Search

Background Demographic changes are leading to an increase in geriatric urolithiasis patients aged ≥70 yr. Published data regarding their management remain sparse. In particular, for the subgroup of patients aged ≥80 yr there is a lack of evidence supporting the hypothesis that stone-removing treatment is effective, safe, and beneficial. Objective To examine the efficiency and safety of stone-removing treatment in geriatric urolithiasis patients aged ≥80 yr compared to their younger geriatric counterparts aged 70–79 yr against the background of their respective life expectancy. Design, setting, and participants Data for the study cohort were extracted from an institutional review board–approved retrospective database with 325 patients aged ≥70 yr (70–79 yr: n = 241; ≥80 yr: n = 84) consecutively admitted to hospital because of symptomatic urolithiasis from 2013 to 2018. Outcome measurements and statistical analysis Baseline characteristics, outcome and follow-up data, and survival were compared using Wilcoxon-Mann-Whitney U tests, χ2 tests, Kaplan-Meier estimation, log-rank tests, and Cox regression. Results and limitations At baseline, the incidence of infected hydronephrosis was greater among patients aged ≥80 yr (p 0.05). Survival analysis for the two groups demonstrated a 2-yr overall survival (OS) rate of 0.91 (95% confidence interval [CI] 0.75–1) for patients aged ≥80 yr and 0.97 (95% CI 0.88–1), for those aged 70–79 yr (p Conclusions Stone-removing treatment for patients aged ≥80 yr proved to be as effective and safe as for patients in their seventies. Although characterized by shorter remaining life expectancy, excellent 2-yr OS for patients aged ≥80 yr supports the hypothesis of equal benefit from stone-removing treatment when compared to septuagenarians. Patient summary There is a lack of evidence supporting the benefit of urinary stone-removing treatment for patients older than 80 yr. Our study included geriatric patients older than 70 yr with symptomatic urinary stone disease for which urinary drainage or stone removal is indicated. We compared treatment outcomes and survival between two age groups: patients aged 70–79 yr and those aged 80 yr or older. We found equivalent outcomes for the two groups and excellent 2-yr overall survival of 91% for those older than 80 yr. The study strengthens the evidence that active stone-removing therapy is safe and beneficial for these patients.

Background: Circular urethral compression with an artificial sphincter allows control of voiding, even in patients with severe stress urinary incontinence, but it heightens the risk of urethral atrophy and erosion. This study of one of the largest populations of patients treated with radiotherapy investigates the additive effect of the post-radiogenic stricture of the membranous urethra/bladder neck on AMS 800 artificial urinary sphincter outcomes. Methods: In a retrospective multicenter cohort study, we analyzed patients fitted with an AMS 800, comparing those who had received radiotherapy with patients presenting a devastated bladder outlet (stricture of the membranous urethra/bladder neck). We determined the correlation between these groups of patients using both univariate and stepwise adjusted multivariate regression. The revision-free interval was estimated by a Kaplan–Meier plot and compared by applying the log-rank test. A p value below 0.05 was considered statistically significant. Results: Of the 123 irradiated patients we identified, 62 (50.4%) had undergone at least one prior desobstruction for bladder-neck/urethra stenosis. After a mean follow-up of 21 months, the latter tended to achieve social continence less frequently (25.7% vs. 35%; p = 0.08). Revision was required significantly more often for this group (43.1% vs. 26.3%; p = 0.05) due to urethral erosion in 18 of 25 cases. A stenosis recurred in five cases; desobstruction was performed in two cases, leading to erosion in both. Multivariate analysis revealed a significantly higher risk of revision when recurrent stenosis necessitated at least two prior desobstructions (HR 2.8; p = 0.003). Conclusions: A devastated bladder outlet is associated with a lower proportion of men with social continence and a significantly higher need for revision compared with irradiated patients without a history of urethral stenosis. Alternative surgical procedures should be discussed beforehand, especially in cases of recurrent urethral stenosis.

