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.

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.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

Twelve-month prostate volume reduction after MRI-guided transurethral ultrasound ablation of the prostate.

PURPOSE: To quantitatively assess 12-month prostate volume (PV) reduction based on T2-weighted MRI and immediate post-treatment contrast-enhanced MRI non-perfused volume (NPV), and to compare measurements with predictions of acute and delayed ablation volumes based on MR-thermometry (MR-t), in a central radiology review of the Phase I clinical trial of MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer. MATERIALS AND METHODS: Treatment day MRI and 12-month follow-up MRI and biopsy were available for central radiology review in 29 of 30 patients from the published institutional review board-approved, prospective, multi-centre, single-arm Phase I clinical trial of TULSA. Viable PV at 12 months was measured as the remaining PV on T2-weighted MRI, less 12-month NPV, scaled by the fraction of fibrosis in 12-month biopsy cores. Reduction of viable PV was compared to predictions based on the fraction of the prostate covered by the MR-t derived acute thermal ablation volume (ATAV, 55°C isotherm), delayed thermal ablation volume (DTAV, 240 cumulative equivalent minutes at 43°C thermal dose isocontour) and treatment-day NPV. We also report linear and volumetric comparisons between metrics. RESULTS: After TULSA, the median 12-month reduction in viable PV was 88%. DTAV predicted a reduction of 90%. Treatment day NPV predicted only 53% volume reduction, and underestimated ATAV and DTAV by 36% and 51%. CONCLUSION: Quantitative volumetry of the TULSA phase I MR and biopsy data identifies DTAV (240 CEM43 thermal dose boundary) as a useful predictor of viable prostate tissue reduction at 12 months. Immediate post-treatment NPV underestimates tissue ablation. KEY POINTS: • MRI-guided transurethral ultrasound ablation (TULSA) achieved an 88% reduction of viable prostate tissue volume at 12 months, in excellent agreement with expectation from thermal dose calculations. • Non-perfused volume on immediate post-treatment contrast-enhanced MRI represents only 64% of the acute thermal ablation volume (ATAV), and reports only 60% (53% instead of 88% achieved) of the reduction in viable prostate tissue volume at 12 months. • MR-thermometry-based predictions of 12-month prostate volume reduction based on 240 cumulative equivalent minute thermal dose volume are in excellent agreement with reduction in viable prostate tissue volume measured on pre- and 12-month post-treatment T2w-MRI.

68Ga-PSMA PET/CT in the evaluation of bone metastases in prostate cancer.

PURPOSE: The aims of this retrospective analysis were to compare 68Ga-PSMA PET findings and low-dose CT findings (120 kV, 30 mA), and to obtain semiquantitative and quantitative 68Ga-PSMA PET data in patients with prostate cancer (PC) bone metastases. METHODS: In total, 152 PET/CT scans from 140 patients were evaluated. Of these patients, 30 had previously untreated primary PC, and 110 had biochemical relapse after treatment of primary PC. All patients underwent dynamic PET/CT scanning of the pelvis and lower abdomen as well as whole-body PET/CT with 68Ga-PSMA-11. The PET/CT scans were analysed qualitatively (visually), semiquantitatively (SUV), and quantitatively based on a two-tissue compartment model and a noncompartmental approach leading to the extraction of the fractal dimension. Differences were considered significant for p values <0.05. RESULTS: In total, 168 68Ga-PSMA-positive and 113 CT-positive skeletal lesions were detected in 37 patients (8 with primary PC, 29 with biochemical recurrence). Of these 168 lesions, 103 were both 68Ga-PSMA PET-positive and CT-positive, 65 were only 68Ga-PSMA-positive, and 10 were only CT-positive. The Yang test showed that there were significantly more 68Ga-PSMA PET-positive lesions than CT-positive lesions. Association analysis showed that PSA plasma levels were significantly correlated with several 68Ga-PSMA-11-associated parameters in bone metastases, including the degree of tracer uptake (SUVaverage and SUVmax), its transport rate from plasma to the interstitial/intracellular compartment (K1), its rate of binding to the PSMA receptor and its internalization (k3), its influx rate (Ki), and its distribution heterogeneity. CONCLUSION: 68Ga-PSMA PET/CT is a useful diagnostic tool in the detection of bone metastases in PC. 68Ga-PSMA PET visualizes more bone metastases than low-dose CT. PSA plasma levels are significantly correlated with several 68Ga-PSMA PET parameters.

