnost™. Damage to the working channel was classified as streaks with superficial stress marks of the surface, scratches with embossed margins, or perforations. RESULTS No scratching or perforation occurred in the insertion sheath group in up to 150 insertions in all working channels and both deflection grades. In the group without insertion sheaths, scratches were visible after 40 to 50 insertions with 50° deflection and 30 insertions with 180° deflection. Perforations of the working channels were seen after 95 insertions with 50° and 60 insertions with 180° deflection. CONCLUSIONS Severe damage to working channels depends on the degree of deflection and may occur after 30 insertions only. Relevant damage to the working channel may be avoided by using a laser fiber insertion sheath.

Incidence of synchronous and metachronous adrenal metastases following tumor nephrectomy in renal cell cancer patients: a retrospective bi-center analysis.

IntroductionSynchronous adrenalectomy has become dispensable since retrospective studies have demonstrated no survival benefit when preoperative imaging was normal. The aim of this large bi-institutional study was to determine the appearance of synchronous and metachronous metastases to the adrenal gland as detected by computed tomography and positron emission tomography or magnetic resonance imaging with consecutive surgical removal of suspicious lesions.Materials and methodsWe retrospectively reviewed the clinico-pathological records of 2720 patients from two urological centers who underwent radical or partial nephrectomy due to kidney cancer disease. Synchronous adrenalectomy was carried out in 548 of all cases (20.2%). Metachronous adrenalectomy was performed in 24 cases due to suspicious imaging in follow-up.ResultsMetastatic spread in patients with synchronous adrenalectomy was found in 29/548 cases (5.3%), as suspected. In metachronous procedures positive pathological results were found in 24 of 24 cases. Among them 54% of all tumor recurrences were detected in the contralateral adrenal gland.ConclusionsIn case of preoperative suspicious imaging an intraoperative frozen section should be performed. Radiological investigations are of high diagnostic value for detecting metachronous tumor growth into the adrenal gland. Surgery in this scenario should be recommended due to the high malignancy rate reported here.

PSA-stratified detection rates for [ 68 Ga]THP-PSMA, a novel probe for rapid kit-based 68 Ga-labeling and PET imaging, in patients with biochemical recurrence after primary therapy for prostate cancer

Purpose[68Ga]Tris(hydroxypyridinone)(THP)-PSMA is a novel radiopharmaceutical for one-step kit-based radiolabelling, based on direct chelation of 68Ga3+ at low concentration, room temperature and over a wide pH range, using direct elution from a 68Ge/68Ga-generator. We evaluated the clinical detection rates of [68Ga]THP-PSMA PET/CT in patients with biochemically recurrent prostate cancer after prostatectomy.MethodsConsecutive patients (n=99) referred for evaluation of biochemical relapse of prostate cancer by [68Ga]THP-PSMA PET/CT were analyzed retrospectively. Patients underwent a standard whole-body PET/CT (1 h p.i.), followed by delayed (3 h p.i.) imaging of the abdomen. PSA-stratified cohorts of positive PET/CT results, standardized uptake values (SUVs) and target-to-background ratios (TBRs) were analyzed, and compared between standard and delayed imaging.ResultsAt least one lesion suggestive of recurrent or metastatic prostate cancer was identified on PET images in 52 patients (52.5%). Detection rates of [68Ga]THP-PSMA PET/CT increased with increasing PSA level: 94.1% for a PSA value of ≥10 ng/mL, 77.3% for a PSA value of 2 to <10 ng/mL, 54.5% for a PSA value of 1 to <2 ng/mL, 14.3% for a PSA value of 0.5 to <1 ng/mL, 20.0% for a PSA value of >0.2 to <0.5, and 22.2% for a PSA value of 0.01 to 0.2 ng/mL. [68Ga]THP-PSMA uptake (SUVs) in metastases decreased over time, whereas TBRs improved. Delayed imaging at 3 h p.i. exclusively identified pathologic findings in 2% of [68Ga]THP-PSMA PET/CT scans. Detection rate was higher in patients with a Gleason score ≥8 (P=0.02) and in patients receiving androgen deprivation therapy (P=0.003).ConclusionsIn this study, [68Ga]THP-PSMA PET/CT showed suitable detection rates in patients with biochemical recurrence of prostate cancer and PSA levels ≥ 2 ng /mL. Detections rates were lower than in previous studies evaluating other PSMA ligands, though prospective direct radiotracer comparison studies are mandatory particularly in patients with low PSA levels to evaluate the relative performance of different PSMA ligands.