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Introduction: This study aims to evaluate the impact of preoperative ureteral stenting on post-operative outcomes, especially the incidence of urinoma, in patients with complex renal tumours undergoing nephron-sparing surgery (NSS)., Methods: A retrospective analysis of 35 patients received preoperative ureteral stenting prior to NSS for complex tumours at the University Hospital of Würzburg between 2002 and 2021. A control group of 115 patients was established through 1:3 propensity score matching based on age, gender, T-stage, and RENAL score. Clinical parameters, surgical outcomes, and complications were assessed, and statistical comparisons were performed using the unpaired Student's t test and chi-square test., Results: While both groups showed comparable tumour complexity (RENAL: 7 vs. 7, p = 0.58; PADUA: 9 vs. 8, p = 0.62), there were no significant differences in median hospital stay (12 vs. 11; p = 0.068), surgical time (183 vs. 190 min; p = 0.37), post-operative haemoglobin levels (11 g/dL vs. 11.1 day/dL; p = 0.9), and renal function (GFR 65 mL/min/m2 in both groups). Moreover complication severity during NSS, defined by Clavien-Dindo classification, was similar (none vs. grade I; p = 0.29). No significant difference in the rate of urinoma was observed (11% vs. 4%, p = 0.93)., Conclusions: This study found no significant benefits of preoperative ipsilateral ureteral stenting on post-operative outcomes, particularly concerning the development of urinoma. Given these findings, preventive ureteral stenting is not recommended prior to partial kidney resection for complex renal tumours., (© 2024 S. Karger AG, Basel.)

High-resolution continuous-wave (cw) laser spectroscopy of nitric oxide (NO) molecules has been performed to study and characterize the energy-level structure of and effects of electric fields on the high Rydberg states. The experiments were carried out with molecules flowing through a room temperature gas cell. Rydberg-state photoexcitation was implemented using the resonance enhanced ( n l ) X +   Σ + 1 ← H   Σ + 2 ← A   Σ + 2 ← X Π 3 / 2 2 three-color three-photon excitation scheme. Excited molecules were detected by high-sensitivity optogalvanic methods. Detailed measurements were made of Rydberg states with principal quantum numbers n = 22 and 32 in the series converging to the lowest rotational and vibrational state of the NO + cation. The experimental data were compared with the results of numerical calculations which provided insight into the orbital angular momentum character of the intermediate H 2 Σ + state, improved determinations of the n f and n g quantum defects, a bound on the magnitude of the n h quantum defect, and information on the decay rates of the n f and n g Rydberg states. These measurements represent a step-change in laser spectroscopic studies of high Rydberg states in small atmospheric molecules. They open opportunities for more detailed studies of slow decay processes of Rydberg NO molecules confined in electrostatic traps, the synthesis of ultralong range Rydberg bimolecules, and the development of optical methods for trace gas detection.

Introduction: Studies comparing refluxing versus non-refluxing ureteric implantation in continent cutaneous urinary diversion (CCUD) are scarce and often characterized by heterogeneous study populations. This work therefore aimed at comparing both techniques regarding long-term outcomes in a propensity-scored approach., Methods: We identified n = 19 patients, totaling n = 38 renal units (RU), who underwent CCUD surgery at our hospital out of a pool of 120 patients. Of these 38 RU, 27 RU were implanted via refluxing ureteric implantation utilizing various procedures due to special intraoperative circumstances (short ureters, damage due to radiation). In terms of preoperative renal function, a comorbidity index (Age-Adjusted Charlson Comorbidity Index [ACCI]), and gender, we compared them to n = 38 patients with a total of 76 RU with non-refluxing ureteric implantation in all RU (1:2 matching). The mean follow-up was 56 (IQR: 23-112) months., Results: Long-term renal function was comparable in CCUD patients receiving refluxing versus non-refluxing ureteric implantation (estimated glomerular filtration rate: 63.11 mL/min vs. 71.7 mL/min, p = 0.22) with an average decline of 17.4 mL/min and 13.69 mL/min during the follow-up period, respectively. Also, the rate of new-onset chronic kidney disease (CKD) (both 15%, p = 1), the need for alkalizing medication, or the number of pyelonephritis episodes did not significantly differ between the groups. In Cox regression analysis, ACCI was the single most predictive parameter for the development of new-onset CKD (HR: 1.71 [1.10-2.66], p = 0.0167). None of the RU in the refluxing group needed revisional surgery concerning the ureterointestinal anastomosis, whereas 7 RU of the non-refluxing group did., Conclusions: Our study confirms that refluxing ureteric implantation in CCUDs is a valid and safe procedure regarding long-term renal, metabolic and functional outcomes. Our data also suggest that patients should be counseled according to their comorbidities regarding long-term renal function., (© 2024 S. Karger AG, Basel.)

Rydberg atom-based radio frequency electromagnetic field sensors are drawing wide-spread interest because of their unique properties, such as small size, dielectric construction, and self-calibration. These photonic sensors use lasers to prepare atoms and read out the atomic response to a radio frequency electromagnetic field based on electromagnetically induced transparency, or related phenomena. Much of the theoretical work has focused on the Autler-Townes splitting induced by the radio frequency wave. The amplitude regime, where the change in transmission observed on resonance is measured to determine electric field strength, has received less attention. In this paper, we deliver analytic expressions that are useful for calculating the absorption coefficient in the amplitude regime. Our main goal is to describe the analytic expressions for the absorption coefficient and demonstrate their validity over a large range of the interesting parameter space. The effect of the thermal motion of the atoms is explicitly addressed. The analytic formulas for the absorption coefficient for different types of Doppler broadening are compared to estimate the sensitivity under conditions where it is limited by the laser shot noise. Residual Doppler shifts are shown to limit sensitivity. The expressions, approximations and descriptions presented in the paper are important for understanding the absorption of Rydberg atom-based sensors in the amplitude regime. This provides insight into the physics of multi-level interference phenomena.

