[New treatment approaches for and ongoing trials in metastatic hormone-sensitive prostate cancer]. / Neue Therapieansätze und Studienübersicht beim metastasierten hormonsensitiven Prostatakarzinom.

BACKGROUND: For many years, therapy for metastatic hormone-sensitive prostate cancer (mHSPC) was dominated by monotherapy using androgen deprivation therapy (ADT). With the demonstration of survival benefit with intensified systemic therapy from the CHAARTED and STAMPEDE trials, this has fundamentally changed. We analyzed the phase III trials that led to the change in therapy in mHSPC. In addition, we summarized ongoing trials in mHSPC. OBJECTIVES: The ongoing studies and current data on systemic therapy in mHSPC were analyzed. RESULTS: Monotherapy with ADT is no longer considered the standard therapy for mHSPC. Combination therapy with ADT and novel androgen receptor targeting agents (ARTAs: abiraterone, apalutamide, enzalutamide) is now the established standard option. The added value of further intensification of therapy was demonstrated in the first trials of triple therapy with ADT + docetaxel + darolutamide or abiraterone in mHSPC. Current studies are also investigating new forms of therapy. Lutetium177-PSMA radioligand therapy is an established standard in metastatic castration-resistant prostate cancer (mCRPC) and is currently being evaluated in combination with ADT + ARTA in mHSPC. The use of PARP inhibitors (PARPi) have been established in mCRPC. Current studies are showing early evidence of benefit from novel combination therapies of PARPi + ARTA, which represent a further expansion of the therapeutic landscape. Experimental therapies are testing another combination, such as an AKT inhibitor with ARTA in patients with PTEN (phosphatase and tensin homolog) loss. Based on the proof of principle in mCRPC, this combination is now being evaluated in earlier stage mHSPC. Other experimental therapies in clinical testing include inhibitors of cyclin dependent kinases (CDK). CONCLUSIONS: Combination therapies are the current standard of care for mHSPC, with the combination of ADT + ARTA dominating. Preliminary results underline the importance of further intensification of therapy by means of triple therapy. However, novel combinations with radioligand therapy or PARP inhibitors are also promising in the treatment of mHSPC. Preliminary results show the principle efficacy of AKT inhibitors in patients with PTEN loss, which similar to therapy with CDK4/6 inhibitors still have to prove their clinical relevance in randomized trials.

Comparative analysis of Bricker versus Wallace ureteroenteric anastomosis and identification of predictors for postoperative ureteroenteric stricture.

PURPOSE: Ureteroenteric anastomosis after cystectomy is usually performed using the Bricker or Wallace technique. Deterioration of renal function is the most common long-term complication of urinary diversion (UD). To improve surgical care and optimize long-term renal function, we compared the Bricker and Wallace anastomotic techniques and identified risk factors for ureteroenteric strictures (UES) in patients after cystectomy. MATERIAL AND METHODS: Retrospective, monocentric analysis of 135 patients who underwent cystectomy with urinary diversion at the University Hospital Essen between January 2015 and June 2019. Pre- and postoperative renal function, relevant comorbidities, prior chemo- or radiotherapy, pathological findings, urinary diversion, postoperative complications, and ureteroenteric strictures (UES) were analyzed. RESULTS: Of all 135 patients, 69 (51.1%) underwent Bricker anastomosis and 66 (48.9%) Wallace anastomosis. Bricker and Wallace groups included 134 and 132 renal units, respectively. At a median follow-up of 14 (6-58) months, 21 (15.5%) patients and 30 (11.27%) renal units developed UES. We observed 22 (16.6%) affected renal units in Wallace versus 8 (5.9%) in Bricker group (p < 0.001). A bilateral stricture was most common in Wallace group (69.2%) (p < 0.001). Previous chemotherapy and 90-day Clavien-Dindo grade ≥ III complications were independently associated with stricture formation, respectively (OR 9.74, 95% CI 2-46.2, p = 0.004; OR 4.01, 95% CI 1.36-11.82, p = 0.013). CONCLUSION: The results of this study show no significant difference in ureteroenteric anastomotic techniques with respect to UES development regarding individual patients but suggest a higher risk of bilateral UES formation in patients undergoing Wallace anastomosis. This is reflected in the increased UES rate under consideration of the individual renal units.

