Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial.

BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) has demonstrated superior overall survival (OS) and durable response benefits versus sunitinib (SUN) with long-term follow-up in patients with advanced renal cell carcinoma (aRCC). We report updated analyses with 8 years of median follow-up from CheckMate 214. PATIENTS AND METHODS: Patients with aRCC (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg Q3W × four doses, followed by NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN (50 mg) once daily for 4 weeks on, 2 weeks off. The endpoints included OS, independent radiology review committee (IRRC)-assessed progression-free survival (PFS), and IRRC-assessed objective response rate (ORR) in intermediate/poor-risk (I/P; primary), intent-to-treat (ITT; secondary), and favorable-risk (FAV; exploratory) patients. RESULTS: With 8 years (99.1 months) of median follow-up, the hazard ratio [HR; 95% confidence interval (CI)] for OS with NIVO+IPI versus SUN was 0.72 (0.62-0.83) in ITT patients, 0.69 (0.59-0.81) in I/P patients, and 0.82 (0.60-1.13) in FAV patients. PFS probabilities at 90 months were 22.8% versus 10.8% (ITT), 25.4% versus 8.5% (I/P), and 12.7% versus 17.0% (FAV), respectively. ORR with NIVO+IPI versus SUN was 39.5% versus 33.0% (ITT), 42.4% versus 27.5% (I/P), and 29.6% versus 51.6% (FAV). Rates of complete response were higher with NIVO+IPI versus SUN in all International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups (ITT, 12.0% versus 3.5%; I/P, 11.8% versus 2.6%; FAV, 12.8% versus 6.5%). The median duration of response (95% CI) with NIVO+IPI versus SUN was 76.2 versus 25.1 months [59.1 months-not estimable (NE) versus 19.8-33.2 months] in ITT patients, 82.8 versus 19.8 months (54.1 months-NE versus 16.4-26.4 months) in I/P patients, and 61.5 versus 33.2 months (27.8 months-NE versus 24.8-51.4 months) in FAV patients. The incidence of treatment-related adverse events was consistent with previous reports. Exploratory post hoc analyses are reported for FAV patients, those receiving subsequent therapy based on their response status, clinical subpopulations, and adverse events over time. CONCLUSIONS: Superior survival, durable response benefits, and a manageable safety profile were maintained with NIVO+IPI versus SUN at 8 years, the longest phase III follow-up for a first-line checkpoint inhibitor combination therapy in aRCC.

Staging accuracy of MRI of the prostate with special reference to the influence of the time of last ejaculation on the detection of seminal vesicle invasion.

AIM: To evaluate the Prostate Imaging Reporting and Data System, version 2.1 (PIRADS V2.1) criteria for seminal vesicle invasion (SVI) and examine whether the timing of last ejaculation influences the detection of SVI. MATERIALS AND METHODS: The study population consisted of 68 patients (34 with SVI, 34 without SVI, matching groups by age and prostate volume) who underwent PIRADS V2.1-compliant multiparametric magnetic resonance imaging (MRI; 34 at 1.5 T, 34 at 3 T). Before the examination, the time of last ejaculation (38/68 ≤ 5 days, 30/68 > 5 days) was collected via a questionnaire. The five PIRADS V2.1 criteria for SVI with subsequent overall assessment were evaluated retrospectively by two independent examiners (examiner 1 with >10 years of experience, examiner 2 with 6 months of experience) in a single-blinded fashion for all patients using a questionnaire and a six-point scale (0 = no, 1 = very likely not, 2 = probably not, 3 = possible, 4 = probable, 5 = certain). RESULTS: E1 achieved high specificity (100%) and positive predictive value (PPV; 100%) in the overall assessment, independent of the time of last ejaculation (sensitivity = 76.5%, negative predictive value [NPV] = 81%). The area under the curve (AUC) value was 0.882; for E2, it was 0.765. At ≤5 days, the AUC values of E1 and E2 differed significantly (0.867 versus 0.681, p=0.016), as did the diffusion restriction criterion (0.833 versus 0.681, p=0.028). E1 showed high AUC values independent of time. E2 had better values for all criteria at >5 days than at ≤5 days. There were no significant differences between the examiners in all observations at >5 days. CONCLUSION: The PIRADS V2.1 criteria are well suited for an experienced examiner to detect SVI independent of time point. An inexperienced examiner will benefit from patients being abstinent >5 days prior to MRI.

Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma.

BACKGROUND: The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma (aRCC). We report updated efficacy data from the second interim analysis. PATIENTS AND METHODS: Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1-positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population. RESULTS: Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 [95% confidence interval (CI) 0.490-0.777]}; one-sided P < 0.0001; median 13.8 (95% CI 10.1-20.7) versus 7.0 months (95% CI 5.7-9.6); overall population: HR 0.69 (95% CI 0.574-0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1-15.3) versus 8.0 months (95% CI 6.7-9.8)]. OS data were immature [PD-L1+ population: HR 0.828 (95% CI 0.596-1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616-1.027); one-sided P = 0.0392]. CONCLUSION: Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature. CLINICAL TRIAL NUMBER: NCT02684006.

Innate immune response of human epidermal keratinocytes and dermal fibroblasts to in vitro incubation of Trichophyton benhamiae DSM 6916.