In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68 Ga- and 18 F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [ 18 F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [ 18 F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUV mean , SUV max , PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 ( P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [ 18 F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Metformin (MF) intake could be associated with a favorable outcome in sunitinib (SUT)- and axitinib (AX)-treated clear cell renal cell carcinoma (ccRCC) patients. Functionally, MF induces miR-205, a microRNA serving as a tumor suppressor in several cancers., Methods: Real-time quantitative PCR, viability assays, and Western blotting analyzed MF and SUT/AX effects in RCC4 and 786-O cells. A tetracycline-inducible overexpression model was used to study the role of miR-205 and its known target gene, VEGFA. We analyzed miR-205 and VEGFA within a public and an in-house ccRCC cohort. Human umbilical vein endothelial cell (HUVEC) sprouting assays examined miR-205 effects on angiogenesis initiation. To determine the influence of the von Hippel-Lindau tumor suppressor (VHL), we examined VHLwt reexpressing RCC4 and 786-O cells., Results: Viability assays confirmed a sensitizing effect of MF toward SUT/AX in RCC4 and 786-O cells. Overexpression of miR-205 diminished VEGFA expression - as did treatment with MF. Tumor tissue displayed a downregulation of miR-205 and an upregulation of VEGFA. Accordingly, miR-205 caused less and shorter vessel sprouts in HUVEC assays. Finally, VHLwt-expressing RCC4 and 786-O cells displayed higher miR-205 and lower VEGFA levels., Conclusion: Our results support the protective role of MF in ccRCC and offer functional insights into the clinical synergism with tyrosine kinase inhibitors., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Continent cutaneous urinary diversion post-cystectomy is an established approach addressing both oncological and functional indications. However, there is a noticeable gap of evidence when it comes to comparing outcomes between these indications, especially concerning the technique of Mainz pouch I (MPI). This study aimed to close the gap by analyzing the long-term functional and renal outcomes of patients with MPI after cystectomy due to both benign and malign bladder pathologies., Methods: In this retrospective study, we examined 173 patients, who underwent MPI surgery between 2000 and 2022. Patients were categorized into a study group (benign conditions, n = 26) and a control group (bladder cancer, n = 52) using propensity score matching. Clinical demographics, surgical outcomes, and functional/renal parameters were analyzed using unpaired t tests and χ2 tests., Results: Patients undergoing cystectomy with MPI due to benign bladder pathologies were significantly younger and had a lower comorbidity burden compared to those with bladder cancer. In contrast to a significantly higher incidence of chemotherapy in the oncological cohort, the long-term renal function was comparable between both populations. Surgical outcomes, revisions, and postoperative complications did not differ significantly between both groups. Nearly 90% of patients in both groups showed full continence., Conclusion: This study demonstrates the efficacy and safety of MPI surgery in both benign and malignant conditions, proving favorable long-term renal and functional outcomes., (© 2024 S. Karger AG, Basel.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

Background: Quantification of [ 68  Ga]-labeled PSMA PET predicts response in patients with prostate cancer (PC) who undergo PSMA-targeted radioligand therapy (RLT). Given the increasing use [ 18 F]-labeled radiotracers, we aimed to determine whether the uptake derived from [ 18 F]PSMA-1007 PET can also identify responders and to assess its prognostic value relative to established clinical parameters., Methods: We retrospectively analyzed 103 patients with metastatic, castration-resistant PC who were treated with [ 177 Lu]Lu-PSMA I&T. We calculated SUV mean , SUV max , PSMA-avid tumor volume (TV), and total lesion PSMA (defined as PSMA-TV*SUV mean ) on pre-therapeutic [ 18 F]PSMA-1007 PET. Laboratory values for hemoglobin, C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alkaline phosphatase (AP) were also collected prior to RLT. We performed univariable Cox regression followed by multivariable and Kaplan-Meier analyses with overall survival (OS) serving as endpoint. Last, we also computed a risk factor (RF) model including all items reaching significance on multivariable analysis to determine whether an increasing number of RFs can improve risk stratification., Results: A total of 48 patients died and median OS was 16 months. On univariable Cox regression, SUV mean , CRP, LDH, hemoglobin, and the presence of liver metastases were significantly associated with OS. On multivariable Cox regression, the following significant prognostic factors for OS were identified: SUV mean (per unit, HR, 0.91; P = 0.04), the presence of liver metastases (HR, 2.37; P = 0.03), CRP (per mg/dl, HR, 1.13; P = 0.003), and hemoglobin (per g/dl, HR, 0.76; P < 0.01). Kaplan-Meier analysis showed significant separation between patients with a SUV mean below or above a median SUV mean of 9.4 (9 vs 19 months, HR 0.57; P = 0.03). Of note, patients with only one RF (median OS not reached) showed longest survival compared to patients with two (11 months; HR 2.43 95% CI 1.07-5.49, P = 0.02) or more than two RFs (7 months; HR 3.37 95% CI 1.62-7.03, P < 0.001)., Conclusion: A lower SUV mean derived from [ 18 F]PSMA-1007, higher CRP, lower hemoglobin, and the presence of liver metastases are associated with reduced OS in patients undergoing RLT. An early RF model also demonstrated that an increasing number of those factors is linked to worse outcome, thereby emphasizing the importance of clinical and imaging parameters for adequate risk stratification., (© 2023. The Author(s).)

