Retrospective Analysis of Fifth-Line Targeted Therapy Efficacy in Patients with Metastatic Renal Cell Carcinoma.

OBJECTIVES: Current evidence of sequence-targeted therapy (TT) for patients with metastatic renal cell carcinoma (mRCC) beyond fourth-line is sparse. The aim of this study was to describe the efficacy and toxicity of fifth-line TT in patients with mRCC. METHODS: Out of 406 patients treated in first-line, 25 patients (6.16%) with more than 4 lines of TT were retrospectively reviewed at a German academic high-volume cancer center. Response was assessed by the use of standard Response Evaluation Criteria in Solid Tumors version 1.0, and toxicity was graded according to the Common Toxicity Criteria for Adverse Events version 3.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazard models were applied to explore predictors of PFS and OS in univariable and multivariable analyses. RESULTS: Disease control rate for fifth-line treatment was 20%. Median OS from the beginning of first-line therapy was 50.2 months (IQR (interquartile range) 38.9-76.7). Median OS from the time of initiation of fifth-line therapy was 6.2 months (IQR 3.1-23.8). Median PFS for fifth-line TT was 4.1 months (IQR 1.81-9.07) and did not correlate to treatment response in first-line TT. CONCLUSIONS: Highly selected patients might benefit from fifth-line treatment independently from treatment response in first-line TT.

Prevalence of Late-Onset Hypogonadism in Men with Localized and Metastatic Renal Cell Carcinoma.

BACKGROUND: Cancer-related fatigue is a common symptom in patients with renal cell carcinoma (RCC) and can be similar to the fatigue found in late-onset hypogonadism (LOH). The aim of this study was to investigate the prevalence of LOH in patients with localized RCC (loRCC) and metastatic RCC (mRCC) disease under targeted therapy (TT) and compare the results to findings of epidemiologic studies. METHODS: A total of 51 mRCC patients under TT and 33 patients with loRCC undergoing nephrectomy were included. Total testosterone (tT) levels and clinical signs of LOH were recorded (testicular volume, body-mass index (BMI), hip-to-waist ratio, International Index of Erectile Function, IIEF-5, Androgen Deficiency in the Aging Male, ADAM, and quality of life questionnaire-C30). LOH was defined according to current guidelines. RESULTS: Morning tT and calculated free testosterone levels showed no significant difference in patients with mRCC and loRCC (p = 0.551 and p = 0.430). A significant difference was found for clinical signs and symptoms including the ADAM score (p = 0.003), hip-to-waist ratio (p = 0.017) and testicular volume (p < 0.001). IIEF-5 score and BMI were not significantly different. The prevalence of LOH according to the current EAU definition was 13.7 and 15.2% for the mRCC and loRCC cohort, respectively (p = 0.302). CONCLUSIONS: LOH was present in a significant proportion of RCC patients. Prevalence rates of LOH were higher in patients with RCC compared to patients without cancer.

Efficacy of fourth-line targeted therapy in patients with metastatic renal cell carcinoma: a retrospective analysis.

INTRODUCTION: Evidence for sequencing targeted therapy (TT) in patients with metastatic renal cell carcinoma (mRCC) beyond third line is limited. Treatment decisions for these sequence options are largely based on individual preferences and experience. The aim of this study was to describe the efficacy and toxicity of fourth-line TT. MATERIALS AND METHODS: We retrospectively reviewed patients treated with fourth-line TT for mRCC after failure of previous treatment lines at a German academic high-volume center. Out of 406 patients treated in first line, 56 patients (14.8 %) were identified with more than three lines of TT. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Cox proportional hazards models were applied to explore predictors of PFS and OS in uni- and multivariable analysis. RESULTS: For the fourth-line treatment, disease control rate was 35.7 %. Median OS from beginning of first-line therapy was 47.4 months (IQR 31.0-76.5). Primary resistance at first-line TT, metastatic disease at initial diagnosis and an intermediate MSKCC score were independent predictors of shorter OS from start of first-line TT. Median OS from the time of initiation of fourth-line therapy was 10.5 months (IQR 5.6-22.6). The corresponding median PFS for fourth-line TT was 3.2 months (IQR 1.6-8.0) and was not correlated with treatment response in first-line TT. The rate of toxicity-induced treatment termination was 16.1 %. Limitations are the retrospective and unicentric design with a limited number of patients. CONCLUSIONS: Patients might benefit from subsequent treatment lines independently from treatment response in first line.

Laparoendoscopic single-site (LESS) varicocelectomy with reusable components: comparison with the conventional laparoscopic technique.