(68)Ga-PSMA-11 dynamic PET/CT imaging in biochemical relapse of prostate cancer.

OBJECTIVES: We aim to investigate the pharmacokinetics and distribution of the recently clinically introduced radioligand (68)Ga-PSMA-11 in men with recurrent prostate cancer (PC) by means of dynamic and whole-body PET/CT. The correlation between PSA levels and (68)Ga-PSMA-11 PET parameters is also investigated. METHODS: 31 patients with biochemical failure after primary PC treatment with curative intent (median age 71.0 years) were enrolled in the analysis. The median PSA value was 2.0 ng/mL (range = 0.1 - 130.0 ng/mL) and the median Gleason score was 7 (range = 5 - 9). 8/31 (25.8 %) of the included patients had a PSA value < 0.5 ng/ml. All patients underwent dynamic PET/CT (dPET/CT) scanning (60 min) of the pelvis and lower abdomen as well as whole-body PET/CT with (68)Ga-PSMA-11. dPET/CT assessment was based on qualitative evaluation, SUV calculation, and quantitative analysis based on a two-tissue compartment model and a non-compartmental approach leading to the extraction of fractal dimension (FD). RESULTS: 22/31 patients (71.0 %) were (68)Ga-PSMA-11-positive, while 9/31 (29.0 %) patients were (68)Ga-PSMA-11-negative. The median PSA value in the (68)Ga-PSMA-11-positive group was significantly higher (median = 2.35 ng/mL; range = 0.19 - 130.0 ng/mL) than in the (68)Ga-PSMA-11-negative group (median value: 0.34 ng/mL; range = 0.10 - 4.20 ng/mL). A total of 76 lesions were semi-quantitatively evaluated. PC recurrence-associated lesions demonstrated a mean SUVaverage = 12.4 (median = 9.0; range = 2.2 - 84.5) and mean SUVmax = 18.8 (median = 14.1; range = 3.1 - 120.3). Dynamic PET/CT studies of the pelvis revealed the following mean values for the PC recurrence-suspicious lesions: K1 = 0.26, k3 = 0.30, influx = 0.14 and FD = 1.24. Time-activity curves derived from PC-recurrence indicative lesions revealed an increasing (68)Ga-PSMA-11 accumulation during dynamic PET acquisition. Correlation analysis revealed a moderate, but significant, correlation between PSA levels and the number of lesions detected on (68)Ga-PSMA-11 PET/CT (r = 0.54) and between PSA levels and SUVaverage (r = 0.48) or SUVmax (r = 0.44). CONCLUSIONS: Ga-PSMA-11 PET/CT demonstrated an overall detection rate of 71.0 % 60 min p.i. of the radiotracer in a mixed patient population with respect to PSA levels and including patients with very low PSA values. Higher PSA values were associated with a higher detection rate. The tracer uptake in PC-recurrence-indicative lesions is increasing during the 60 minutes of dynamic PET acquisition.

Follow-up after focal therapy in renal masses: an international multidisciplinary Delphi consensus project.

PURPOSE: To establish consensus on follow-up (FU) after focal therapy (FT) in renal masses. To formulate recommendations to aid in clinical practice and research. METHODS: Key topics and questions for consensus were identified from a systematic literature research. A Web-based questionnaire was distributed among participants selected based on their contribution to the literature and/or known expertise. Three rounds according to the Delphi method were performed online. Final discussion was conducted during the "8th International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer" among an international multidisciplinary expert panel. RESULTS: Sixty-two participants completed all three rounds of the online questionnaire. The panel recommended a minimum follow-up of 5 years, preferably extended to 10 years. The first FU was recommended at 3 months, with at least two imaging studies in the first year. Imaging was recommended biannually during the second year and annually thereafter. The panel recommended FU by means of CT scan with slice thickness ≤3 mm (at least three phases with excretory phase if suspicion of collecting system involvement) or mpMRI. Annual checkup for pulmonary metastasis by CT thorax was advised. Outside study protocols, biopsy during follow-up should only be performed in case of suspicion of residual/persistent disease or radiological recurrence. CONCLUSIONS: The consensus led to clear FU recommendations after FT of renal masses supported by a multidisciplinary expert panel. In spite of the low level of evidence, these recommendations can guide clinicians and create uniformity in the follow-up practice and for clinical research purposes.