To investigate the efficacy and safety of multi-tract percutaneous nephrolithotomy (PNL) against the benchmark of the single-tract approach.A retrospective analysis of 391 consecutive PNL procedures was conducted in our tertiary referral center between April 2016 and March 2020. Clinical outcome parameters such as stone-free rate, operation time, postoperative complications according to Clavien-Dindo, length of hospital stay and time to ipsilateral recurrence resulting in active treatment were assessed.Multi-tract PNL and single-tract PNL were performed in 37 (9%) and 354 (91%) cases respectively. At baseline, compared to single-tract PNL, multi-tract PNL cases were characterized by significantly larger stone burden (2.62 vs 0.97 cmIn this retrospective single-center analysis, a multi-tract PNL has been proved to be an efficient and safe expansion of single-tract PNL for large stone burden and complex kidney stone disease. Future prospective research should focus on the procedure's potential effectiveness in reducing the number of interventions until stone-free status in patients with massive stone disease.

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer.

Purpose: The death ligand tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its receptors (TRAIL-R) are involved in immune surveillance and tumor development. Here, we studied a possible association between the expression of TRAIL/TRAIL-Rs and the prognosis in patients with renal cell carcinomas (RCC).Experimental Design: A tissue microarray containing RCC tumor tissue samples and corresponding normal tissue samples from 838 patients was generated. Expression of TRAIL and TRAIL-Rs was examined by immunohistochemistry and the effect of TRAIL and TRAIL-R expression on disease-specific survival was assessed.Results: High TRAIL-R2 expression levels were associated with high-grade RCCs (P < 0.001) and correlated negatively with disease-specific survival (P = 0.01). Similarly, high TRAIL expression was associated with a shorter disease-specific survival (P = 0.01). In contrast, low TRAIL-R4 expression was associated with high-stage RCCs (P < 0.001) as well as with the incidence of distant metastasis (P = 0.03) and correlated negatively with disease-specific survival (P = 0.02). In patients without distant metastasis, multivariate Cox regression analyses revealed that TRAIL-R2 and TRAIL are independent prognostic factors for cancer-specific survival (in addition to tumor extent, regional lymph node metastasis, grade of malignancy, and type of surgery).Conclusion: High TRAIL-R2, high TRAIL, and low TRAIL-R4 expression levels are associated with a worse disease-specific survival in patients with RCCs. Therefore, the assessment of TRAIL/TRAIL-R expression offers valuable prognostic information that could be used to select patients for adjuvant therapy studies. Moreover, our findings are of relevance for a potential experimental therapeutic administration of TRAIL-R agonists in patients with RCCs.

Supplementary Data from Prognostic Value of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL) and TRAIL Receptors in Renal Cell Cancer

Combined cisplatin–gemcitabine (GC) application is standard for treating muscle-invasive bladder cancer. However, since rapid resistance to treatment often develops, many patients turn to supplements in the form of plant-based compounds. Sulforaphane (SFN), derived from cruciferous vegetables, is one such compound, and the present study was designed to investigate its influence on growth and proliferation in a panel of drug-sensitive bladder cancer cell lines, as well as their gemcitabine- and cisplatin-resistant counterparts. Chemo-sensitive and -resistant RT4, RT112, T24, and TCCSUP cell lines were exposed to SFN in different concentrations, and tumor growth, proliferation, and clone formation were evaluated, in addition to apoptosis and cell cycle progression. Means of action were investigated by assaying cell-cycle-regulating proteins and the mechanistic target of rapamycin (mTOR)/AKT signaling cascade. SFN significantly inhibited growth, proliferation, and clone formation in all four tumor cell lines. Cells were arrested in the G2/M and/or S phase, and alteration of the CDK–cyclin axis was closely associated with cell growth inhibition. The AKT/mTOR signaling pathway was deactivated in three of the cell lines. Acetylation of histone H3 was up-regulated. SFN, therefore, does exert tumor-suppressive properties in cisplatin- and gemcitabine-resistant bladder cancer cells and could be beneficial in optimizing bladder cancer therapy.

