Standardized PSMA-PET Imaging of Advanced Prostate Cancer.

Imaging of advanced prostate cancer is a challenging task, as it requires longitudinal characterization of disease extent in a standardized way to enable appropriate treatment selection and evaluation of treatment efficacy. In the last years, prostate-specific membrane antigen (PSMA)-PET/CT has become the reference standard examination for patients with advanced prostate cancer. Together with the rise of PSMA-PET, standardized frameworks for the reporting of image findings have been proposed, eg, the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) and the structured reporting system for PSMA targeted PET imaging (PSMA-RADS) framework. Therefore, recent evidence on PSMA-PET derived tumor volume as useful a biomarker for outcome prognostication and related frameworks will be discussed in the article. The PROMISE framework recommends quantifying the tumor volume per-organ system, which accounts for the fact that the location of the metastases greatly influence its biological aggressiveness. In addition, changes in PSMA-PET derived tumor volume have been shown to be promising biomarkers for response assessment. Limitations of PSMA-PET will also be discussed because the tumor volume might not always be suited for response assessment. As a pitfall of PSMA-based systems, decreasing PSMA-expression might erroneously be interpreted as response to therapy. Also, especially for patients with limited disease, the tumor volume might not be ideal for response assessment. Therefore, various frameworks have been introduced to objectively measure response to therapy with PSMA-PET. Amongst these, the PSMA-PET progression (PPP) criteria and the response evaluation criteria in PSMA (RECIP) are optimized for earlier and later phenotypes of advanced prostate cancer, respectively. Variables needed to determine PPP or RECIP outcome on PSMA-PET are recorded under the umbrella of PROMISE recommendations. In this article, various reporting and response assessment frameworks are explained and discussed. Also, recent evidence for the relevance of PSMA-PET biomarkers for clinical management and outcome prognostication are shown.

Next generation radiotheranostics promoting precision medicine.

Radiotheranostics is a field of rapid growth with some approved treatments including 131I for thyroid cancer, 223Ra for osseous metastases, 177Lu-DOTATATE for neuroendocrine tumors, and 177Lu-PSMA (prostate-specific membrane antigen) for prostate cancer, and several more under investigation. In this review, we will cover the fundamentals of radiotheranostics, the key clinical studies that have led to current success, future developments with new targets, radionuclides and platforms, challenges with logistics and reimbursement and, lastly, forthcoming considerations regarding dosimetry, identifying the right line of therapy, artificial intelligence and more.

[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.

[Treatment of primary oligometastatic prostate cancer]. / Die Therapie des primär oligometastasierten Prostatakarzinoms.

BACKGROUND: Multimodal treatment concepts are gaining in importance in the treatment of prostate cancer patients with primary oligometastatic disease. Data from randomized studies show that survival advantages can be achieved in this patient collective by the combination of local and systemic treatment compared to systemic treatment alone. OBJECTIVE: To analyze the available data on therapeutic approaches for oligometastatic prostate cancer. MATERIAL AND METHODS: Summary and discussion of current studies on systemic and local treatment of de novo oligometastatic prostate cancer. RESULTS: Systemic treatment continues to be the standard of care in the oligometastatic stage of prostate cancer. Furthermore, irradiation of the prostate is recommended for patients with a low metastasis burden after this led to an extension of the overall survival in a randomized phase III study. Large case series suggest that radical prostatectomy can also improve oncological endpoints. The results of prospective phase II studies on metachronous metastatic disease provide evidence that local ablative radiotherapy of individual metastases can improve progression-free survival; however, the value of this approach in de novo metastatic disease is just as unclear as that of a triple treatment combination consisting of local and extended systemic treatment. CONCLUSION: In addition to systemic treatment, irradiation of the prostate is a new standard of care for the oligometastatic stage ("low tumour burden").

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.

M0CRPC overview of management options.

