Patient Benefits of Radical Prostatectomy in Certified Prostate Cancer Centers: Comparative Results from the Multicenter IMPROVE Study.

INTRODUCTION: We investigated differences in treatment outcomes following radical prostatectomy (RP) between certified centers (CCs) and noncertified centers (nCCs) within the IMPROVE study group. METHODS: A validated survey assessing various factors, including stress urinary incontinence (SUI) and decision regret (DR), was administered to 950 patients who underwent RP across 19 hospitals (12 CCs and 7 nCCs) at a median follow-up of 15 months after RP (interquartile range: 11-20). The response rate was 74%, with 703 patients participating, including 480 (68%) from CCs. Multivariate binary regression models were used to analyze differences between CCs and nCCs regarding the following binary endpoints: nerve-sparing (NS), positive surgical margins (PSM), SUI (defined as >1 safety pad), complications based on the Clavien-Dindo classification (grade ≥1, grade ≥3) and DR (>15 points indicating critical DR). RESULTS: Considering the multivariate analysis, the rate of NS surgery was lower in CCs than in nCCs (OR = 0.52; p = 0.004). No significant differences were observed in the PSM rate (OR = 1.67; p = 0.051), SUI (OR = 1.03; p = 0.919), and DR (OR = 1.00; p = 0.990). SUI (OR 0.39; p < 0.001) and DR (OR 0.62; p = 0.026) were reported significantly less frequently by patients treated with robotic-assisted RP, which was significantly more often performed in CCs than in nCCs (68.3% vs. 18%; p < 0.001). The total complication rate was 45% lower in CCs (OR = 0.55; p = 0.004), although the number of complications requiring intervention (Clavien-Dindo classification ≥3) did not differ significantly between CCs and nCCs (OR = 2.52; p = 0.051). CONCLUSION: Within the IMPROVE study group, similarly favorable outcomes after RP were found in both CCs and nCCs, which, however, cannot be transferred to the general treatment landscape of PCA in Germany. Of note, robotic-assisted RP was more often performed in CCs and associated with less SUI and DR, while open prostatectomy was the treatment of choice in low-volume nCCs. Future prospective and region wide studies should also investigate the surgeon caseload and experience as well as a spillover effect of the certification process on nCCs.

Analysis of the Impact of Clinical Factors on Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction.

INTRODUCTION: Predictive factors for the treatment success of low-intensity extracorporeal shockwave therapy (Li-ESWT) for erectile dysfunction (ED) are still under debate. METHODS: Li-ESWT was performed in 50 patients suffering from ED by applying 3,000 shock waves once a week over a period of 6 weeks. Treatment success was defined as an increase in the International Index of Erectile Function 5 (IIEF-5) score by ≥5 points or an Erectile Hardness Score (EHS) of ≥3 points. IIEF-5 and EHS were measured at baseline and at 3 and 6 months of follow-up. RESULTS: Treatment success according to either the IIEF-5 score or EHS at any time of follow-up was achieved in 28 patients (56%). Twenty-five patients (50%) experienced an improvement during the first 3 months, which lasted for 6 months in 8 cases (16%). Three patients reported improved erectile function only after 6 months. When stratifying the cohort with regard to potential influencing factors, a significantly improved IIEF-5 score could be achieved in men with cardiovascular risk factors (p = 0.026) and in men with antihypertensive medication (p = 0.009). Men without cardiovascular risk factors showed no therapeutic benefit from Li-ESWT. DISCUSSION/CONCLUSION: Li-ESWT is a valid but often short-lived treatment option for ED, especially in men with cardiovascular risk factors or controlled hypertension. Future studies should assess the feasibility and safety of repeated applications of Li-ESWT.

Geriatric Assessments Can Predict Functional Outcome and Mortality after Urological Tumor Surgery.