Combined cisplatin–gemcitabine treatment causes rapid resistance development in patients with advanced urothelial carcinoma. The present study investigated the potential of the natural isothiocyanates (ITCs) allyl-isothiocyanate (AITC), butyl-isothiocyanate (BITC), and phenylethyl-isothiocyanate (PEITC) to suppress growth and proliferation of gemcitabine- and cisplatin-resistant bladder cancer cells lines. Sensitive and gemcitabine- and cisplatin-resistant RT112, T24, and TCCSUP cells were treated with the ITCs, and tumor cell growth, proliferation, and clone formation were evaluated. Apoptosis induction and cell cycle progression were investigated as well. The molecular mode of action was investigated by evaluating cell cycle-regulating proteins (cyclin-dependent kinases (CDKs) and cyclins A and B) and the mechanistic target of the rapamycin (mTOR)-AKT signaling pathway. The ITCs significantly inhibited growth, proliferation and clone formation of all tumor cell lines (sensitive and resistant). Cells were arrested in the G2/M phase, independent of the type of resistance. Alterations of both the CDK–cyclin axis and the Akt–mTOR signaling pathway were observed in AITC-treated T24 cells with minor effects on apoptosis induction. In contrast, AITC de-activated Akt–mTOR signaling and induced apoptosis in RT112 cells, with only minor effects on CDK expression. It is concluded that AITC, BITC, and PEITC exert tumor-suppressive properties on cisplatin- and gemcitabine-resistant bladder cancer cells, whereby the molecular action may differ among the cell lines. The integration of these ITCs into the gemcitabine-/cisplatin-based treatment regimen might optimize bladder cancer therapy.

The objective of our study is to examine the impact of monorchism on contralateral testicular size in children with non-palpable testis (NPT). Enhanced contralateral testicular volume or longitudinal diameter (length) serves as a predictor of monorchism. In the present study, we assessed the ability of ultrasound measured enlarged contralateral testicular length for predicting monorchism (and hence a testicular nubbin) in children with NPT. Furthermore, we evaluated the general prevalence of viable versus non-viable testes in patients referred to our institution with unilateral undescended testis between 2005 and 2020.We analysed the records of 54 patients who underwent diagnostic laparoscopy for NPT between 2005 and 2020 in a European tertiary care centre. Testicular lengths (longitudinal diameter) and testicular volume of the contralateral testis, as well as surgeon (surgeon 1 vs surgeon 2 vs others) and age at surgery (months) were assessed and stratified according to intraoperative findings (presence or absence of a testicular nubbin). Testicular length and volume were evaluated by ultrasound examination in office prior to surgery. Chi-square and t-test for descriptive analyses as well as uni- and multivariable logistic regression analyses were performed using R Version 3.1.0 (R Project for Statistical Computing, www.R-project.org).A total of 15 children presented with viable testes and 39 patients with testicular nubbin. Mean age was 20.5 months in the overall cohort and 22.6 vs 19.7 months in children with viable testis vs testicular nubbin (p = 0.4). In patients with presence of a testicular nubbin, the contralateral testis was larger (median length 17 mm (16-19.2)) as compared to patients with a viable testis (median length 15 mm (14-17), p = 0.001). Similarly, contralateral testicular volume was lower in patients with a present viable testis (0.6 ccm vs 0.8 ccm; p 0-001). This effect remained statistically significant when logistic regression analyses were adjusted for age and weight at surgery, year of surgery, surgeon, and laterality. OR (odds ratio) for presence of a testicular nubbin was 1.6 (per mm) [95% CI (confidence interval) 1.13-2.17; p = 0.007].Patients with preoperative increased length and volume of the contralateral testis in the ultrasound examination are at significantly higher risk of monorchism than their counterparts with lower testicular length. This should be emphasized during counselling of the parents prior to surgery. In our experience parents cope more easily with the diagnosis of monorchism, once this has already been discussed and explained thoroughly prior to surgery.