In patients with prostate cancer scheduled for systemic treatment, being overweight is linked to prolonged overall survival (OS), whereas sarcopenia is associated with shorter OS. We investigated fat-related and body composition parameters in patients undergoing prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) to assess their predictive value for OS. Methods: Body mass index (BMI, in kg/m 2 ) and CT-derived body composition parameters (total, subcutaneous, visceral fat area, and psoas muscle area at the L3-L4 level) were determined for 171 patients scheduled for PSMA-directed RLT. After normalization for stature, the psoas muscle index was used to define sarcopenia. Outcome analysis was performed using Kaplan-Meier curves and Cox regression including fat-related and other clinical parameters (Gleason score, C-reactive protein [CRP], lactate dehydrogenase [LDH], hemoglobin, and prostate-specific antigen levels). The Harrell C-index was used for goodness-of-fit analysis. Results: Sixty-five patients (38%) had sarcopenia, and 98 patients (57.3%) had increased BMI. Relative to the 8-mo OS in normal-weight men (BMI < 25), overweight men (25 ≥ BMI > 30) and obese men (BMI ≥ 30) achieved a longer OS of 14 mo (hazard ratio [HR], 0.63; 95% CI, 0.40-0.99; P = 0.03) and 13 mo (HR, 0.47; 95% CI, 0.29-0.77; P = 0.004), respectively. Sarcopenia showed no impact on OS (11 vs. 12 mo; HR, 1.4; 95% CI, 0.91-2.1; P = 0.09). Most of the body composition parameters were tightly linked to OS on univariable analyses, with the highest C-index for BMI. In multivariable analysis, a higher BMI (HR, 0.91; 95% CI, 0.86-0.97; P = 0.006), lower CRP (HR, 1.09; 95% CI, 1.03-1.14; P < 0.001), lower LDH (HR, 1.08; 95% CI, 1.03-1.14; P < 0.001), and longer interval between initial diagnosis and RLT (HR, 0.95; 95% CI, 0.91-0.99; P = 0.02) were significant predictors of OS. Conclusion: Increased fat reserves assessed by BMI, CRP, LDH, and interval between initial diagnosis and RLT, but not CT-derived body composition parameters, were relevant predictors for OS. As BMI can be altered, future research should investigate whether a high-calorie diet before or during PSMA RLT may improve OS., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Immunotherapies using bispecific antibodies and chimeric antigen receptor (CAR) T cells do not depend on previous activation of T cells by the human leukocyte antigen (HLA) system. These HLA-independent approaches displayed groundbreaking clinical results in hematological malignancies-leading to drug approvals for diseases like acute lymphocytic leukemia (ALL), B-cell Non-Hodgkin's lymphoma and multiple myeloma. Currently, several phase I/II trials are investigating the transferability of these results to solid tumors-especially prostate cancer. Compared to established immune checkpoint blockade, bispecific antibodies and CAR T cells have novel and heterogenous side effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Treating these side effects and identifying suitable trial participants requires an interdisciplinary treatment approach., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Introduction: Contrary to current recommendations, palliative co-management of tumor patients often occurs late in daily clinical practice. Palliative care specialist (PCS) co-management should be considered at the latest after a 6-month prognosis has been presumed. Therefore, identifying patients with a limited prognosis is a reasonable measure., Methods: Patients were identified using a screening tool for limited prognosis, which combined their tumor stage and data from the nursing anamnesis. In this retrospective study, a monocentric cohort of patients with urological malignancies-UICC (Union for International Cancer Control) stages III and IV - were enrolled from March to December 2019, with a 6-month follow-up period ending in May 2020., Results: Most patients were male and suffered from prostate cancer. Patients with uro-oncological tumors dying within 6 months correlated significantly with the presence of repeated hospitalizations within three months, pain on admission, malnutrition, impaired breathing and reduced mobility (P < 0.001). The test was fair in quality (AUC 0.727) at a cut-point of five; a sensitivity of 97% and a specificity of 25% were obtained. The PPV was 0.64 and NPV was 0.82., Discussion/conclusion: We specifically identified the predictors of limited prognosis in urological cancer patients across several entities using an automated scoring system based on tumor stage and data from the nursing anamnesis. Therefore, we recognized hospitalization as an important transition point and determined nurses to be valuable partners in identifying unmet palliative care needs without additional technical, personnel or financial effort., Competing Interests: Conflicts of interest The authors have nothing to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC IVC ) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier-containing miR-21-5p, miR-126-3p and miR-221-3p expression-which significantly predicted the cancer-specific survival (CSS) of ccRCC IVC patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC IVC , we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan-Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan-Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC IVC according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC IVC cohort.

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database-representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.

Introduction: In men with metastatic castration-resistant prostate cancer (mCRPC) scheduled for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), biochemical response is assessed based on repeated measurements of prostate-specific antigen (PSA) levels. We aimed to determine overall survival (OS) in patients experiencing sustained PSA increase, decrease, or fluctuations during therapy., Materials and Methods: In this bicentric study, we included 176 mCRPC patients treated with PSMA-directed RLT. PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. We calculated relative changes in PSA levels compared to baseline. Kaplan-Meier curves as well as log-rank test were used to compare OS of different subgroups, including patients with sustained PSA increase, decrease, or fluctuations (defined as change after initial decrease or increase after the first cycle)., Results: Sixty-one out of one hundred seventy-six (34.7%) patients showed a sustained increase and 86/176 (48.8%) a sustained decrease in PSA levels. PSA fluctuations were observed in the remaining 29/176 (16.5%). In this subgroup, 22/29 experienced initial PSA decrease followed by an increase (7/29, initial increase followed by a decrease). Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels (19 vs. 8 months; HR 0.35, 95% CI 0.22-0.56; P &lt; 0.001). Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels (18 vs. 8 months; HR 0.49, 95% CI 0.30-0.80; P &lt; 0.01), but no significant difference relative to men with sustained PSA decrease (18 vs. 19 months; HR 1.4, 95% CI 0.78-2.49; P = 0.20). In addition, in men experiencing PSA fluctuations, median OS did not differ significantly between patients with initial decrease or initial increase of tumor marker levels (16 vs. 18 months; HR 1.2, 95% CI 0.38-4.05; P = 0.68)., Conclusion: Initial increase or decrease of PSA levels is sustained in the majority of patients undergoing RLT. Sustained PSA decrease was linked to prolonged survival and men with PSA fluctuations under treatment experienced comparable survival benefits. As such, transient tumor marker oscillations under RLT should rather not lead to treatment discontinuation, especially in the absence of radiological progression., (© 2022. The Author(s).)

