A non‐inferiority comparative analysis of micro‐ultrasonography and MRI‐targeted biopsy in men at risk of prostate cancer

Objective: To compare the efficacy of multiparametric magnetic resonance imaging (mpMRI)-directed and micro-ultrasonography (micro-US)-directed biopsy for detecting clinically significant (Grade Group >1) prostate cancer (csPCa). Materials and methods: A total of 203 patients were prospectively enrolled at three institutions across Germany and Austria in the period from January 2019 to December 2019. During each biopsy, the urologist was blinded to the mpMRI report until after the micro-US targets had been assessed. After unblinding, targets were then sampled using software-assisted fusion, followed by systematic samples. The primary outcome measure was non-inferiority of micro-US to detect csPCa, with a detection ratio of at least 80% that of mpMRI. Results: A total of 79 csPCa cases were detected overall (39%). Micro-US-targeted biopsy detected 58/79 cases (73%), while mpMRI-targeted biopsy detected 60/79 (76%) and non-targeted (completion sampling) samples detected 45/79 cases (57%). mpMRI-targeted samples alone detected 7/79 (9%) csPCa cases which were missed by micro-US-targeted and non-targeted samples. Three of these seven were anterior lesions with 2/7 in the transition zone. Micro-US-targeted samples alone detected 5/79 (6%) and completion sampling alone detected 4/79 cases (5%). Micro-US was non-inferior to mpMRI and detected 97% of the csPCa cases detected by mpMRI-targeted biopsy (95% CI 80-116%; P = 0.023). Conclusions: This is the first multicentre prospective study comparing micro-US-targeted biopsy with mpMRI-targeted biopsy. The study provides further evidence that micro-US can reliably detect cancer lesions and suggests that micro-US biopsy might be as effective as mpMRI for detection of csPCA. This result has significant implications for increasing accessibility, reducing costs and expediting diagnosis

Extended Criteria Donors in Living Kidney Transplantation Including Donor Age, Smoking, Hypertension and BMI

Purpose: An expansion of selection criteria for deceased organ transplantation already exists to manage the current donor shortage. Comparable evaluation of risk factors for living donors should be investigated to improve this issue. Patients and methods: Our retrospective single-centre study analysed 158 patients with living kidney transplants performed between February 2006 and June 2012. We investigated the influence of donor risk factors (RF) including body mass index over 30 kg/m2, age >60 years, active nicotine abuse and arterial hypertension on postoperative kidney function with focus on the recipients. This was measured for long-term survival and glomerular filtration rate (GFR) in a 5-year follow-up. Results: Overall, out of 158 living donors, 84 donors were identified to have no risk factors, whereas 74 donors had at least one risk factor. We noted a significant higher delayed graft function (p=0.042) in the first 7 days after transplantation, as well as lower GFR of recipients of allografts with risk factors in the first-year after transplantation. In our long-term results, there was no significant difference in the functional outcome (graft function, recipient and graft survival) between recipients receiving kidneys from donors with no and at least one risk factors. In the adjusted analysis of subgroups of different risk factors, recipients of donors with "age over 60 years" at time of transplantation had a decreased transplant survival (p=0.014). Conclusion: Thus, a careful expansion for selection criteria for living donors with critical evaluation could be possible, but especially the age of the donors could be a limited risk factor

Morphological analysis of injured gluteal muscles after intraoperative transplantation of allogeneic mesenchymal stromal cells in THA patients