Purpose EAU guidelines recommend multiparametric MRI of the prostate (mpMRI) prior to biopsy to increase accuracy and reduce biopsies. Whether biopsy can be avoided in case of negative mpMRI remains unclear. Aim of this study is to evaluate predictors of overall prostate cancer (PCa) in negative mpMRI. Methods A total of 216 patients from 2018 to 2020 with suspicion of PCa and negative mpMRI (PI-RADS ≤ 2) were interviewed by telephone about outcome and further follow-up. Clinically significant PCa (csPCa) was defined as ISUP ≥ 2. Patients with vs. without biopsy and with vs. without PCa were compared. Univariate and multivariate analyses were performed to evaluate predictors of PCa occurrence in patients with negative mpMRI. Results 15.7% and 5.1% of patients with PI-RADS ≤ 2 on mpMRI showed PCa and csPCa, respectively. PCa patients had higher PSAD (0.14 vs. 0.09 ng/ml2; p = 0.001) and lower prostate volume (50.5 vs. 74.0 ml; p = 0.003). Patients without biopsy (25%) after MRI were older (69 vs. 65.5 years; p = 0.027), showed lower PSA (5.7 vs. 6.73 ng/ml; p = 0.033) and lower PSA density (0.09 vs. 0.1 ng/ml2; p = 0.027). Multivariate analysis revealed age (OR 1.09 [1.02–1.16]; p = 0.011), prostate volume (OR 0.982 [0.065; 0.997]; p = 0.027), total PSA level (OR 1.22 [1.01–1.47], p = 0.033), free PSA (OR 0.431 [0.177; 0.927]; p = 0.049) and no PI-RADS lesion vs PI-RADS 1–2 lesion (OR 0.38 [0.15–0.91], p = 0.032.) as predictive factors for the endpoint presence of PCa. Conclusions Biopsy for selected patient groups (higher age, prostate volume and free PSA as well as lower PSA-Density) with negative mpMRI can be avoided, if sufficient follow-up care is guaranteed. Detailed counseling regarding residual risk for undetected prostate cancer should be mandatory.

Voiding cystourethrogram (VCUG) used in the radiologic evaluation of the upper and lower urinary tract can be performed by suprapubic puncture (SP) or by transurethral catheterization (TC). Data on which instillation technique is superior are scarce. VCUG tends to be a distressing procedure for both parents and children.We evaluated the experience of VCUG analyzing 417 families with focus on contrast medium instillation in groups of single and repeated VCUGs and assessed quality and complication rate. The median age of children who had undergone VCUG was 38.6 months (0 - 159 months). Satisfaction with informed consent (IC), degree of fear and pain in parents and children prior and during VCUG were recorded. VCUG was compared to blood withdrawal and vaccination.Satisfaction with IC was higher for repeated VCUG (p= 0.024) which resulted in a lower degree of fear in parents and children. The fear of children during VCUG was lower when SP was performed rather than TC. This was in contrast to parental fear of SP (all p0.05). In repeated VCUGs, children who underwent SP were less afraid. Better diagnostic quality was more commonly reported with SP, yet the complication rate was higher (p=0.035).Our study highlights the importance of IC as a pivotal necessity before VCUG is conducted. SP might be beneficial over TC in terms of fear and distress in the case of repeated VCUGs. Diagnostic quality is comparable, both methods are safe and complications are low.

World journal of urology 40(10), 2529-2534 (2022). doi:10.1007/s00345-022-04129-6, Published by Springer, Berlin ; Heidelberg

Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting. ispartof: CANCERS vol:14 issue:7 ispartof: location:Switzerland status: published

Background: Radical cystectomy has high complication rates and, consequently, a high socioeconomic burden. The association between preoperative electrolyte levels and postoperative outcomes after radical cystectomy has not been investigated. Therefore, we aimed to investigate the association between preoperative potassium level and clinical (30-day morbidity) and economical (length of hospital stay) postoperative outcomes of patients undergoing radical cystectomy. Materials and Methods: We retrospectively evaluated clinical data of 317 patients who had undergone radical cystectomy for bladder cancer. Univariate and multivariate logistic regression analyses were performed to determine whether preoperative patient clinical factors influence clinical (30-day morbidity according to the Clavien-Dindo classification) and economical (length of hospital stay) postoperative outcomes. Results: In univariate analysis, low Charlson comorbidity score (p = 0.011), low ASA score (p = 0.015), no aspirin intake (p = 0.048) and high-normal preoperative potassium level (p = 0.034) were associated with reduced 30-day morbidity. In multivariate analysis, only high preoperative potassium remained an independent predictive factor for a reduced risk of postoperative complications (odds ratio 0.67, 95% confidence interval (0.48, 0.92), p = 0.014). Furthermore, high-normal preoperative potassium was the only preoperative factor associated with a shorter hospital stay ≤21 days (p = 0.007). Conclusions: High-normal preoperative potassium level was associated with better clinical (lower 30-day morbidity) and economical (shorter hospital stay) outcomes in patients undergoing radical cystectomy. We recommend that a randomized controlled trial be performed to investigate whether there is a causal relationship between preoperative potassium supplementation and postoperative complications and length of hospital stay.