Transrectal Ultrasound Guided Hydrodistension - A New Surgical Way in Transgender Surgery.

BACKGROUND: Creating the neovaginal canal in transwomen is one of the most delicate steps of Genital Gender Affirming Surgery (GGAS). Injury to the rectum is a rare but serious complication that can lead to further surgery and even creation of a colostomy. AIM: Implementation of a novel hydrospacing technique (HST) based on transrectal ultrasound (TRUS)-guided hydrodistension. METHODS: Between June 2018 and June 2020 54 transwomen received GGAS with HST. Immediately before GGAS transperineal hydrodistension was performed using a TSK-Supra-Needle (20 Gauge, 120 mm length), that was placed under direct TRUS-guided visual control between Denonvilliers' fascia and the anterior rectal wall. 40 - 60 ml normal saline were administered perineally to separate Denonvilliers' fascia from the anterior rectal wall to create a dissection of at least 20 mm. For better intraoperative visualization the hydrodissected space was also dyed using 2ml of methylenblue while retracting the needle. A retrospectively analysed, clinically and demographically comparable series of 84 transwomen who underwent GGAS between June 2016 and June 2018 served as control group. All 138 surgeries were performed by the same experienced surgeon. OUTCOMES: The effect of the novel hydrospacing technique on neovaginal dimensions and operating time. RESULTS: Patients in both groups did not differ in baseline patient characteristics such as age and body mass index (HST 35 vs 38 years in control group, P = .44 and body mass index 26 vs 25 kg/m2, P = .73). Vaginal depth and width were significantly larger in the HST subgroup as compared to controls (14.4 cm vs 13.5 cm, P = .01 and 4.2 cm vs 3.8 cm, P < .001). No statistically significant difference occurred in intraoperative rectal injury (n = 0 in HST group, n = 2 in control group, P = .26). Median total OR-time was comparable for GGAS including HST before vaginoplasty to standard technique (211 minutes for HST vs 218 minutes; P = 0.19). CLINICAL IMPLICATIONS: The proposed additional surgical step during GGAS is minimally invasive and safe, simplifies GGAS and potentially helps to avoid complications such as rectal injury. STRENGTH & LIMITATIONS: Single-surgeon series, limited follow-up time and no prospective randomization. CONCLUSION: HST is a safe and feasible procedure, which facilitates a safe preparation of the neovaginal canal during male to female GGAS. Panic A, Rahmani N, Kaspar C, et al. Transrectal Ultrasound Guided Hydrodistension - A New Surgical Way in Transgender Surgery. J Sex Med 2021;18:1135-1141.

The value of an additional scrotal suture during orchidopexy.

INTRODUCTION: Undescended testes present in 3-5% of male infants at birth. Orchidopexy is indicated to improve fertility and reduce the risk of testicular tumors. Guidelines recommend orchidopexy as early as six months of age, treatment should be finished within the age of 18 months. So far, no unequivocal proof demonstrated the superiority of one of the different surgical techniques. OBJECTIVE: To evaluate the value of an additional scrotal suture between the tunica albuginea and the dartos fascia during orchidopexy in an outpatient setting. It is yet unclear, whether the suture influences the incidence of secondary cryptorchidism or recurrence. STUDY DESIGN: This is a retrospective cohort study. Between 2010 and 2018 two experienced surgeons performed 561 inguinal orchidopexy-procedures in an open technique (375 boys). In group 1 (2010-2014) they managed 234 IOP (156 boys) without an additional scrotal suture. Since 2014, in group 2 an additional suture has been performed in 327 IOP (219 boys). Statistically, we compared both groups over a period of consecutive 4 years after the model of a life table analysis (Logrank). RESULTS: The numbers of boys with complete follow-up were 118 of 156 in group 1 and 154 of 219 in group 2, demonstrating 7 (5.9%) and 7 (4.5%) recurrences, respectively. There was no statistically significant difference in recurrences between group 1 and group 2 (Logrank-Test, p = 0.97). Orchidopexie failure was detected between 0.9 and 23.1 months after the IOP in group 1 and between 3.2 and 17.7 months in group 2. Mean age in months at the operation in both groups was significantly higher than the recommended 6-18 months in the EAU/AUA-guidelines. Both groups showed similar rates of postoperative complications. DISCUSSION: Orchidopexy is a safe procedure in an outpatient setting. So far there is no evidence that performing an additional scrotal suture decreases the operative failure rate in inguinal standard orchidopexy procedures.