BACKGROUND: This study aimed to compare laparoendoscopic single-site varicocelectomy (LESSV) with multiport laparoscopic varicocelectomy (MLV) in terms of intraoperative parameters and postoperative outcomes. METHODS: A retrospective case-control study investigated 10 male adolescents and 89 adults who underwent either LESSV or MLV at the authors' center. The reusable X-Cone single port was inserted transumbilically. A 5-mm 30° telescope was used together with a straight and a prebent laparoscopic instrument. The MLV procedure was performed using two 5-mm ports and one 10-mm port. RESULTS: Between January 2009 and November 2012, 20 patients underwent LESSV and 79 patients underwent MLV. The demographic data were comparable between the two groups. The mean operating time was 59.1 ± 15.5 min for LESSV and 51.2 ± 14.4 min for MLV (P = 0.04). In the LESSV group, no conversion to MLV was necessary. The hospital stay was 1.6 ± 0.7 days in the LESSV group versus 1.8 ± 0.5 days in the MLV group (P = 0.17). The postoperative pain scores did differ between the two groups. By day 2, significantly more patients in the LESSV group than in the MLV group fully recovered their normal physical activity (P = 0.02). Comparison of pre- and postoperative values showed relief of testicular pain and improvement of semen parameters for the majority of the patients. The overall incidence of complications was distributed equally between the two groups as follows: paresthesia of the upper thigh (8 %), wound infection (5 %), epididymitis (3 %) and hydrocele (4 %). All the patients in the LESSV group were fully satisfied with their cosmetic results compared with only 76 % of the patients in the MLV group (P = 0.01). CONCLUSIONS: The LESSV procedure performed with the reusable X-Cone is as safe and efficient as MLV. After LESSV, the parameters measuring postoperative patient satisfaction are significantly improved. Given its reusable components, including prebent laparoscopic instruments, the X-Cone platform is a cost-effective alternative to disposable or homemade single ports.

Sperm and testicular tissue cryopreservation and assisted reproductive technology outcomes in male cancer patients: a 15-year experience.

OBJECTIVE: To explore the characteristics of cancer patients who cryopreserved sperm/testicular tissue samples in the Cryobank of Charité-Universitätsmedizin Berlin between 2004 and 2019, and the ART utilization rate with associated outcomes. METHODS: Retrospective data were available for 506 cancer patients, of which 46 (9.1%) had used their samples for artificial reproductive technologies (ART). Corresponding cycle information was collected from external fertility centers. RESULTS: Our cohort included 53/506 (10.5%) patients aged < 18 years at diagnosis. While adolescents and adults mainly banked sperm, adolescents showed higher rates of testicular tissue cryopreservation before (11.8%, 6/51 vs. 6.4%, 26/406) and after treatment (16.7%, 4/24 vs. 7.8%, 13/167). At study conduction, storage had been ended for 44.8% (269/601) of samples. The majority of samples used for ART were requested within the first 3 years after cryopreservation (71.5%, 28/39, range = 0-12 years). Pregnancy rate was 51.4% (19/37 cycles), resulting in 11 singleton births, 3 twin pairs, and 4 miscarriages. CONCLUSION: With the new advantage of public health insurance coverage of fertility preservation (FP) in Germany, an increased utilization has already been noticed in our center, emphasizing the necessity of further knowledge for individual counseling. Adolescent cancer patients need to be addressed specifically, as these patients show especially low cryopreservation rates.

Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

Introduction: Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status. Methods: To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format. Results: The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis. Conclusion: Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

Outcomes of Deceased Donor Kidney Transplantation in the Eurotransplant Senior Program with A Focus on Recipients ≥75 Years.

To evaluate the outcomes of kidney transplantations (KTs) in the Eurotransplant Senior Program (ESP) with a focus on the very old, defined as recipients ≥75 years. This retrospective clinical study included 85 patients, who under the ESP protocol underwent deceased donor kidney transplantation from January 2010 to July 2018 at the Charité-Universitätsmedizin Berlin in Germany. Recipients were divided in three age groups, i.e., Group 65-69, Group 70-74, Group ≥75, and compared. Prognostic risk factors for short and long-term outcomes of kidney transplantations were investigated. Graft survival at 1 and 5 years were respectively 90.7% and 68.0% for group 65-69, 88.9% and 76.2% for Group 70-74, and 100% and 71.4% for Group ≥75. Patient survival at 1 and 5 years were respectively 92.9% and 68.0% for Group 65-69, 85.7% and 61.5% for Group 70-74 and 100% and 62.5% for Group ≥75. Serum creatinine did not significantly differ between the three groups, with the exception of serum creatinine at 1 year. Increased recipient age and prolonged time on dialysis correlated with increased occurrence of postoperative complication. An increase in BMI, pretransplant diabetes mellitus and prolonged time on dialysis correlated with the occurrence of delayed graft function (DGF). History of smoking was identified as an independent risk factor for events of rejection. Increased human leukocyte antigen mismatches (HLA-MM) and prolonged cold ischemia time (CIT) correlated with higher rates of intensive care unit (ICU) treatment. This study supports kidney transplantations for the very old. End-stage renal disease (ESRD) patients ≥75 years of age who underwent kidney transplantation experienced comparable results to their younger counterparts. A comprehensive evaluation of ESRD patients with consideration of prognostic risk factor is the most suitable mean of identifying adequate kidney transplant candidates.