INTRODUCTION: Older patients undergoing major urological tumor surgery are at severe risk of functional deterioration, complications, and mortality. We prospectively evaluated geriatric assessment tools and developed a novel easy-to-use assessment tool for clinical use. METHODS: In 159 patients, geriatric assessment tools were used prior to cystectomy, prostatectomy, and renal tumor surgery, and their peri- and postoperative courses were recorded. Using all the tests, a short and easy-to-use assessment tool was developed, and nomograms were generated to predict functional outcomes and mortality. RESULTS: Of all the patients, 13.8% underwent radical cystectomy, 37.7% underwent radical prostatectomy, and 48.4% underwent tumor surgery of the kidney at the age of 70 years or older. The average age was 75.6 years. Incomplete functional recovery at day 30 and day 180 was observed in 37.7% and 36.1% of the patients, respectively, and incomplete functional recovery was associated with impaired mobility, previous care dependency, frailty, comorbidities, and a high ASA score. The only predictor for high-grade complications was comorbidities, whereas mortality was associated with the geriatric screening tool scores, impaired mobility, preoperative care dependency, and comorbidities. The Erlangen Index (EI), a combination of the selected assessment tools, showed a good prediction of early (p = 0.002) and medium-term (p = 0.002) functional outcomes and mortality (p = 0.001). CONCLUSION: Our prospective evaluation confirms the high risk of incomplete functional recovery, high-grade complications, and mortality in older patients undergoing major urological tumor surgery. The EI is an easy-to-use preoperative assessment tool and therefore should be used in preoperative patient counseling.

[Geriatric assessment - What should be done and considered before starting therapy of mHSPC and mCRPC?] / Geriatrisches Assessment ­ Was sollte vor Therapiebeginn des mHSPC und des mCRPC gemacht und bedacht werden?

The systemic treatment of prostate cancer nowadays is predominantly carried out with combination therapies. A range of aspects should be respected in older and comorbid patients, in order to avoid toxicities and to achieve a successful therapy alongside good quality of life. The definition of geriatric patients is not primarily based on chronological age but rather on the overall health condition and life expectancy. Comorbid patients > 70 years should undergo a three-step geriatric screening before treatment initiation. If the G8 screening and/or mini-COG shows abnormalities (taking into account nutrition, comorbidity/medication, mobility, and cognition), a simplified geriatric assessment is recommended. Patients can then be stratified into three groups (fit, vulnerable, frail). Only a few cases warrant a complete geriatric assessment. Treatable deficits in the above mentioned domains should be improved if possible. When choosing a systemic therapy, fit patients can be treated the same as non-geriatric patients. Vulnerable and frail patients are under a higher risk for toxicities, so special care should be taken. While the diverse substances of hormonal therapy are usually well tolerated (even though some substance-specific toxicities can occur), haematotoxic substances such as taxanes or olaparib can only be recommended in select cases. As falls - especially under hormonal therapy - are a common problem, osteoprotective therapy should especially be considered. Upon progression of the tumour disease, there should not be a reflex to simply switch to the next line of treatment, but an individual concept should be established together with the patient and his relatives, taking into account aspects of palliative care and patient needs and focussing on quality of life and also setting therapy limitations.

Patient's Desire and Real Availability Concerning Supportive Measures Accompanying Radical Prostatectomy: Differences between Certified Prostate Cancer Centers and Non-Certified Centers Based on Patient-Reported Outcomes within the Cross-Sectional Study Improve.

Certification as a prostate cancer center requires the offer of several supportive measures to patients undergoing radical prostatectomy (RP). However, it remains unclear how patients estimate the relevance of these measures and whether the availability of these measures differs between certified prostate cancer centers (CERTs) and non-certified centers (NCERTs). In 20 German urologic centers, a survey comprising questions on the relevance of 15 supportive measures was sent to 1000 patients at a median of 15 months after RP. Additionally, patients were asked to rate the availability of these measures using a four-item Likert scale. The aim of this study was to compare these ratings between CERTs and NCERTs. The response rate was 75.0%. In total, 480 patients underwent surgery in CERTs, and 270 in NCERTs. Patients rated 6/15 supportive measures as very relevant: preoperative medical counselling concerning treatment options, a preoperative briefing answering last questions, preoperative pelvic floor exercises (PFEs), postoperative PFEs, postoperative social support, and postoperative rehabilitation addressing physical fitness recovery. These ratings showed no significant difference between CERTs and NCERTs (p = 0.133-0.676). In addition, 4/9 of the remaining criteria were rated as more detailed by patients in CERTs. IMPROVE represents the first study worldwide to evaluate a patient-reported assessment of the supportive measures accompanying RP. Pertinent offers vary marginally between CERTs and NCERTs.