Though prostate cancer usually responds to androgen deprivation therapy (ADT) in the beginning, the majority of prostate cancers will develop castration resistance over time. The androgen receptor (AR) pathway is often found to be activated in castration resistant prostate cancer (CRPC). Thus, AR signalling remains a therapeutic target upon the development of CRPC. The term M0CRPC is used when ADT leads to castration resistance and there are no metastases detectable by means of conventional imaging. Until recently, there was no therapeutic standard for this group of patients. With the PROSPER-, SPARTAN- and ARAMIS-studies three large placebo-controlled phase III trials have been published lately that showed a significant benefit in metastasis-free survival in men with M0CRPC and short PSA doubling time (PSADT). The efficacy data are very similar in these studies, meaning that the drugs' safety profiles, final analyses of overall survival and their availability will be more important to help clinicians decide which of these three drugs they use for their patients with M0CRPC.

The prognostic value of serum MMP-7 levels in prostate cancer patients who received docetaxel, abiraterone, or enzalutamide therapy.

OBJECTIVES: The rapidly changing treatment landscape in metastatic castration-resistant prostate cancer (mCRPC) calls for biomarkers to guide treatment decisions. We recently identified MMP-7 as a potential serum marker for the prediction of response and survival in mCRPC patients who received docetaxel (DOC) chemotherapy. Here, we aimed to test this finding in an independent patient cohort and in addition to explore the prognostic potential of serum MMP-7 in abiraterone (ABI) or enzalutamide (ENZA) treated patients. METHODS AND MATERIALS: MMP-7 levels were measured in 836 serum samples from 320 mCRPC patients collected before and during DOC (n = 95), ABI (n = 140), or ENZA (n = 85) treatment by using the ELISA method. Results were correlated with clinical and follow-up data. RESULTS: MMP-7 baseline levels were similar between the 3 treatment groups. In the ABI and ENZA cohorts, baseline MMP-7 levels were lower in patients with prior radical prostatectomy (P = 0.058 and P = 0.041, respectively). Baseline MMP-7 levels above the median were associated with shorter overall survival for the DOC (P = 0.001) and ENZA (P = 0.006) cohorts. Multivariable analyses in the DOC and ENZA cohorts revealed that high pretreatment MMP-7 level is an independent risk factor for patients' survival. In addition, in DOC-treated patients with high baseline MMP-7 level, marker decrease at the third DOC cycle was associated with improved survival. Patients with high baseline MMP-7 levels had better survival when treated with ABI compared to DOC or ENZA. CONCLUSIONS: We confirmed the prognostic value of pretreatment MMP-7 serum level and its changes as independent predictors of survival in DOC-treated mCRPC patients. In addition, high MMP-7 was a negative predictor in ENZA-treated but not in ABI-treated patients. These results warrant further research to confirm the predictive value of serum MMP-7 and to explore the potential mechanistic involvement of MMP-7 in DOC and ENZA resistance of mCRPC patients.

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.

[Treatment concepts for primary oligometastatic prostate cancer]. / Therapiekonzepte beim primär oligometastasierten Prostatakarzinom.

BACKGROUND: About 5% of prostate cancer patients have distant metastases at diagnosis. In these metastatic hormone-sensitive prostate cancers (mHSPC), systemic therapy is recommended, according to the guidelines. Moreover, metastasis-directed therapy (MDT) is discussed to prolong survival. OBJECTIVES: The contemporary literature concerning local therapy and MDT in patients with mHSPC is summarized. METHODS: Selective literature search. RESULTS: In 2018, randomized controlled data on local therapy in mHSPC patients were published by the authors of the STAMPEDE study. Here, patients were randomized between standard of care (SOC) ± radiotherapy to the prostate (RT). Within the overall cohort, no difference regarding 3­year overall survival (OS) was observed. Within a prespecified subgroup of patients with low metastatic burden. Similar results were observed in numerous retrospective studies analyzing radical prostatectomy; prospective randomized studies are pending. For MDT, there are no sufficient data in mHSPC patients yet. CONCLUSIONS: In the current guidelines, systematic therapy is standard of care in mHSPC patients. In patients with low metastatic burden, a survival benefit was observed when adding percutaneous RT to the prostate. Retrospective studies also suggest a benefit when adding RP. However, whether MDT prolongs survival is still unknown.