MRI-guided targeted biopsy has become standard of care for diagnosis of prostate cancer, with establishment of several biopsy techniques and platforms. Augmented reality smart glasses have emerged as novel technology to support image-guided interventions. We aimed to investigate its usage while prostate biopsy.MRI with PIRADS-lesions ≥3 was uploaded to smart glasses (Vuzix BladeSMART-TB was performed for four patients. Prostate cancer detection was more likely for SMART-TB (46%; 13/28) than for systematic biopsy (27%; 13/48). Feasibility scores were high [8-10] for practicality, multitasking, execution speed, comfort and device weight and low [1-4] for handling, battery and image quality. Median execution time: 28 min; Investment cost smart glass: 1017 USD.First description of SMART-TB demonstrated convenient feasibility. This novel technology might enhance diagnosis of prostate cancer in future.

Claudins are promising biomarkers for diagnosis and prognosis or targets for treatment. They play a major role in signal transduction and are important in nearly all aspects of tumorigenesis. Claudin 6 is a member of the claudin family and is part of the tight junction molecule. It is reactivated in several cancer types and serves as prognostic marker in, for example, gastric, breast or non small cell lung cancer. The prognostic role of Claudin 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), is still unclear.The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Claudin 6 was determined by immunohistochemistry.In total, Claudin 6 staining was positive in 55 of 240 type 1 and 30 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed an overall survival of 84% for Claudin 6- compared to 78% for Claudin 6 + in pRCC type 1 tumors (p = 0.449, log-rank) and 68% for Claudin 6- compared to 65.4% for Claudin 6 + in pRCC type 2 tumors (p = 0.364, log-rank).In this study, claudin 6 expression showed no significant association regarding overall survival (OS) and therefore did not qualify as a prognostic marker in pRCC. Future studies will have to determine, whether Claudin 6 plays a prognostic role in other RCC entities. In addition, the function of Claudin 6 as a predictive marker for therapeutic approaches has to be evaluated in future studies.

Purpose Clinical stage I (CSI) testicular germ cell tumors (TGCT) represents disease confined to the testis without metastasis and CSIS is defined as persistently elevated tumor markers (TM) after orchiectomy, indicating subclinical metastatic disease. This study aims at assessing clinical characteristics and oncological outcome in CSIS. Methods Data from five tertiary referring centers in Germany were screened. We defined correct classification of CSIS according to EAU guidelines. TM levels, treatment and relapse-free survival were assessed and differences between predefined groups (chemotherapy, correct/incorrect CSIS) were analyzed with Fisher’s exact and Chi-square test. Results Out of 2616 TGCT patients, 43 (1.6%) were CSIS. Thereof, 27 were correctly classified (cCSIS, 1.03%) and 16 incorrectly classified (iCSIS). TMs that defined cCSIS were in 12 (44.4%), 10 (37%), 3 (11.1%) and 2 (7.4%) patients AFP, ß-HCG, AFP plus ß-HCG and LDH, respectively. In the cCSIS group, six patients were seminoma and 21 non-seminoma. Treatment consisted of active surveillance, carboplatin-mono AUC7 and BEP (bleomycin, etoposide and cisplatin). No difference between cCSIS and iCSIS with respect to applied chemotherapy was found (p = 0.830). 5-year relapse-free survival was 88.9% and three patients (11%) in the cCSIS group relapsed. All underwent salvage treatment (3xBEP) with no documented death. Conclusion Around 1% of all TGCT were classified as cCSIS patients. Identification of cCSIS is of critical importance to avoid disease progression and relapses by adequate treatment. We report a high heterogeneity of treatment patterns, associated with excellent long-term survival irrespective of the initial treatment approach.