Background: Radioligand therapy (RLT) with 177 Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [ 177 Lu]Lu-PSMA I&T RLT in a long-term follow-up., Materials and Methods: Ninety-two mCRPC patients treated with [ 177 Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (interval Diagnosis-RLT , per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan-Meier analyses., Results: Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02-1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01-1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06-1.26; P = 0.001), and interval Diagnosis-RLT (HR, 0.95, 95% CI 0.91-0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and interval Diagnosis-RLT , 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan-Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged interval Diagnosis-RLT (P ≤ 0.01, respectively)., Conclusion: In mCRPC patients treated with [ 177 Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [ 177 Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors., (© 2022. The Author(s).)

Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) is increasingly incorporated in the therapeutic algorithm of patients with metastatic castration-resistant prostate cancer (mCRPC). We aimed to elucidate the predictive performance of early biochemical response for overall survival (OS)., Materials and Methods: In this bicentric analysis, we included 184 mCRPC patients treated with 177 Lu-PSMA RLT. Response to treatment was defined as decrease in prostate-specific antigen (PSA) levels 8 weeks after the first cycle of RLT (any decline or >50% according to Prostate Cancer Working Group 3). OS of responders and nonresponders was then compared using Kaplan-Meier curves and log-rank comparison., Results: A total of 114/184 patients (62.0%) showed any PSA decline (PSA response >50%, 55/184 [29.9%]). For individuals exhibiting a PSA decline >50%, OS of 19 months was significantly longer relative to nonresponders (13 months; hazard ratio of death [HR] = 0.64, 95% confidence interval [95% CI] = 0.44-0.93; p = 0.02). However, the difference was even more pronounced for any PSA decline, with an OS of 19 months in responders, but only 8 months in nonresponders (HR = 0.39, 95% CI = 0.25-0.60; p < 0.001)., Conclusions: In mCRPC patients scheduled for RLT, early biochemical response was tightly linked to prolonged survival, irrespective of the magnitude of PSA decline. As such, even in patients with PSA decrease of less than 50%, RLT should be continued., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: A recent meta-analysis showed that penile cancer (PeC) is associated with the human papilloma virus (HPV) in 50 % of patients in Europe. It is unknown whether urologists are aware of the impact of viral carcinogenesis., Methods: A (German-language) survey comprising 14 items was created and sent to urologists of 45 clinical centres in Germany (n = 34), Austria (n = 8), Switzerland (n = 2) and Italy/South Tyrol (n = 1) once in Q3/2018. According to a predefined quality standard, a total of 557 surveys were eligible for final data analysis (response rate: 85.7 %). Among other questions, urologists were asked to state the frequency of HPV-associated PeC in Europe. 4 potential answers were provided: (A)-"< 25 %", (B)-"25 - 50 %", (C)-"> 50 - 75 %", (D)-"level of association unknown". For the final calculation, a tolerance of ± 50 % was considered acceptable, so B and C were deemed correct answers. Based on a bootstrap-adjusted multivariate logistic regression model, criteria independently predicting a correct answer were identified., Results: Categories A-D were selected in 19.2 % (n = 107), 48.8 % (n = 272), 12.9 % (n = 72) and 19 % (n = 106), respectively, representing a rate of 61.8 % of urologists (n = 344) reaching the endpoint (B + C). Autonomous performance of chemotherapy for PeC by urologists within the given centre (OR 1.55, p[Bootstrap] = 0.036) and the centre's number of urological beds (OR 1.02, p[Bootstrap] = 0.025) were the only parameters showing a significant independent impact on the endpoint. In contrast, the status of a university centre (p = 0.143), a leading position of the responding urologist (p = 0.375) and the number of PeC patients treated per year and centre (p = 0.571) did not significantly predict a correct answer., Conclusions: Our results demonstrate insufficient knowledge on the association of PeC and HPV among German-speaking urologists., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Purpose: The purpose of this study was to immunohistochemically validate the primary tumor PSMA expression in prostate cancer (PCa) patients imaged with [ 68 Ga]Ga-PSMA PET/CT prior to surgery, with special consideration of PET-negative cases., Methods: The study included 40 men with newly diagnosed treatment-naïve PCa imaged with [ 68 Ga]Ga-PSMA I&T PET/CT as part of the diagnostic work-up prior to radical prostatectomy. All primary tumors were routinely stained with H&E. In addition, immunohistochemical staining of PSMA was performed and the immunoreactive score (IRS) was computed as semiquantitative measure. Subsequently, imaging findings were correlated to histopathologic results., Results: Eighty-three percent (33/40) of patients presented focal uptake of [ 68 Ga]Ga-PSMA I&T in the primary tumor in at least one prostate lobe. Among PSMA-PET positive patients, one-third had lymph node metastases (LNM) detected by post-operative histopathology, while in PET negative patients, only 1 out of 7 presented with regional LN involvement; PSMA-avid distant lesions, predominantly in bones, were observed in 15% and 0% of patients, respectively. The median IRS classification of PSMA expression in tumor tissue was 2 (range, 1-3) both in PSMA-PET positive and negative prostate lobes, with significantly different interquartile range: 2-3 vs. 2-2, respectively (p = 0.03). The median volume of PSMA-PET positive tumors was 5.4 mL (0.2-32.9) as compared to 1.6 mL (0.3-18.3) of PET-negative tumors (p < 0.001). There was a significant but weak correlation between SUV max and percentage of PSMA-positive tumor cells (r = 0.46, p < 0.001). A total of 35/44 (~80%) lobes were positive in PSMA-PET imaging, when a cut-off percentage of PSMA-positive cells was ≥ 90%, while 19/36 (~53%) lobes with < 90% PSMA-positive cells were PSMA-PET negative., Conclusion: Positive [ 68 Ga]Ga-PSMA I&T PET/CT scan of primary tumor of PCa results from a combination of factors, such as homogeneity and intensity of PSMA expression, tumor volume and grade, with a cutoff value of ≥ 90% PSMA-positive cells strongly determining PET-positivity. Focal accumulation of [ 68 Ga]Ga-PSMA in the primary tumor may correlate positively with aggressiveness of prostate cancer, harboring higher risk of regional LN involvement and distant metastatic spread., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans., Objective: To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa., Patients and Methods: Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome., Main Outcome Measure: Biochemical recurrence (BCR) free survival., Results: SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target., (© 2021. The Author(s).)