[A retrospective analysis of functional and oncologic outcomes following surgical treatment of patients with pT1/pT2 renal cell carcinoma at a tertiary referral centre]. / Peri- und postoperatives Ergebnis nach Nierentumorchirurgie bei pT1/pT2 Nierenzellkarzinom ­ eine retrospektive Zentrumsanalyse der funktionellen und onkologischen Ergebnisse.

INTRODUCTION: In patients with localised renal cell carcinoma, the only curative treatment option is surgical tumour excision. The aim of this study was to evaluate peri- and postoperative outcomes as well as oncologic and functional long-term results following surgical treatment of patients with renal cell carcinoma (pT1/pT2) at a tertiary referral centre. PATIENTS AND METHODS: This retrospective study included a total of 758 patients with localised renal cell carcinoma (pT1 /pT2), who underwent radical (RN) or partial (PN) nephrectomy between 01/2008 and 10/2014. Pre-, peri- and postoperative parameters were recorded. Oncologic and functional long-term data were retrieved through questionnaires and structured telephone interviews. RESULTS: Laparoscopic RN or PN resulted in less blood loss and lower peri- and postoperative complication rates compared to open procedures. Regarding short- and long-term renal function, a higher increase in serum creatinine levels was detected after RN. No difference was noted in health status and quality of life. Median follow-up was 36 months. A total of 10.4 % of patients died during follow-up. 4.7 % and 8.4 % developed a relapse or metastatic disease. No difference was found between laparoscopic and open RN/PNs in terms of oncologic long-term results. DISCUSSION: In conclusion, all surgical techniques evaluated in this study provided good oncologic and functional short-/long-term outcomes.

Complications, functional and quality of life outcomes following primary and secondary implantation of penile prosthesis at a tertiary referral center.

The implantation of a penile prosthesis (PP) may be recommended in patients with severe erectile dysfunction (ED) who do not respond to conservative treatments. The aim of this study was to evaluate complications, as well as functional and quality of life outcomes following primary and secondary implantation of PP at a tertiary referral center. In this retrospective study, a total of 51 patients (41 patients with primary (PPP) and 10 with secondary PP (SPP)) were included. Patients and operative characteristics were recorded and complications were analyzed using the Clavien-Dindo classification. To evaluate satisfaction of patients and their partners, as well as PP long-term function, follow-up data were collected by using questionnaires (Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) and QLQC30). Fifty-one patients with a median age of 61 years (IQR 52-68) received PP implantation (44 AMS 700, 7 Coloplast Titan). Main causes of ED were after radical prostatectomy (27.5%), diabetes (21,6%), and other unknown reasons (43.1%). Median time of intervention was 94.5 min (IQR 80.8-110.3) with no significant difference between PPP and SPP. Only one patient undergoing PPP surgery had grade 3 complication. Follow-up data from a total of 43 patients (84.3%) with a median follow-up of 26 months (IQR 17-41 mo) was recorded. At the time of follow-up, 88.4% of the PPs were still functional (PPP n = 34 (94.4%), SPP n = 4 (57.1%), p = 0.024). Overall estimated mean PP survival was 63.0 mo ((95% CI) 56.2-70.8 mo) with no significant difference between PPP and SPP. Overall satisfaction (EDITS und QLQC30) was high in both groups with no significant difference. PP implantation shows to be a safe treatment option in the management of severe ED.

[The use of partial nephrectomy in the treatment of patients with pT1/pT2 renal cell carcinoma: a trend analysis from a tertiary referral centre]. / Anwendung der organerhaltenden Nierentumorchirurgie in der Behandlung von Patienten mit Nierenzellkarzinom im Stadium pT1/pT2 ­ eine unizentrische Trendanalyse.