Purpose Women are underrepresented at scientific conferences, decreasing the visibility of female role models, which are vital for aspiring young female scientists. This investigation aimed to evaluate female representation at the German Society of Urology's (GSoU) annual meeting. Methods The programs of the GSoU meeting of 2011, 2018, 2019 and the virtual conference in 2020 were retrospectively quantified by gender and categorized by chair or speaker, type, and topic of the session. Descriptive analysis was applied. Univariate and multivariate analyses were performed to identify gender inequity and variables influencing gender distribution. A p value of Results A total of 2.504 chairs and speakers were invited to the GSoU meeting in 2018 and 2019. Female speakers or chairs were represented in 17.8%, indicating a gender gap of 64.7%. There were significant differences between session type, topic, and gender distribution for chairs and speakers. The topic surgical techniques were independent variables for both, underrepresented female chairs and speakers, respectively (p Conclusion There is still a significant discrepancy between gender representation at the GSoU annual meetings, and gender equity is currently not expected before 50 years. Future efforts should address the implementation of established guidelines for achieving gender equity at urological conferences.

525 Background: Cabozantinib inhibits c-Met , AXL, RET, and VEGFR and has been FDA and EMA approved for the treatment of medullary thyroid cancer, hepatocellular carcinoma and renal cell carcinoma. In this trial (NCT04066595) we wanted to gain more insights about the potential of Cabozantinib in patients with advanced urothelial carcinoma (UC) ineligible for cisplatin-based chemotherapy and in patients with chemo and/or PD-1- and PD-L1 resistant UC. Methods: This investigator-sponsored Phase II multicenter single-arm trial assessed ORR to Cabozantinib in patients with locally advanced or metastatic UC, who have been pre-treated with checkpoint inhibitors only (cohort 1) or cisplatin-based chemotherapy and checkpoint inhibitors (cohort 2). Secondary outcome measurements were PFS, OS, CBR, DOR, and patient safety. All radiologic findings were determined using RECIST 1.1. Patients commenced treatment with Cabozantinib 60 mg given per os once per day continuously. Participants continued on trial as long as their cancer was not worsened and side effects were not too severe. For the assessment of side effects the severity was qualified in accordance with NCI CTCAE, version 5.0. The primary outcome measure of ORR was reported as percentages and associated 95% confidence interval for each cohort. For planning Simon's two-stage minimax design (Simon, 1989) was used. A total of 44 patients (total 88 patients) were planned to be included into each cohort. Results: Seven patients were included in cohort 2. The patients in cohort 2 (N = 7) had a median age of 69 y, 6 male patients and one female patient. All patients had an ECOG PS 0 (n=2) or 1 (n=5). All tumors were originated from the urinary bladder, two of them showing histological subtypes. PD-L1 status was available in two patients. Visceral metastases were evident in 3 patients. At December 20th 2021 data cutoff no patient was alive. The overall response rate was 0%. The median progression free survival was 2,9 months (range 1-5,4 months). The median overall survival was 3 months (range 1-18,3 months) 3 patients showed a stable disease. All patients (n=7) revealed TRAEs, 3 patients each (43%) showed endocrine disorders, metabolic and nutrition disorders and nervous system disorders. In 5 patients (71%) respiratory AEs and in 86% (n=6) gastrointestinal AEs were evident. In 86% of patients (n=6) SAEs led to treatment dose reduction or discontinuation. In 43% of patients (n=3) grade 5 SAEs were evident. Treatment-related SAEs were notified in 57% of patients (n=4). Conclusions: Cabozantinib was administered in 7 patients without clinical response. Due to low patient recruitment and no adequate response rates the study was discontinued early. Cabozantinib in this study does not reveal a clinical benefit for patients with metastatic UC with prior chemotherapy and IO. Clinical trial information: NCT04066595 .