Background: Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT., Materials and Methods: A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [ 177 Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [ 177 Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared., Results: Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [ 177 Lu]Lu-PSMA I&T and five (9.1%) for [ 177 Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [ 177 Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [ 177 Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [ 177 Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89)., Conclusion: In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed., (© 2022. The Author(s).)

We exploit the effect of light-induced atomic desorption to produce high atomic densities (n≫k^{3}) in a rubidium vapor cell. An intense off-resonant laser is pulsed for roughly one nanosecond on a micrometer-sized sapphire-coated cell, which results in the desorption of atomic clouds from both internal surfaces. We probe the transient atomic density evolution by time-resolved absorption spectroscopy. With a temporal resolution of ≈ 1 ns, we measure the broadening and line shift of the atomic resonances. Both broadening and line shift are attributed to dipole-dipole interactions. This fast switching of the atomic density and dipolar interactions could be the basis for future quantum devices based on the excitation blockade.

(1) Background: Prostate-specific membrane antigen (PSMA) positron emission tomography (PET)-derived parameters, such as the commonly used standardized uptake value (SUV) and PSMA-positive tumor volume (PSMA-TV), have been proposed for response assessment in metastatic prostate cancer (PCa) patients. However, the calculation of whole-body PSMA-TV remains a time-consuming procedure. We hypothesized that it may be possible to quantify changes in PSMA-TV by considering only a limited number of representative lesions. (2) Methods: Sixty-five patients classified into different disease stages were assessed by PSMA PET/CT for staging and restaging after therapy. Whole-body PSMA-TV and whole-body SUV max were calculated. We then repeated this calculation only including the five or ten hottest or largest lesions. The corresponding serum levels of prostate-specific antigen (PSA) were also determined. The derived delta between baseline and follow-up values provided the following parameters: ΔSUV maxall , ΔSUV max10 , ΔSUV max5 , ΔPSMA-TV all , ΔPSMA-TV 10 , ΔPSMA-TV 5 , ΔPSA. Finally, we compared the findings from our whole-body segmentation with the results from our keyhole approach (focusing on a limited number of lesions) and correlated all values with the biochemical response (ΔPSA). (3) Results: Among patients with metastatic hormone-sensitive PCa (mHSPC), none showed a relevant deviation for ΔSUV max10 /ΔSUV max5 or ΔPSMA-TV 10 /ΔPSMA-TV 5 compared to ΔSUV maxall and ΔPSMA-TV all . For patients treated with taxanes, up to 6/21 (28.6%) showed clinically relevant deviations between ΔSUV maxall and ΔSUV max10 or ΔSUV max5 , but only up to 2/21 (9.5%) patients showed clinically relevant deviations between ΔPSMA-TV all and ΔPSMA-TV 10 or ΔPSMA-TV 5 . For patients treated with radioligand therapy (RLT), up to 5/28 (17.9%) showed clinically relevant deviations between ΔSUV maxall and ΔSUV max10 or ΔSUV max5 , but only 1/28 (3.6%) patients showed clinically relevant deviations between ΔPSMA-TV all and ΔPSMA-TV 10 or ΔPSMA-TV 5 . The highest correlations with ΔPSA were found for ΔPSMA-TV all (r ≥ 0.59, p ≤ 0.01), followed by ΔPSMA-TV 10 (r ≥ 0.57, p ≤ 0.01) and ΔPSMA-TV 5 (r ≥ 0.53, p ≤ 0.02) in all cohorts. ΔPSA only correlated with ΔSUV maxall (r = 0.60, p = 0.02) and with ΔSUV max10 (r = 0.53, p = 0.03) in the mHSPC cohort, as well as with ΔSUV maxall (r = 0.51, p = 0.01) in the RLT cohort. (4) Conclusion: Response assessment using PSMA-TV with a reduced number of lesions is feasible, and may allow for a simplified evaluation process for PSMA PET/CT.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