Narrow-band imaging assisted cystoscopy in the follow-up of patients with transitional cell carcinoma of the bladder: a randomized study in comparison with white light cystoscopy.

PURPOSE: To evaluate the diagnostic accuracy of a second look narrow-band imaging (NBI) cystoscopy in the follow-up of patients with NMIBC as compared to a second white light cystoscopy (WLI). PATIENTS AND METHODS: From August 2013 to October 2014, 600 patients with history of non-muscle invasive bladder cancer (NMIBC), who presented for follow-up cystoscopy at an academic outpatient clinic, were randomized to flexible WLI-cystoscopy plus second look NBI-cystoscopy (n = 300) or flexible WLI-cystoscopy plus second look WLI-cystoscopy (n = 300) in the same session. We analysed the detection rate of bladder tumours in second look cystoscopy as primary endpoint. In addition, we evaluated recurrence rates before study enrolment and after transurethral resection (TUR-BT) in each group. RESULTS: In 600 patients with a history of NMIBC, 78 out of 300 patients (26%) with WLI-NBI-cystoscopy and 70 out of 300 patients (23%) with WLI-WLI-cystoscopy were diagnosed with cancer recurrence (p = 0.507). Overall, WLI-NBI detected 404 and WLI-WLI 234 lesions, respectively. The second look cystoscopy detected 57 additional cancer lesions: 45 tumours in 18 patients with WLI-NBI and 12 tumours in 9 patients with WLI-WLI (p = 0.035). After initial examination without tumour detection an improvement was determined by the second cystoscopy in 3 patients (75 vs. 78 pat.) with WLI-NBI and in only one patient (69 vs. 70 pat.) with WLI-WLI (p = 0.137). Second look cystoscopy did not influence the detection of carcinoma in situ in both groups (p = 0.120). After TUR-BT the median recurrence-free survival was 4 months in 57 recurring patients (73%) in the group with WLI-NBI- and 6 months in 56 patients (80%) with WLI-WLI-cystoscopy (p = 0.373), respectively. CONCLUSION: Our study showed no differences in per-patient tumour detection between WLI and NBI. Although NBI has significant benefits for detecting individual lesions overlooked by WLI-cystoscopy, this did not positively affect recurrence-free survival after transurethral resection.

STIP1 Tissue Expression Is Associated with Survival in Chemotherapy-Treated Bladder Cancer Patients.

To optimize treatment decisions in advanced bladder cancer (BC), we aimed to assess the therapy predictive value of STIP1 with regard to cisplatin therapy. Cisplatin-based chemotherapy represents the standard first-line systemic treatment of advanced bladder cancer. Since novel immunooncologic agents are already available for cisplatin-resistant or ineligible patients, biological markers are needed for the prediction of cisplatin resistance. STIP1 expression was analyzed in paraffin-embedded bladder cancer tissue samples of 98 patients who underwent adjuvant or salvage cisplatin-based chemotherapy by using immunohistochemistry. Furthermore, pre-chemotherapy serum STIP1 concentrations were determined in 48 BC patients by ELISA. Results were correlated with the clinicopathological and follow-up data. Stronger STIP1 nuclear staining was associated with worse OS in both the whole patient group (p = 0.034) and the subgroup of patients who received at least 2 cycles of chemotherapy (p = 0.043). These correlations remained significant also in the multivariable analyses (p = 0.035 and p = 0.040). Stronger STIP1 cytoplasmatic immunostaining correlated with shorter PFS both in the whole cohort (p = 0.045) and in the subgroup of patients who received at least 2 cycles of chemotherapy (p = 0.026). Elevated STIP1 serum levels were associated with older patient's age, but we found no correlation between STIP1 serum levels and patients' outcome. Our results suggest that tissue STIP1 analysis might be used for the prediction of cisplatin-resistance in BC. In contrast, pretreatment STIP1 serum levels showed no predictive value for chemotherapy response and survival.