Femtosecond diode-pumped solid-state laser with a repetition rate of 4.8 GHz.

We report on a diode-pumped Yb:KGW (ytterbium-doped potassium gadolinium tungstate) laser with a repetition rate of 4.8 GHz and a pulse duration of 396 fs. Stable fundamental modelocking is achieved with a semiconductor saturable absorber mirror (SESAM). The average output power of this compact diode-pumped solid state laser is 1.9 W which corresponds to a peak power of 0.9 kW and the optical-to-optical efficiency is 36%. To the best of our knowledge, this is the femtosecond DPSSL with the highest repetition rate ever reported so far.

High-spectral-radiance, red-emitting tapered diode lasers with monolithically integrated distributed Bragg reflector surface gratings.

A red-emitting tapered diode laser with a monolithically integrated distributed Bragg reflector grating is presented. The device is able to emit up to 1 W of spectrally stabilized optical output power at 5°C. Depending on the period of the tenth order surface grating the emission wavelengths of these devices from the same gain material are 635 nm, 637 nm, and 639 nm. The emission is as narrow as 9 pm (FWHM) at 637.6 nm. The lateral beam quality is M(2)(1/e(2)) = 1.2. Therefore, these devices simplify techniques such as wavelength multiplexing and fiber coupling dedicating them as light sources for µ-Raman spectroscopy, absolute distance interferometry, and holographic imaging.

Multi-Dimensional Regression Models for Predicting the Wall Thickness Distribution of Corrugated Pipes.

Corrugated pipes offer both higher stiffness and higher flexibility while simultaneously requiring less material than rigid pipes. Production rates of corrugated pipes have therefore increased significantly in recent years. Due to rising commodity prices, pipe manufacturers have been driven to produce corrugated pipes of high quality with reduced material input. To the best of our knowledge, corrugated pipe geometry and wall thickness distribution significantly influence pipe properties. Essential factors in optimizing wall thickness distribution include adaptation of the mold block geometry and structure optimization. To achieve these goals, a conventional approach would typically require numerous iterations over various pipe geometries, several mold block geometries, and then fabrication of pipes to be tested experimentally-an approach which is very time-consuming and costly. To address this issue, we developed multi-dimensional mathematical models that predict the wall thickness distribution in corrugated pipes as functions of the mold geometry by using symbolic regression based on genetic programming (GP). First, the blow molding problem was transformed into a dimensionless representation. Then, a screening study was performed to identify the most significant influencing parameters, which were subsequently varied within wide ranges as a basis for a comprehensive, numerically driven parametric design study. The data set obtained was used as input for data-driven modeling to derive novel regression models for predicting wall thickness distribution. Finally, model accuracy was confirmed by means of an error analysis that evaluated various statistical metrics. With our models, wall thickness distribution can now be predicted and subsequently used for structural analysis, thus enabling digital mold block design and optimizing the wall thickness distribution.

The Human Leukocyte Antigen G as an Immune Escape Mechanism and Novel Therapeutic Target in Urological Tumors.

The non-classical human leukocyte antigen G (HLA-G) is a potent regulatory protein involved in the induction of immunological tolerance. This is based on the binding of membrane-bound as well as soluble HLA-G to inhibitory receptors expressed on various immune effector cells, in particular NK cells and T cells, leading to their attenuated functions. Despite its restricted expression on immune-privileged tissues under physiological conditions, HLA-G expression has been frequently detected in solid and hematopoietic malignancies including urological cancers, such as renal cell and urothelial bladder carcinoma and has been associated with progression of urological cancers and poor outcome of patients: HLA-G expression protects tumor cells from anti-tumor immunity upon interaction with its inhibitory receptors by modulating both the phenotype and function of immune cells leading to immune evasion. This review will discuss the expression, regulation, functional and clinical relevance of HLA-G expression in urological tumors as well as its use as a putative biomarker and/or potential therapeutic target for the treatment of renal cell carcinoma as well as urothelial bladder cancer.