(1) Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) has shown remarkable results in patients with advanced prostate cancer. We aimed to evaluate the toxicity profile of the PSMA ligand [ 177 Lu]Lu-PSMA I&T. (2) Methods: 49 patients with metastatic, castration-resistant prostate cancer treated with at least three cycles of [ 177 Lu]Lu-PSMA I&T were evaluated. Prior to and after RLT, we compared leukocytes, hemoglobin, platelet counts, and renal functional parameters (creatinine, eGFR, n = 49; [ 99m Tc]-MAG3-derived tubular extraction rate (TER), n = 42). Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and KDIGO Society. To identify predictive factors, we used Spearman's rank correlation coefficient. (3) Results: A substantial fraction of the patients already showed impaired renal function and reduced leukocyte counts at baseline. Under RLT, 11/49 (22%) patients presented with nephrotoxicity CTCAE I or II according to creatinine, but 33/49 (67%) according to eGFR. Only 5/42 (13%) showed reduced TER, defined as <70% of the age-adjusted mean normal values. Of all renal functional parameters, absolute changes of only 2% were recorded. CTCAE-based re-categorization was infrequent, with creatinine worsening from I to II in 2/49 (4.1%; GFR, 1/49 (2%)). Similar results were recorded for KDIGO (G2 to G3a, 1/49 (2%); G3a to G3b, 2/49 (4.1%)). After three cycles, follow-up eGFR correlated negatively with age (r = -0.40, p = 0.005) and the eGFR change with Gleason score (r = -0.35, p < 0.05) at baseline. Leukocytopenia CTCAE II occurred only in 1/49 (2%) (CTCAE I, 20/49 (41%)) and CTCAE I thrombocytopenia in 7/49 (14%), with an absolute decrease of 15.2% and 16.6% for leukocyte and platelet counts. Anemia CTCAE II occurred in 10/49 (20%) (CTCAE I, 36/49 (73%)) with a decrease in hemoglobin of 4.7%. (4) Conclusions: After PSMA-targeted therapy using [ 177 Lu]Lu-PSMA I&T, no severe (CTCAE III/IV) toxicities occurred, thereby demonstrating that serious adverse renal or hematological events are unlikely to be a frequent phenomenon with this agent.

Prostate-specific membrane antigen (PSMA)-directed positron emission tomography/computed tomography (PET/CT) is increasingly utilized for staging of men with prostate cancer (PC). To increase interpretive certainty, the standardized PSMA reporting and data system (RADS) has been proposed. Using PSMA-RADS, we characterized lesions in 18 patients imaged with 18 F-PSMA-1007 PET/CT for primary staging and determined the stability of semi-quantitative parameters. Six hundred twenty-three lesions were categorized according to PSMA-RADS and manually segmented. In this context, PSMA-RADS-3A (soft-tissue) or -3B (bone) lesions are defined as being indeterminate for the presence of PC. For PMSA-RADS-4 and -5 lesions; however, PC is highly likely or almost certainly present [with further distinction based on absence (PSMA-RADS-4) or presence (PSMA-RADS-5) of correlative findings on CT]. Standardized uptake values (SUV max , SUV peak , SUV mean ) were recorded, and volumetric parameters [PSMA-derived tumor volume (PSMA-TV); total lesion PSMA (TL-PSMA)] were determined using different maximum intensity thresholds (MIT) (40 vs. 45 vs. 50%). SUV max was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories ( p ≤ 0.0322). In particular, the clinically challenging PSMA-RADS-3A lesions showed significantly lower SUV max and SUV peak compared to the entire PSMA-RADS-4 or -5 cohort ( p < 0.0001), while for PSMA-RADS-3B this only applies when compared to the entire PSMA-RADS-5 cohort ( p < 0.0001), but not to the PSMA-RADS-4 cohort (SUV max , p = 0.07; SUV peak , p = 0.08). SUV mean ( p = 0.30) and TL-PSMA ( p = 0.16) in PSMA-RADS-5 lesions were not influenced by changing the MIT, while PSMA-TV showed significant differences when comparing 40 vs. 50% MIT ( p = 0.0066), which was driven by lymph nodes ( p = 0.0239), but not bone lesions ( p = 0.15). SUV max was significantly higher in PSMA-RADS-5 lesions compared to all other PSMA-RADS categories in 18 F-PSMA-1007 PET/CT. As such, the latter parameter may assist the interpreting molecular imaging specialist in assigning the correct PSMA-RADS score to sites of disease, thereby increasing diagnostic certainty. In addition, changes of the MIT in PSMA-RADS-5 lesions had no significant impact on SUV mean and TL-PSMA in contrast to PSMA-TV.

Purpose: To explore the usability and diagnostic accuracy for prostate cancer of three multiparametric magnetic resonance imaging (mpMRI)/transrectal ultrasound (TRUS)-guided fusion biopsy systems operated by the same urologists., Methods: We performed a prospective, observational study including patients that underwent prostate biopsy due to a visible lesion in mpMRI (PI-RADS ≥ 3). We consecutively assessed two platforms with a rigid image registration (BioJet, D&K Technologies and UroNav, Invivo Corporation) and one with an elastic registration (Trinity, KOELIS). Four urologists evaluated each fusion system in terms of usability based on the System Usability Scale and diagnostic accuracy based on the detection of prostate cancer., Results: We enrolled 60 consecutive patients that received mpMRI/TRUS-guided prostate biopsy with the BioJet (n = 20), UroNav (n = 20) or Trinity (n = 20) fusion system. Comparing the rigid with the elastic registration systems, the rigid registration systems were more user-friendly compared to the elastic registration systems (p = 0.012). Similarly, the prostate biopsy with the rigid registration systems had a shorter duration compared to the elastic registration system (p < 0.001). Overall, 40 cases of prostate cancer were detected. Of them, both the BioJet and UroNav fusion systems detected 13 prostate cancer cases, while the Trinity detected 14. No significant differences were demonstrated among the three fusion biopsy systems in terms of highest ISUP Grade Group (p > 0.99)., Conclusions: Rigid fusion biopsy systems are easier to use and provide shorter operative time compared to elastic systems, while both types of platforms display similar detection rates for prostate cancer. Still, further high-quality, long-term results are mandatory., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa., (© 2021. The Author(s).)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Lymph-node (LN) metastasis in prostate cancer (PC) is a main risk factor for tumor recurrence after radical prostatectomy (RP). Molecular analysis facilitates detection of small-volume LN metastases with higher sensitivity than histopathology. We aimed to prospectively evaluate six candidate gene markers for detection of pelvic LN metastases and to determine their ability to predict biochemical recurrence-free survival (bRFS) in patients treated with RP., Methods: The expression of kallikrein 2, 3, and 4 (KLK2, KLK3, and KLK4), prostate-specific membrane antigen (PSMA), transmembrane serine protease 2 (TMPRSS2) and transient receptor potential cation channel subfamily M member 8 (TRPM8) was assessed using qPCR. We analyzed LNs from 111 patients (intermediate PC, n = 32 (29%); high-risk PC, n = 79 (71%)) who underwent RP and extended pelvic lymph-node dissection without neoadjuvant treatment., Results: Overall, 2411 LNs were examined by molecular and histopathologic examination. Histopathology detected 69 LN metastases in 28 (25%) patients. KLK2 and KLK3 diagnostically performed best and classified all pN1-patients correctly as molecular node-positive (molN1/pN1). The concordance on LN level was best for KLK3 (96%). KLK2, KLK3, KLK4, PSMA, TMPRSS2, and TRPM8 reclassified 27 (24%), 32 (29%), 29 (26%), 8 (7%), 13 (12%), and 23 (21%) pN0-patients, respectively, as node-positive (pN0/molN1). On multivariable cox regression analysis molecular LN status (molN1 vs. molN0) using KLK3 (HR 4.0, p = 0.04) and TMPRSS2 (HR 5.1, p = 0.02) were independent predictors of bRFS. Median bRFS was shorter in patients with only molecular positive LNs (molN1/pN0) for KLK3 (24 months, p = 0.001) and for TMPRSS2 (12 months, p < 0.001) compared to patients with negative nodes (molN0/pN0) (median bRFS not reached)., Conclusions: For diagnostic purposes, KLK3 showed highest concordance with histopathology for detection of LN metastases in PC patients undergoing RP. For prognostic purposes, KLK3 and TMPRSS2 expression were superior to histopathologic LN status and other transcripts tested for molecular LN status. We suggest a combined KLK3/TMPRSS2 panel as a valuable diagnostic and prognostic tool for molecular LN analysis.