Einleitung: Beim transglutealen Zugang zur Implantation einer Hüfttotalendoprothese (HTEP) wird der Musculus gluteus medius (GM) inzidiert, um eine optimale Darstellung für den Gelenkersatz zu erreichen. Vor allem bei schwereren Muskelschädigungen kann es zu einer unvollständigen Reparatur kommen, die auf Basis des Verlustes kontraktiler Einheiten sowie deren Ersatz durch Fett- und Bindegewebe zu funktionellen Einschränkungen führt. Die Möglichkeit Regenerationsprozesse durch zellbasierte Therapieansätze zu unterstützen wird aktuell vielseitig untersucht. Ziel dieser Arbeit ist es, den Einfluss von mesenchymalen Stromazellen der Plazenta (Placental expanded stromal cell product, PLX Zellen) auf den traumatisierten GM nach einer HTEP- Implantation anhand von morphologischen Parametern zu evaluieren. Methodik: In einer monozentrischen, placebo-kontrollierten, doppelblinden, prospektiven Studie wurden 20 Patienten drei Gruppen randomisiert zugeordnet und untersucht. Nach der HTEP-Implantation wurden folgende Studieninterventionen verglichen: intramuskuläre Applikation von 1) Placebo (N=7), 2) 150 x 106 (N=7) und 3) 300 x 106 (N=6) PLX Zellen. Zur Analyse der Makromorphologie wurden Magnetresonanztomografie- (MRT) Aufnahmen präoperativ und 6, 12 sowie 26 Wochen postoperativ durchgeführt und das Muskelvolumen und die fettige Infiltration analysiert. Für die Mikrostruktur wurden intraoperativ und 12 Wochen postoperativ eine Muskelbiopsie des GM entnommen und folgende histologische Analysen durchgeführt: Muskelfaserdurchmesser, Anzahl der Regeneratfasern, Fasertypverteilung, Gefäßdichte, Infiltration mit T-Lymphozyten und Makrophagen. Ergebnisse: 26 Wochen postoperativ zeigte die MRT-Analyse einen signifikanten Unterschied der Muskelvolumenzunahme bei Patienten, welche mit 150M PLX Zellen therapiert worden waren im Vergleich zur Placebogruppe (p=0.004). Patienten der 300M Gruppe erwiesen sich als inferior zur 150M Gruppe mit einem GM Volumen, das zwischen Placebo und 150M lag. Die Veränderung des intramuskulären Fettanteils war in allen Gruppen gleich. In der mikromorphologischen Analyse zeigte sich ein Muster, welches schneller ablaufende Regenerationsvorgänge nach Zelltherapie beschrieb. Gekennzeichnet war dies durch noch bestehende Anzeichen für Regeneration in der Placebogruppe, wie Myoblasten und kleinere Faserdurchmesser, 12 Wochen postoperativ. Angiogene Effekte sowie Veränderungen der Fasertypverteilung konnten in der Biopsie nicht beobachtet werden. Ein Einfluss der Zelltherapie auf lokale immunologische Parameter, wie Lymphozyten- und Makrophageninfiltration, konnte ebenfalls nicht nachgewiesen werden. Schlussfolgerung: Die mikro- und makromorphologische Untersuchung des traumatisierten GM nach klinischer Anwendung von PLX Zellen weist auf einen möglichen Wirkmechanismus über die Zunahme kontraktilen Muskelgewebes hin. Eine schnellere Regeneration könnte ebenfalls eine Rolle spielen. Für definitive Aussagen sind weitere Studien mit größeren Patientenzahlen notwendig.Introduction: During transgluteal total hip arthroplasty (THA) the gluteus medius muscle (GM) is incised to achieve an ideal exposure for the hip replacement. Particularly severe muscle traumas can induce an insufficient repair which can lead to functional limitations based on a lack of contractile units and a replacement by fatty and fibrotic tissue. Currently the potential to support the regeneration process by cell-based therapies is investigated widely. The aim of this thesis is to evaluate the influence of mesenchymal stromal cells of the placenta (placental expanded stromal cell product, PLX cells) on the traumatized GM after THA with the focus on morphological parameters. Method: In a monocentric, placebo-controlled, double blind, prospective study 20 patients were randomized in three groups and examined. After the THA the following study interventions were compared: intramuscular application of 1) placebo (N=7), 2) 150 x 106 (N=7) and 3) 300 x 106 (N=6) PLX cells. For the macromorphological analysis magnet resonance imaging (MRI) images were investigated for muscle volume and fatty infiltrations preoperatively and 6, 12, as well as 26 weeks postoperatively. For the analysis of the microstructure muscle biopsies of the GM were removed intraoperatively and 12 weeks postoperatively for the following measurements: muscle fibre diameter, amount of regenerated fibres, fibre type distribution, vessel density, infiltration of t- lymphocytes and macrophages. Results: 26 weeks postoperatively the MRI analysis demonstrated a significant difference in the increase of muscle volume in patients treated with 150M PLX cells in comparison to the placebo group (p=0.004). Patients of the 300M group represented inferior to the 150M group with a GM volume which was between the placebo and 150M. The change of intramuscular fat was equal in all groups. The micromorphological analysis presented a pattern describing faster regeneration processes after cell therapy. This was marked by ongoing regeneration in the placebo group 12 weeks postoperatively, as represented by myoblasts and minor fibre size diameter. Angiogenic effects and changes in fibre type distribution were not detected in the biopsy. An influence of the cell therapy on local immunological parameters, like the infiltration of the lymphocytes and the macrophages, was equally not established. Conclusion: The micro- and macromorphological analysis of the traumatised GM after clinical application of PLX cells indicate an increase of contractile muscle tissue as a potential mode of action. A faster regeneration could also be relevant. For definitive statements further studies with higher number of patients are necessary