Patients Regret Their Choice of Therapy Significantly Less Frequently after Robot-Assisted Radical Prostatectomy as Opposed to Open Radical Prostatectomy: Patient-Reported Results of the Multicenter Cross-Sectional IMPROVE Study.

Patient's regret (PatR) concerning the choice of therapy represents a crucial endpoint for treatment evaluation after radical prostatectomy (RP) for prostate cancer (PCA). This study aims to compare PatR following robot-assisted (RARP) and open surgical approach (ORP). A survey comprising perioperative-functional criteria was sent to 1000 patients in 20 German centers at a median of 15 months after RP. Surgery-related items were collected from participating centers. To calculate PatR differences between approaches, a multivariate regressive base model (MVBM) was established incorporating surgical approach and demographic, center-specific, and tumor-specific criteria not primarily affected by surgical approach. An extended model (MVEM) was further adjusted by variables potentially affected by surgical approach. PatR was based on five validated questions ranging 0−100 (cutoff >15 defined as critical PatR). The response rate was 75.0%. After exclusion of patients with laparoscopic RP or stage M1b/c, the study cohort comprised 277/365 ORP/RARP patients. ORP/RARP patients had a median PatR of 15/10 (p < 0.001) and 46.2%/28.1% had a PatR >15, respectively (p < 0.001). Based on the MVBM, RARP patients showed PatR >15 relative 46.8% less frequently (p < 0.001). Consensual decision making regarding surgical approach independently reduced PatR. With the MVEM, the independent impact of both surgical approach and of consensual decision making was confirmed. This study involving centers of different care levels showed significantly lower PatR following RARP.

Diode-pumped mode-locked Yb:YCOB laser generating 35 fs pulses.

Direct sub-50-fs pulse generation is demonstrated with a mode-locked Yb:YCa4O(BO3)3 laser. With external compression, pulses as short as 35 fs are generated at 1055 nm. The oscillator operating at a repetition rate of 95 MHz is pumped by a two-section distributed Bragg reflector tapered diode laser and mode locked by a semiconductor saturable absorber mirror. The onset of self-Raman-conversion for pulse spectral bandwidths exceeding 40 nm (FWHM) is observed.

42-fs diode-pumped Yb:Ca4YO(BO3)3 oscillator.

We demonstrate a passively mode-locked femtosecond laser based on the self-frequency-doubling crystal Yb:Ca4YO(BO3)3. The oscillator is pumped by a novel two-section distributed Bragg-reflector tapered diode-laser. Pulses as short as 46 fs and 42 fs at 1050 nm are achieved for the E//Z polarization without and with external compression, respectively. These are, to the best of our knowledge, the shortest pulses obtained from an oscillator based on Yb3+-doped bulk material.

Diode-pumped gigahertz femtosecond Yb:KGW laser with a peak power of 3.9 kW.

We present a diode-pumped Yb:KGW laser with a repetition rate of 1 GHz and a pulse duration of 281 fs at a wavelength of 1041 nm. A high brightness distributed Bragg reflector tapered diode laser is used as a pump source. Stable soliton modelocking is achieved with a semiconductor saturable absorber mirror (SESAM). The obtained average output power is 1.1 W and corresponds to a peak power of 3.9 kW and a pulse energy of 1.1 nJ. With harmonic modelocking we could increase the pulse repetition rate up to 4 GHz with an average power of 900 mW and a pulse duration of 290 fs. This Yb:KGW laser has a high potential for stable frequency comb generation.

Diode-pumped mode-locked Yb:LuScO(3) single crystal laser with 74 fs pulse duration.

The mode locking of the mixed sesquioxide single crystal Yb:LuScO(3) is demonstrated. This crystal is locally disordered and has the broadest emission spectrum of all sesquioxides known so far. Pulse durations as short as 111 and 74 fs were obtained using the semiconductor saturable absorber mirror and Kerr-lens mode locking, respectively. The latter regime was reached using a two-section distributed Bragg-reflector tapered diode laser as a pump source.