Whole-Body Integrated [68Ga]PSMA-11-PET/MR Imaging in Patients with Recurrent Prostate Cancer: Comparison with Whole-Body PET/CT as the Standard of Reference.

PURPOSE: The aim of this study was to evaluate the detection rate of [68Ga]prostate-specific membrane antigen ([68Ga]PSMA-11) positron emission tomography (PET)/magnetic resonance imaging (MRI) and to compare it with [68Ga]PSMA-11 PET/X-ray computed tomography (CT) in patients with recurrent prostate cancer (PC) after radical prostatectomy. PROCEDURES: A total of 93 patients with biochemically recurrent prostate cancer underwent [68Ga]PSMA-11 PET/CT and subsequently a whole-body integrated PET/MRI examination. Board certified nuclear medicine physicians and radiologists evaluated PET/CT and PET/MRI datasets regarding identification of tumor lesions ((i) lymph nodes, (ii) bone lesions, (iii) local recurrence, and (iv) parenchymal lesions) based on maximum [68Ga]PSMA-11 uptake as well as morphological changes. Quality of PET images for both PET/CT and PET/MRI were rated using a 5-point scoring system by evaluating lesion homogeneity, contrast, contour, and delineation. Wilcoxon signed-rank tests were used to determine statistical differences. RESULTS: PC relapse was detected in 62/93 patients. PET/MRI detected 148 out of 150 lesions described in PET/CT. In addition, PET/MRI detected 11 lesions not detected in PET/CT (5 lymph nodes, 6 local recurrences). The exact McNemar statistical test (one-sided) showed significant difference between PET/CT and PET/MRI for diagnosis of local recurrence (p value = 0.031). Diagnostic confidence for (iii) was higher in PET/MRI compared with PET/CT (PET/CT = 1.1; PET/MRI = 4.9). Diagnostic confidence for (i) (PET/CT = 4.9; PET/MRI = 4.6), (ii) (PET/CT = 4.9; PET/MRI = 4.6), and (iv) (PET/CT = 4.6; PET/MRI = 4.8) was equivalent between PET/MRI and PET/CT. CONCLUSIONS: Integrated [68Ga]PSMA-11 PET/MRI provides a similarly high diagnostic performance for localization of recurrent PC as PET/CT. For the detection of local recurrences [68Ga]PSMA-11 PET/MRI is superior compared with [68Ga]PSMA-11 PET/CT.

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.

[Urachal Cancer: an update of current molecular findings]. / Das Urachuskarzinom: Ein Update aktueller molekularer Ergebnisse.

BACKGROUND: Urachal cancer is a rare type of cancer, often following a clinically aggressive course. Due to its rarity, knowledge about its molecular background is still limited. In addition, no sufficiently reliable diagnostic markers are available. OBJECTIVES: The aim of the present study is to give an overview of our recent molecular projects on urachal cancer and to connect it with current literature in the field. MATERIALS AND METHODS: Three projects are introduced. The first project identified and validated diagnostic biomarkers in urachal adenocarcinomas compared to colorectal adenocarcinomas and primary adenocarcinomas of the bladder using various proteomic methods. In the second project, the most relevant differential diagnostic markers between urachal adenocarcinomas and colorectal adenocarcinomas compared to normal tissue (urachal remnants) were determined by analyzing a miRNA panel. Sequence analyses were performed in the third project. The focus was on molecular differences to colorectal adenocarcinomas and urothelial carcinomas. RESULTS AND CONCLUSIONS: We detected potential biomarker candidates for the immunohistochemical differential-diagnosis and generated a miRNA-based diagnostic scoring system with a potentially high differential-diagnostic significance. The sequence analyses data confirm the molecular autonomy of the urachal adenocarcinomas compared to other entities.