Despite recent advances in the treatment of metastatic prostate cancer (PCa), resistance development after taxane treatments is inevitable, necessitating effective options to combat drug resistance. Previous studies indicated antitumoral properties of the natural compound amygdalin. However, whether amygdalin acts on drug-resistant tumor cells remains questionable. An in vitro study was performed to investigate the influence of amygdalin (10 mg/mL) on the growth of a panel of therapy-naïve and docetaxel- or cabazitaxel-resistant PCa cell lines (PC3, DU145, and LNCaP cells). Tumor growth, proliferation, clonal growth, and cell cycle progression were investigated. The cell cycle regulating proteins (phospho)cdk1, (phospho)cdk2, cyclin A, cyclin B, p21, and p27 and the mammalian target of rapamycin (mTOR) pathway proteins (phospho)Akt, (phospho)Raptor, and (phospho)Rictor as well as integrin β1 and the cytoskeletal proteins vimentin, ezrin, talin, and cytokeratin 8/18 were assessed. Furthermore, chemotactic activity and adhesion to extracellular matrix components were analyzed. Amygdalin dose-dependently inhibited tumor growth and reduced tumor clones in all (parental and resistant) PCa cell lines, accompanied by a G0/G1 phase accumulation. Cell cycle regulating proteins were significantly altered by amygdalin. A moderate influence of amygdalin on tumor cell adhesion and chemotaxis was observed as well, paralleled by modifications of cytoskeletal proteins and the integrin β1 expression level. Amygdalin may, therefore, block tumor growth and disseminative characteristics of taxane-resistant PCa cells. Further studies are warranted to determine amygdalin’s value as an antitumor drug.

Despite the establishment of new therapy options during the last decades, advanced renal cell carcinoma (RCC) remains an uncurable disease, due to evolving drug-resistance. New, more efficient treatment strategies are still in urgent demand. Shikonin (SHI) from Traditional Chinese Medicine has exhibited anti-tumor properties in several tumor entities. Thus, in the current investigation we evaluated the impact of SHI on progressive growth and metastatic behavior, not only in therapy-sensitive (parental) but also in therapy-resistant RCC cells. Parental and sunitinib-resistant RCC cells, Caki-1, 786-O, KTCTL-26, and A498, were treated with SHI. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis) and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI did not affect cell motility but led to significant inhibition of progressive tumor cell growth in both therapy-sensitive and therapy-resistant RCC cells. Thereby, SHI significantly inhibited the growth, proliferation and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins, blocking cell division. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the Akt/mTOR pathway, pivotal for cell survival and growth. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC. Citation Format: Eva Juengel, Sascha D. Markowitsch, Olesya Vakhrusheva, Yasminn Akele, Jovanna Kitanovic, Patricia Schupp, Kimberly S. Slade, Anita Thomas, Igor Tsaur, Rene Mager, Thomas Efferth, Axel Haferkamp. Cell growth of sunitinib-resistant renal cell carcinoma was inhibited by Shikonin through necroptosis induction and Akt/mTOR signaling inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5384.

Therapy resistance remains a major challenge in treating advanced renal cell carcinoma (RCC), making more effective treatment strategies crucial. Shikonin (SHI) from traditional Chinese medicine has exhibited antitumor properties in several tumor entities. We, therefore, currently investigated SHI’s impact on progressive growth and metastatic behavior in therapy-sensitive (parental) and therapy-resistant Caki-1, 786-O, KTCTL-26, and A498 RCC cells. Tumor cell growth, proliferation, clonogenic capacity, cell cycle phase distribution, induction of cell death (apoptosis and necroptosis), and the expression and activity of regulating and signaling proteins were evaluated. Moreover, the adhesion and chemotactic activity of the RCC cells after exposure to SHI were investigated. SHI significantly inhibited the growth, proliferation, and clone formation in parental and sunitinib-resistant RCC cells by G2/M phase arrest through down-regulation of cell cycle activating proteins. Furthermore, SHI induced apoptosis and necroptosis by activating necrosome complex proteins. Concomitantly, SHI impaired the AKT/mTOR pathway. Adhesion and motility were cell line specifically affected by SHI. Thus, SHI may hold promise as an additive option in treating patients with advanced and therapy-resistant RCC.