[Modern imaging of renal tumors - application in diagnostics and therapy. Characterization, operation planning and therapy monitoring of renal lesions]. / Moderne Bildgebung von Nierentumoren - Anwendung in Diagnostik und Therapie: Charakterisierung, Operationsplanung und Therapiemonitoring von Nierenläsionen.

This article elucidates the various tools used for the diagnostics and characterization of renal lesions. The advantages and limitations of ultrasound, contrast-enhanced ultrasound (CEUS), computed tomography (CT) and magnetic resonance imaging (MRI) are presented and discussed. In addition, modern imaging features of CT and MRI, such as iodine quantification in CT as well as diffusion-weighted and perfusion imaging in MRI are presented. Lastly, recent developments in standardized reporting of renal tumors regarding the intraoperative surgical risk are presented.

Comparison of PET/CT and PET/MRI hybrid systems using a 68Ga-labelled PSMA ligand for the diagnosis of recurrent prostate cancer: initial experience.

PURPOSE: (68)Ga-labelled HBED-CC-PSMA is a highly promising tracer for imaging recurrent prostate cancer (PCa). The intention of this study was to evaluate the feasibility of PET/MRI with this tracer. METHODS: Twenty patients underwent PET/CT 1 h after injection of the (68)Ga-PSMA ligand followed by PET/MRI 3 h after injection. Data from the two investigations were first analysed separately and then compared with respect to tumour detection rate and radiotracer uptake in various tissues. To evaluate the quantification accuracy of the PET/MRI system, differences in SUVs between PET/CT and corresponding PET/MRI were compared with differences in SUVs between PET/CT 1 h and 3 h after injection in another patient cohort. This cohort was investigated using the same PET/CT system. RESULTS: With PET/MRI, different diagnostic sequences, higher contrast of lesions and higher resolution of MRI enabled a subjectively easier evaluation of the images. In addition, four unclear findings on PET/CT could be clarified as characteristic of PCa metastases by PET/MRI. However, in PET images of the PET/MRI, a reduced signal was observed at the level of the kidneys (in 11 patients) and around the urinary bladder (in 15 patients). This led to reduced SUVs in six lesions. SUVmean values provided by the PET/MRI system were different in muscles, blood pool, liver and spleen. CONCLUSION: PCa was detected more easily and more accurately with Ga-PSMA PET/MRI than with PET/CT and with lower radiation exposure. Consequently, this new technique could clarify unclear findings on PET/CT. However, scatter correction was challenging when the specific (68)Ga-PSMA ligand was used. Moreover, direct comparison of SUVs from PET/CT and PET/MR needs to be conducted carefully.

Evaluation of the ESUR PI-RADS scoring system for multiparametric MRI of the prostate with targeted MR/TRUS fusion-guided biopsy at 3.0 Tesla.

OBJECTIVES: To evaluate the Prostate Imaging Reporting and Data System (PI-RADS) proposed by the European Society of Urogenital Radiology (ESUR) for detection of prostate cancer (PCa) by multiparametric magnetic resonance imaging (mpMRI) in a consecutive cohort of patients with magnetic resonance/transrectal ultrasound (MR/TRUS) fusion-guided biopsy. METHODS: Suspicious lesions on mpMRI at 3.0 T were scored according to the PI-RADS system before MR/TRUS fusion-guided biopsy and correlated to histopathology results. Statistical correlation was obtained by a Mann-Whitney U test. Receiver operating characteristics (ROC) and optimal thresholds were calculated. RESULTS: In 64 patients, 128/445 positive biopsy cores were obtained out of 95 suspicious regions of interest (ROIs). PCa was present in 27/64 (42%) of the patients. ROC results for the aggregated PI-RADS scores exhibited higher areas under the curve compared to those of the Likert score. Sensitivity/Specificity for the following thresholds were calculated: 85 %/73 % and 67 %/92 % for PI-RADS scores of 9 and 10, respectively; 85 %/60 % and 56 %/97 % for Likert scores of 3 and 4, respectively [corrected. CONCLUSIONS: The standardised ESUR PI-RADS system is beneficial to indicate the likelihood of PCa of suspicious lesions on mpMRI. It is also valuable to identify locations to be targeted with biopsy. The aggregated PI-RADS score achieved better results compared to the single five-point Likert score. KEY POINTS: • The ESUR PI-RADS scoring system was evaluated using multiparametric 3.0-T MRI. • To investigate suspicious findings, transperineal MR/TRUS fusion-guided biopsy was used. • PI-RADS can guide biopsy locations and improve detection of clinically significant cancer. • Biopsy procedures can be optimised, reducing unnecessary negative biopsies for patients. • The PI-RADS scoring system may contribute to more effective prostate MRI.

PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.

PURPOSE: Prostate-specific membrane antigen (PSMA) is a cell surface protein with high expression in prostate carcinoma (PC) cells. Recently, procedures have been developed to label PSMA ligands with (68)Ga, (99m)Tc and (123/124/131)I. Our initial experience with Glu-NH-CO-NH-Lys-(Ahx)-[(68)Ga(HBED-CC)]((68)Ga-PSMA) suggests that this novel tracer can detect PC relapses and metastases with high contrast. The aim of this study was to investigate its biodistribution in normal tissues and tumour lesions. METHODS: A total of 37 patients with PC and rising prostate-specific antigen (PSA) levels were subjected to (68)Ga-PSMA positron emission tomography (PET)/CT. Quantitative assessment of tracer uptake was performed 1 and 3 h post-injection (p.i.) by analysis of mean and maximum standardized uptake values (SUVmean/max) of several organs and 65 tumour lesions. Subsequently, tumour to background ratios were calculated. RESULTS: The PET/CT images showed intense tracer uptake in both kidneys and salivary glands. Moderate uptake was seen in lacrimal glands, liver, spleen and in small and large bowel. Quantitative assessment revealed excellent contrast between tumour lesions and most normal tissues. Of 37 patients, 31 (83.8 %) showed at least one lesion suspicious for cancer at a detection rate of 60 % at PSA <2.2 ng/ml and 100 % at PSA >2.2 ng/ml. Median tumour to background ratios were 18.8 (2.4-158.3) in early images and 28.3 (2.9-224.0) in late images. CONCLUSION: The biodistribution of the novel (68)Ga-PSMA tracer and its ability to detect PC lesions was analysed in 37 patients. Within healthy organs, kidneys and salivary glands demonstrated the highest radiotracer uptake. Lesions suspicious for PC presented with excellent contrast as early as 1 h p.i. with high detection rates even at low PSA levels.

[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.

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.

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.

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.

[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.

[Oncolytic vesicular stomatitis viruses as intravesical agents against non-muscle-invasive bladder cancer]. / Intravesikale Therapie nicht muskelinvasiver Blasentumoren mit onkolytischen Vesikular-Stomatitisviren.

Patients with high-risk bladder cancer who do not respond to bacillus Calmette-Guerin (BCG) immunotherapy represent a significant therapeutic challenge. The addition of interferon to BCG has recently evolved as a second-line treatment option; however, many high-grade tumors are nonresponsive to interferon. Thus, replication-competent oncolytic vesicular stomatitis viruses (VSV) that selectively target interferon-refractory tumors are promising intravesical agents. In vitro, wild-type VSV as well as a mutant variant (AV3) that has an impaired ability to shut down innate immunity preferentially killed undifferentiated, interferon-nonresponsive bladder cancer cells. Testing of these viruses in an orthotopic murine model of high-grade bladder cancer, which we have recently validated, revealed that both AV3 and wild-type VSV significantly inhibited orthotopic tumor growth. Despite the use of immunocompromised nude mice, there was no evidence of toxicity. In conclusion, VSV instillation therapy demonstrated strong antitumor activity and safety in an orthotopic model of high-risk disease. These findings provide preclinical proof-of-principle for the intravesical use of VSV, especially in interferon-refractory patients.

[Stress proteins in prostate cancer. Challenge and promise]. / Stressproteine bei der Pathogenese des Prostatakarzinoms. Herausforderung und Versprechen an die Zukunft.

Therapeutic resistance is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress proteins, including heat shock proteins and clusterin. These molecular chaperones interact with various client proteins to assist in their folding and enhance cellular recovery from stress conditions. Cellular stress and cell death are linked, as the induction of chaperones appear to function at key regulatory points in the control of apoptosis. On this basis and on the role of stress proteins in the regulation of steroid receptors, kinases, caspases, and other protein remodeling events, it is not surprising that molecular chaperones have been implicated in resistance to anticancer treatments. Recently, several chaperones have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the events initiated by treatment-induced stress and discuss the potential role of chaperone inhibitors in prostate cancer treatment.