Controlling coherent interaction between optical fields and quantum systems in scalable, integrated platforms is essential for quantum technologies. Miniaturised, warm alkali-vapour cells integrated with on-chip photonic devices represent an attractive system, in particular for delay or storage of a single-photon quantum state. Hollow-core fibres or planar waveguides are widely used to confine light over long distances enhancing light-matter interaction in atomic-vapour cells. However, they suffer from inefficient filling times, enhanced dephasing for atoms near the surfaces, and limited light-matter overlap. We report here on the observation of modified electromagnetically induced transparency for a non-diffractive beam of light in an on-chip, laterally-accessible hollow-core light cage. Atomic layer deposition of an alumina nanofilm onto the light-cage structure was utilised to precisely tune the high-transmission spectral region of the light-cage mode to the operation wavelength of the atomic transition, while additionally protecting the polymer against the corrosive alkali vapour. The experiments show strong, coherent light-matter coupling over lengths substantially exceeding the Rayleigh range. Additionally, the stable non-degrading performance and extreme versatility of the light cage provide an excellent basis for a manifold of quantum-storage and quantum-nonlinear applications, highlighting it as a compelling candidate for all-on-chip, integrable, low-cost, vapour-based photon delay.

Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups-clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups. Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256). Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin ( mixed subgroup )-demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature-a trait previously known for chRCC-across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC-and a highly significant longer overall survival for chRCC patients. Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Marquardt, Solimando, Kerscher, Bittrich, Kalogirou, Kübler, Rosenwald, Bargou, Kollmannsberger, Schilling, Meierjohann and Krebs.)

Background: Complex soft tissue defects involving the lower abdomen, perineum, and groin (LAPG) represent reconstructive challenges following urologic surgery. Consequently, these often require an interdisciplinary approach involving plastic surgery. While pedicled flaps from the lower abdomen are a reliable option, previous placement of colostomies and urinary urostomies renders these flap types unavailable. Here, the pedicled anterolateral thigh perforator (ALT) flap represents a reliable pedicled alternative which can harvest from the thigh., Materials and Methods: A retrospective data analysis of pedicled perforator flaps harvested from the thigh to reconstruct soft tissue defects was conducted. Seven patients treated in the urology department with soft tissue defects following tumor resection, infection, and dehiscence were included., Results: In all patients, the ALT flap was utilized successfully to reconstruct soft tissue defects up to 450 cm2 in size. All flaps survived. In 1 case, prolonged wound healing was observed. All defects were adequately addressed with no recurrence of dehiscence or fistula formation., Conclusions: Pedicled perforator flaps represent a valid option for the soft tissue reconstruction of the lower abdomen and perineum when a pedicled rectus abdominis flap is no longer available. This flap is, therefore, a good option in an interdisciplinary approach to soft tissue reconstruction, especially following urologic surgery, which is predominantly performed in the LAPG region., (© 2021 The Author(s). Published by S. Karger AG, Basel.)

Prostate-specific membrane antigen (PSMA) ligand PET/CT enables the localization of tumor lesions in patients with recurrent prostate cancer, but it is unclear whether androgen deprivation therapy (ADT) influences diagnostic accuracy. The aim of this study was to evaluate the effect of ADT on the detection rate of 68 Ga-PSMA ligand PET/CT. Thus, 399 patients with initial radical prostatectomy and 68 Ga-PSMA ligand PET/CT during PSA relapse were retrospectively evaluated. Propensity score matching was used to create two balanced groups of 62 subjects who either did or did not receive ADT within six months before imaging. All 68 Ga-PSMA ligand PET/CT were evaluated visually and with semiquantitative measures. The detection rate of tumor recurrence was significantly higher in the group with ADT (88.7% vs. 72.6%, p = 0.02) and improved with increasing PSA-levels in both groups. In subjects with pathological PET/CT and ADT, whole-body total lesion PSMA ( p < 0.01) and PSMA-derived tumor volume ( p < 0.01) were significantly higher than in those without ADT. More PSMA-positive lesions and higher PSMA-derived volumetric parameters in patients with ADT suggest that a better detection rate is related to a (biologically) more advanced disease stage. Due to high detection rates in patients with PSA-levels < 2 ng/mL, the withdrawal of ADT before PSMA ligand PET/CT cannot be recommended.