Renal duplication with ureter duplex not following Meyer-Weigert-Rule with development of a megaureter of the lower ureteral segment due to distal stenosis - A case report.

Meyer-Weigert-Rule predicts the draining pattern of duplex ureters in bipolar renal duplications. The upper pole is normally seen as ectopic and therefore dysplastic due to obstruction, whereas the lower pole is related to vesicoureteral reflux. In our case, this rule is violated with uncrossed ureter duplex and a dysplastic lower pole in connection with obstruction.

[Systemic treatment of metastatic tumors of the upper urinary tract]. / Systemtherapie des metastasierten Tumors des oberen Harntraktes.

BACKGROUND: Similar to bladder cancer, more than 95% tumors of the upper urinary tract are urothelial carcinoma. At initial diagnosis approximately 60% of the tumors are already invasive. In case of distant metastasis (M+) there is no benefit of radical nephroureterectomy. In those cases, systemic therapy is indicated. OBJECTIVES: The aim of this article is to present a systematic overview of different therapies in patients with metastatic upper tract urothelial carcinoma (UTUC). RESULTS: Currently there are insufficient data upon which the recommendations for treatment of locally advanced and metastatic UTUC can be based. Cisplatin-based chemotherapy is the gold standard in first-line treatment of metastatic UTUC. Due to a lower toxicity compared to MVAC (methotrexate, vinblastine, adriamycin plus cisplatin), gemcitabine and cisplatin have become standard. However, carboplatin-based chemotherapies should not be considered interchangeable. Immunomodulatory therapies using checkpoint inhibition, particularly with antibodies directed against PD-1 (programmed cell death 1), PD-L1 (programmed cell death ligand 1) or CTLA-4 (cytotoxic T­lymphocyte antigen-4) have shown significant antitumor activity with tolerable safety profiles and durable responses in patients with locally advanced and metastatic urothelial carcinoma. In those patients, unfit for cisplatin-based chemotherapy, good response rates have been reported in case of a positive PD-L1 status. However, preliminary data of the KEYNOTE-361 and IMvigor130 studies showed a reduced survival in case of low PD-L1 expression.

Epstein-Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol-3 kinase activation.

Expression of the Epstein-Barr virus (EBV) immediate-early (IE) protein BRLF1 induces the lytic form of viral replication in most EBV-positive cell lines. BRLF1 is a transcriptional activator that binds directly to a GC-rich motif present in some EBV lytic gene promoters. However, BRLF1 activates transcription of the other IE protein, BZLF1, through an indirect mechanism which we previously showed to require activation of the stress mitogen-activated protein kinases. Here we demonstrate that BRLF1 activates phosphatidylinositol-3 (PI3) kinase signaling in host cells. We show that the specific PI3 kinase inhibitor, LY294002, completely abrogates the ability of a BRLF1 adenovirus vector to induce the lytic form of EBV infection, while not affecting lytic infection induced by a BZLF1 adenovirus vector. Furthermore, we demonstrate that the requirement for PI3 kinase activation in BRLF1-induced transcriptional activation is promoter dependent. BRLF1 activation of the SM early promoter (which occurs through a direct binding mechanism) does not require PI3 kinase activation, whereas activation of the IE BZLF1 and early BMRF1 promoters requires PI3 kinase activation. Thus, there are clearly two separate mechanisms by which BRLF1 induces transcriptional activation.