Compact second-harmonic generation laser module with 1 W optical output power at 490 nm.

We demonstrate continues-wave 1 W at 490 nm on a 2.5 cm(3) micro-optical bench using single-path second-harmonic generation with a periodically poled MgO:LiNbO(3) bulk crystal. The pump laser is a distributed Bragg reflector tapered diode laser having a single-frequency spectrum and a pump power of 9.5 W. Based on that 1 W blue light could be achieved resulting in an optical conversion efficiency of 11%. Furthermore, the module has an output power stability of better than 2% and the blue laser beam shows an nearly diffraction limited beam quality of M(2)(sigma) = 1.2 in vertical and M(2)(sigma) = 2 in lateral direction.

Mitochondrial Dysfunction in Astrocytes Impairs the Generation of Reactive Astrocytes and Enhances Neuronal Cell Death in the Cortex Upon Photothrombotic Lesion.

Mitochondria are key organelles in regulating the metabolic state of a cell. In the brain, mitochondrial oxidative metabolism is the prevailing mechanism for neurons to generate ATP. While it is firmly established that neuronal function is highly dependent on mitochondrial metabolism, it is less well-understood how astrocytes function rely on mitochondria. In this study, we investigate if astrocytes require a functional mitochondrial electron transport chain (ETC) and oxidative phosphorylation (oxPhos) under physiological and injury conditions. By immunohistochemistry we show that astrocytes expressed components of the ETC and oxPhos complexes in vivo. Genetic inhibition of mitochondrial transcription by conditional deletion of mitochondrial transcription factor A (Tfam) led to dysfunctional ETC and oxPhos activity, as indicated by aberrant mitochondrial swelling in astrocytes. Mitochondrial dysfunction did not impair survival of astrocytes, but caused a reactive gliosis in the cortex under physiological conditions. Photochemically initiated thrombosis induced ischemic stroke led to formation of hyperfused mitochondrial networks in reactive astrocytes of the perilesional area. Importantly, mitochondrial dysfunction significantly reduced the generation of new astrocytes and increased neuronal cell death in the perilesional area. These results indicate that astrocytes require a functional ETC and oxPhos machinery for proliferation and neuroprotection under injury conditions.

Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.

Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

Cement directed kyphoplasty reduces cement leakage as compared with vertebroplasty: results of a controlled, randomized trial.

STUDY DESIGN: A novel randomized, controlled, unblinded clinical trial comparing 2 procedural interventions for painful osteoporotic vertebral compression fractures. OBJECTIVE: The primary study objective was to evaluate cement leakage for a cement directed kyphoplasty system (CDKS) with anteriorly biased cement flow and vertebroplasty. The secondary study objective was to compare adjacent level fracture rates and vertebral body height for these 2 intervention methods. SUMMARY OF BACKGROUND DATA: Cement leakage remains a significant clinical problem associated with vertebroplasty and kyphoplasty procedures. Uncontrolled cement flow in the posterior direction can result in leakage into the vertebral veins or spinal canal, leading to potentially serious clinical complications. METHODS: Seventy-seven patients with painful osteoporotic vertebral compression fractures were enrolled. Patients were randomized 2:1 for treatment with CDKS (49 patients, 65 levels) or vertebroplasty (28 patients, 39 levels). Cement leakage was evaluated from radiographs and computed tomographic scans. Three- and 12-month follow-ups included additional radiographs and computed tomographic scans to assess changes in vertebral body height and the incidence of new fractures. RESULTS: Treatment with CDKS significantly reduced the number of levels with leaks and the total number of leaks per level, as compared with vertebroplasty (P = 0.0132 and P = 0.0012, respectively). Significantly, fewer lateral cortical and spinal canal leaks (posterior leaks) occurred in the CDKS group (P = 0.0050, P = 0.02260, respectively). Three adjacent level fractures occurred in the vertebroplasty group, as compared with 2 in the CDKS group. Vertebral body height maintenance was equivalent. CONCLUSION: Cement directed kyphoplasty effectively reduces posterior cement leakage, reducing the risk of leakage related complications. LEVEL OF EVIDENCE: 2.