INTRODUCTION: In patients with localised renal cell carcinoma, the only curative treatment option is surgical tumour excision. Current national and European guidelines recommend partial nephrectomy in the form of an open or minimally-invasive procedure in case of small tumours. The aim of this study was to examine the use of radical (RN) or partial (PN) nephrectomy performed as open or minimally-invasive procedures in patients with pT1 /pT2 renal cell carcinoma at a tertiary referral centre. PATIENTS AND METHODS: This retrospective study included a total of 758 patients with localised renal cell carcinoma (pT1/pT2), who underwent PN or RN between 01/2008 and 10/2014. Nephrectomy was either performed as an open (OPN, ORN), laparoscopic (LPN, LRN) or robot-assisted laparoscopic (RAPN) procedure. RESULTS: Out of 758 patients, 439 (57.9 %) underwent PN performed as an LPN in n = 254 (57.9 %) and OPN in n = 185 (42.1 %). 319 patients (42.1 %) underwent RN performed as an LRN in n = 250 (78.4 %) and ORN in n = 69 (21.6 %). Between 2008 and 2014, there was a trend towards the use of PN, especially in patients with pT1a and pT1b. The majority of patients with pT2 underwent RN, performed as an LRN in 40 - 53.9 %. DISCUSSION: The results of this trend analysis from a tertiary referral centre demonstrate an increased use of PN and minimally-invasive procedures over time, as recommend by national and European guidelines.

Categories of response to first line vascular endothelial growth factor receptor targeted therapy and overall survival in patients with metastatic renal cell carcinoma.

INTRODUCTION: Sequential use of targeted therapy (TT) has improved overall survival (OS) of patients with metastatic renal cell carcinoma (mRCC). The value of objective response (OR) as compared to stable disease (SD) is unclear. We aimed to investigate OR of first-line TT and its impact on OS. MATERIAL AND METHODS: Retrospective analysis of OS among 331 mRCC patients with a first-line assessment according to RECIST 1.0. Characteristics between objective responders (complete response [CR] or partial remission [PR]), patients with SD and non-responders (progressive disease [PD] and toxicity [Tox]) were compared with the Chi-square test and the Kruskal-Wallis test. Kaplan-Meier analysis of OS and progression-free survival (PFS). Cox model analysis of Predictors of OS . RESULTS: Best response was CR, PR, SD, PD and Tox in 9 (2.7%), 61 (18.4%), 167 (50.5%), 80 (24.2%) and 14 (4.2%) patients respectively resulting in an OR rate of 21%. Median OS in months: CR 63.2; PR 37.6; SD 35.9; PD 14.6; TOX 22.5 (p<0.0001). Median PFS for responders was 14.8, 11.5 for patients with SD and 2.5 for non-responders (p<0.0001). Similarly median OS was 38.7, 35.9 and 15.5 (p<0.00001). Primary resistance and a first-line PFS <6months were the strongest independent predictors of OS. The achievement of OR as compared to SD did not impact OS. CONCLUSIONS: In our cohort of unselected patients OR was not associated with superior OS as compared to SD.

Cellular localization of THIK-1 (K(2P)13.1) and THIK-2 (K(2P)12.1) K channels in the mammalian kidney.

K(+)-channels fulfill several important functions in the mammalian kidney such as volume regulation, recirculation and secretion of K(+) ions, and maintaining the resting potential. In this study we used immunocytochemical methods, in situ hybridization, and nephron segment-specific RT-PCR to obtain a detailed picture of the cellular localization of two tandem pore domain potassium (K(2P)) channels, THIK-1 (K(2P)13.1, KCNK13) and THIK-2 (K(2P)12.1, KCNK12). Monospecific antibodies against C-terminal domains of rat THIK-1 and THIK-2 proteins (GST-fusion proteins) were raised in rabbits, freed from cross-reactivity, and affinity purified. All antibodies were validated by Western blot analysis, competitive ELISA, and preabsorption experiments. The expression of THIK channels in specific nephron segments was confirmed by double staining with marker proteins. Results indicate that in rat and mouse THIK-1 and THIK-2 were expressed in the proximal tubule (PT), thick ascending limb (TAL), connecting tubule (CNT), and cortical collecting duct (CCD). In human kidney THIK-1 and THIK-2 were localized in PT, TAL and CCD. Immunostaining of rat tissue revealed an intracellular expression of THIK-1 and THIK-2 throughout the identified nephron segments. However in mouse kidney THIK-2 was identified in basolateral membranes. Overall, the glomerulus, thin limbs and medullary collecting ducts were devoid of THIK-1 and THIK-2 signal. In summary, THIK-1 and THIK-2 are abundantly expressed in the proximal and distal nephron of the mammalian kidney.