Purpose: Congenital penile curvature (CPC) is a rare condition with surgical correction being the standard therapy. In the current study, we report long-term results analyzing the surgical and functional outcomes using a modified Nesbit technique., Materials and Methods: Patients with CPC were included. After penile degloving and mobilization of the neurovascular bundle an artificial erection was performed. An ellipsoid part of the tunica albuginea was excised at the point of maximum curvature on the convex side of deviation. The tunical defect was then closed by interrupted absorbable sutures with inverted knots. Results of correction were documented intra- and postoperatively by artificial erection. Pre- and postoperative evaluation included measurement of penile length and curvature after pharmacological erection. Erectile function, alteration in glans sensation, palpable suture as well as short- and long-term complication were also recorded using validated questionnaires and objective examinations., Results: Fifty-five patients with mean age 26.93 years (14-66 years) and mean curvature 69.81° (25°-90°) were included in the study. Ventral or ventrolateral curvature was observed in 83.6%. Mean operative time was 106.8 minutes (55-169 minutes). Totally straightness of the penis was achieved in 51/55 patients (92.8%). After a mean long-term follow-up of 36.68 months (4-87 months), erectile function worsened in 3.6% of patients. Median penile length loss associated with this technique was 1.7 cm (0-3.0 cm)., Conclusions: Surgical therapy of CPC using our modified Nesbit technique is feasible, safe and provides reliable long-term outcomes, representing an alternative for surgical correction of CPC., Competing Interests: The authors have nothing to disclose., (Copyright © 2020 Korean Society for Sexual Medicine and Andrology.)

We study an integrated silicon photonic chip, composed of several sub-wavelength ridge waveguides, and immersed in a micro-cell with rubidium vapor. Employing two-photon excitation, including a telecom wavelength, we observe that the waveguide transmission spectrum gets modified when the photonic mode is coupled to rubidium atoms through its evanescent tail. Due to the enhanced electric field in the waveguide cladding, the atomic transition can be saturated at a photon number ≈80 times less than a free-propagating beam case. The non-linearity of the atom-clad Si-waveguide is about 4 orders of magnitude larger than the maximum achievable value in doped Si photonics. The measured spectra corroborate well with a generalized effective susceptibility model that includes the Casimir-Polder potentials, due to the dielectric surface, and the transient interaction between flying atoms and the evanescent waveguide mode. This work paves the way towards a miniaturized, low-power, and integrated hybrid atomic-photonic system compatible with CMOS technologies.

The development of highly customized technical devices is a decisive feature of technically complex setups, as frequently observed in quantum experiments. This paper describes the development and realization of an Yb-doped all-fiber amplifier system designed for such a special application, more specifically, an on-demand single-photon source based on four-wave mixing with rubidium Rydberg atoms. The laser is capable of generating bandwidth-limited configurable nanosecond pulses up to peak powers of >100 W and with pulse repetition frequencies (PRF) between 50 Hz and 1 MHz at selectable wavelengths (1008-1024 nm). Especially the amplification of the 1010 nm reference seed at the lower edge of the amplification range for Yb-based fibers is challenging and tends to produce amplified spontaneous emission (ASE) at higher wavelengths. To achieve high ASE suppression, particularly at low pulse repetition frequencies, two acousto-optical modulators (AOM) are utilized both for pulse picking and for temporal filtering. The synchronization between pulse repetition frequency and AOM driver signal allows pulse amplitude fluctuations to be kept below 1%, while ASE is suppressed by at least 85 dB (PRF = 1 MHz) and 65 dB (PRF = 1 kHz).

Background: Expression of circulating serum microRNAs has not been studied in a cohort of patients with papillary renal cell carcinoma (pRCC) so far. We hypothesized that miRNA deregulation in malignant tissue is reflected in serum and could be used for non-invasive diagnosis of pRCC as well as differentiation between type 1 and type 2 pRCC., Methods: We selected 11 differentially regulated miRNAs from the Cancer Genome Atlas (TCGA) pRCC data set as potential serum validation candidates. Serum miRNA expression was determined by qRT-PCR in a total of 34 pRCC type 1, 33 pRCC type 2 and 33 control subjects of three german high-volume medical centers., Results: Heatmap and principal component analysis showed that miRNA expression did not cluster the samples into distinct sample groups and that miRNA levels did not significantly discriminate healthy individuals from patients with pRCC, nor between patients with type 1 and type 2 pRCC. However, miR-21-5p levels were significantly increased in patients with advanced pRCC (>pT3, and/or pN+ and/or pM+) in comparison to localized pRCC. Moreover, adding the expression of miR-210-3p, which was significantly down-regulated in localized pRCC sera in comparison to healthy sera, additionally increased diagnostic accuracy in our study cohort., Conclusions: In our multicenter cohort, we were not able to identify a single miRNA serum marker for pRCC including its subclasses. However, our study revealed that miR-21-5p levels were elevated in advanced disease (with added diagnostic accuracy via addition of miR-210-3p expression), proposing these two miRs as potential biomarkers in pRCC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau.2020.03.18). The authors have no conflicts of interest to declare., (2020 Translational Andrology and Urology. All rights reserved.)

(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods: 68 Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland-Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible., Competing Interests: The authors declare no conflict of interest.

Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort ( n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.

Background: Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer., Methods: Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients., Discussion: This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019., Trial Registration: Protocol Code RACE IT: AB 65/18; EudraCT: 2018-001823-38; Clinicaltrials.gov: NCT03529890; Date of registration: 27 June 2018.