The Ureter in the Kidney Transplant Setting: Ureteroneocystostomy Surgical Options, Double-J Stent Considerations and Management of Related Complications

Purpose of Review: In the setting of kidney transplantation, the ureter is a common source for complications. As a result, prevention of ureteral complications and their management is of crucial importance. In this context, the purpose of this review is to summarize recent literature on the ureter in the kidney transplant setting with a special focus on new findings. We conducted a PubMed and Medline search over the last 10 years to identify all new publications related to ureteroneoimplantations, stents and management of complications in the kidney transplant setting. Recent Findings: Performance of the “Lich-Gregoir” technique for ureteroneocystostomy seems to be favourable in regard to postoperative complications when compared with other methods described in the literature. Moreover, major urologic complications can be further reduced by ureteral stenting. Summary: A new approach for management of ureteral strictures in renal transplants is presented. We discussed the usage of a ureteral stent covered with a biostable polymer aiming to prevent tissue ingrowth into the lumen as a new option for management of ureteral stricture in the kidney transplant setting

Follow-Up of Men Who Have Undergone Focal Therapy for Prostate Cancer with HIFU—A Real-World Experience

Purpose: To determine oncological and functional outcomes and side effects after focal therapy of prostate cancer (PCa) with high-intensity focused ultrasound (HIFU). Methods: This retrospective single-center study included 57 consecutive patients with localised PCa. Aged 18–80 with ≤2 suspicious lesions on mpMRI (PIRADS ≥ 3), PSA of ≤15 ng/mL, and an ISUP GG of ≤2. HIFU was performed between November 2014 and September 2018. All men had an MRI/US fusion-guided targeted biopsy (TB) combined with a TRUS-guided 10-core systematic biopsy (SB) prior to focal therapy. HIFU treatment was performed as focal, partial, or hemiablative, depending on the prior histopathology. Follow-up included Questionnaires (IIEF-5, ICIQ, and IPSS), prostate-specific antigen (PSA) measurement, follow-up mpMRI, and follow-up biopsies. Results: The median age of the cohort was 72 years (IQR 64–76), and the median PSA value before HIFU was 7.3 ng/mL (IQR 5.75–10.39 ng/mL). The median follow-up was 27.5 (IQR 23–41) months. At the time of the follow-up, the median PSA value was 2.5 ng/mL (IQR 0.94–4.96 ng/mL), which shows a significant decrease (p p < 0.001). The rate of post-HIFU complications was low, at 19.3% (11 patients). The limitation of this study is the lack of long-term follow-up. Conclusions: HIFU as a therapy option for nonmetastatic, significant prostate cancer is effective in the short term for carefully selected patients and shows a low risk of adverse events and side effects

Immunomodulatory placental‐expanded, mesenchymal stromal cells improve muscle function following hip arthroplasty

Abstract Background No regenerative approach has thus far been shown to be effective in skeletal muscle injuries, despite their high frequency and associated functional deficits. We sought to address surgical trauma‐related muscle injuries using local intraoperative application of allogeneic placenta‐derived, mesenchymal‐like adherent cells (PLX‐PAD), using hip arthroplasty as a standardized injury model, because of the high regenerative and immunomodulatory potency of this cell type. Methods Our pilot phase I/IIa study was prospective, randomized, double blind, and placebo‐controlled. Twenty patients undergoing hip arthroplasty via a direct lateral approach received an injection of 3.0 × 108 (300 M, n = 6) or 1.5 × 108 (150 M, n = 7) PLX‐PAD or a placebo (n = 7) into the injured gluteus medius muscles. Results We did not observe any relevant PLX‐PAD‐related adverse events at the 2‐year follow‐up. Improved gluteus medius strength was noted as early as Week 6 in the treatment‐groups. Surprisingly, until Week 26, the low‐dose group outperformed the high‐dose group and reached significantly improved strength compared with placebo [150 M vs. placebo: P = 0.007 (baseline adjusted; 95% confidence interval 7.6, 43.9); preoperative baseline values mean ± SE: placebo: 24.4 ± 6.7 Nm, 150 M: 27.3 ± 5.6 Nm], mirrored by an increase in muscle volume [150 M vs. placebo: P = 0.004 (baseline adjusted; 95% confidence interval 6.0, 30.0); preoperative baseline values GM volume: placebo: 211.9 ± 15.3 cm3, 150 M: 237.4 ± 27.2 cm3]. Histology indicated accelerated healing after cell therapy. Biomarker studies revealed that low‐dose treatment reduced the surgery‐related immunological stress reaction more than high‐dose treatment (exemplarily: CD16+ NK cells: Day 1 P = 0.06 vs. placebo, P = 0.07 vs. 150 M; CD4+ T‐cells: Day 1 P = 0.04 vs. placebo, P = 0.08 vs. 150 M). Signs of late‐onset immune reactivity after high‐dose treatment corresponded to reduced functional improvement. Conclusions Allogeneic PLX‐PAD therapy improved strength and volume of injured skeletal muscle with a reasonable safety profile. Outcomes could be positively correlated with the modulation of early postoperative stress‐related immunological reactions

PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors

Abstract Background A high level of PD-L1 expression is the most relevant predictive parameter for response to immune checkpoint inhibitor (CPI) therapy in urinary bladder cancer. Existing data on the relationship between PD-L1 expression and the natural course of disease are controversial and sparse. Methods To expand our understanding of the relationship between PD-L1 expression and parameters of cancer aggressiveness, PD-L1 was analyzed on tissue microarrays containing 2710 urothelial bladder carcinomas including 512 patients with follow-up data who underwent radical cystectomy and follow-up therapies in the pre-immune checkpoint inhibitor therapy era. Results Tumor cell positivity in ≥10% of cells were seen in 513 (20%) and an immune cell positivity occurred in 872 (34%) of 2566 interpretable cancers. PD-L1 positivity in tumor cells increased from pTaG2 low grade (0.9% positive) to pTaG3 high grade (4.1%; p = 0.0255) and was even higher in muscle-invasive (pT2–4) carcinomas (29.3%; p < 0.0001). However, within pT2–4 carcinomas, PD-L1 positivity was linked to low pT stage (p = 0.0028), pN0 (p < 0.0001), L0 status (p = 0.0005), and a better prognosis within 512 patients with cystectomy who never received CPIs (p = 0.0073 for tumor cells and p = 0.0086 for inflammatory cells). PD-L1 staining in inflammatory cells was significantly linked to PD-L1 staining in tumor cells (p < 0.0001) and both were linked to a positive p53 immunostaining (p < 0.0001). Conclusion It cannot be fully excluded that the strong statistical link between PD-L1 status and favorable histological tumor features as well as better prognosis could influence the outcome of studies evaluating CPIs in muscle-invasive urothelial carcinoma

CEA (CEACAM5) expression is common in muscle‐invasive urothelial carcinoma of the bladder but unrelated to the disease course

Abstract Objectives Carcinoembryonic antigen (CEA) is a cell surface glycoprotein that represents a promising therapeutic target. Serum measurement of shedded CEA can be utilized for monitoring of cancer patients. Material and Methods To evaluate the potential clinical significance of CEA expression in urothelial bladder neoplasms, CEA was analysed by immunohistochemistry in more than 2500 urothelial bladder carcinomas in a tissue microarray format. Results CEA staining was largely absent in normal urothelial cells but was observed in 30.4% of urothelial bladder carcinomas including 406 (16.7%) with weak, 140 (5.8%) with moderate, and 192 (7.9%) with strong staining. CEA positivity occurred in 10.9% of 411 pTaG2 low‐grade, 32.0% of 178 pTaG2 high‐grade, and 43.0% of 93 pTaG3 tumours (p  0.25). Conclusion CEA increases markedly with grade progression in pTa tumours, and expression occurs in a significant fraction of pT2–4 urothelial bladder carcinomas. The high rate of CEA positivity in pT2–4 carcinomas offers the opportunity of using CEA serum measurement for monitoring the clinical course of these cancers. Moreover, CEA positive urothelial carcinomas are candidates for a treatment by targeted anti‐CEA drugs

Additional file 1 of PD-L1 expression in tumor and inflammatory cells is associated with favorable tumor features and favorable prognosis in muscle-invasive urothelial carcinoma of the bladder not treated by immune checkpoint inhibitors

Supplementary Material 1