BACKGROUND: Superficial cutaneous infection caused by the zoophilic dermatophyte Trichophyton benhamiae is often associated with a highly inflammatory immune response. As non-professional immune cells, epidermal keratinocytes and dermal fibroblasts contribute to the first line of defence by producing pro-inflammatory cytokines and antimicrobial peptides (AMP). OBJECTIVE: Purpose of this study was to gain a deeper understanding of the pathogenesis and the fungal-host interaction as not much is known about the innate immune response of these cutaneous cells against T. benhamiae. METHODS: Using a dermatophytosis model of fibroblasts and keratinocytes incubated with T. benhamiae DSM 6916, analyses included determination of cell viability and cytotoxicity, effects on the innate immune response including expression and secretion of pro-inflammatory cytokines/chemokines and expression of AMP, as well as alterations of genes involved in cell adhesion. RESULTS: Trichophyton benhamiae DSM 6916 infection led to severe cell damage and direct induction of a broad spectrum of pro-inflammatory cytokines and chemokines in both cutaneous cells. Only keratinocytes differentially up-regulated AMP genes expression after T. benhamiae DSM 6916 infection. Expression of AMPs in fibroblasts was not inducible by fungal infection, whereas their absences potentially contributed to a continuous increase in the fungal biomass on fibroblasts, which in turn was reduced in keratinocytes possibly due to the antimicrobial actions of induced AMPs. On mRNA level, T. benhamiae DSM 6916 infection altered cell-cell contact proteins in keratinocytes, indicating that targeting specific cell-cell adhesion proteins might be part of dermatophytes' virulence strategy. CONCLUSION: This study showed that in addition to immune cells, keratinocytes and fibroblasts could participate in antimicrobial defence against an exemplary infection with T. benhamiae DSM 6916.

Identification of high-risk patients with clear cell renal cell carcinoma based on interphase-FISH.

BACKGROUND: The aim of this study was to examine the prognostic value of four significant aberrations based on our previous studies by array-CGH to develop a prognostic Fluorescence-in situ-hybridisation (FISH) assay for clear cell renal cell carcinomas (ccRCC). METHODS: Fluorescence-in situ-hybridisation experiments were performed on 100 ccRCCs (52 metastasised out of 48 non-metastasised). The mean/median follow up of patients was 59/54 months. Commercially available FISH probes were used for each critical chromosomal region (1q21.3, 7q36.3, 9p21.3p24.1 and 20q11.21q13.32). The total number of specific aberrations (TNSA) was calculated for each tumour based on the specific genomic alterations. RESULTS: Total number of specific aberrations was the best predictor of metastasis (area under the curve (AUC)=0.814) compared with single aberrations (AUC: 0.619-0.708) and to 11 different combinations of these 4 aberrations in the receiver operating characteristic curve analysis. Total number of specific aberrations, tumour grade and tumour size were independent predictors of metastasis in the multivariate analysis (P<0.001) for the whole cohort as well as for organ-confined tumours. Total number of specific aberrations and grade could also independently predict cancer-specific mortality (CSM). Total number of specific aberrations demonstrated the highest significance in COX proportional hazard models of overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). CONCLUSIONS: We identified TNSA as an independent prognostic factor which is associated with metastasis occurrence, CSM, OS, CSS and PFS in patients with ccRCCs.

Placental Schistosoma haematobium infection in a German returnee from Malawi.

Schistosomiasis is a widespread helminthic infection which sometimes may affect travelers to endemic areas. We report on a case of urogenital and placental schistosomiasis in a 28-year-old German woman who had been exposed to schistosomiasis in Lake Malawi one year earlier. She experienced painless macrohaematuria in her 21st week of pregnancy. Cystoscopy revealed vesical lesions typical for urogenital schistosomiasis. Histopathology confirmed ova of Schistosoma (S.) haematobium. The patient was treated with praziquantel 40 mg/kg/body weight/day for 3 days. After 285 days of gestation and 18 weeks post treatment, the patient delivered a healthy girl. Histopathology of placenta revealed eggs of S. haematobium in placental stroma. The infant proved negative for anti-Schistosoma spp. antibodies at the age of 15 months. This is the first report on placental schistosomiasis since 1980 and the first case occurring in a traveler.

Avelumab first-line maintenance treatment for advanced urothelial carcinoma: review of evidence to guide clinical practice.

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

Association of C-reactive protein with efficacy of avelumab plus axitinib in advanced renal cell carcinoma: long-term follow-up results from JAVELIN Renal 101.

BACKGROUND: C-reactive protein (CRP) is an important prognostic and predictive factor in advanced renal cell carcinoma (aRCC). We report the association of CRP levels at baseline and early after treatment with efficacy of avelumab plus axitinib or sunitinib from the phase III JAVELIN Renal 101 trial. PATIENTS AND METHODS: Patients were categorized into normal (baseline CRP <10 mg/l), normalized (baseline CRP ≥10 mg/l and ≥1 CRP value decreased to <10 mg/l during 6-week treatment), and non-normalized (CRP ≥10 mg/l at baseline and during 6-week treatment) CRP groups. Progression-free survival and best overall response from the second interim analysis and overall survival (OS) from the third interim analysis were assessed. RESULTS: In the avelumab plus axitinib and sunitinib arms, respectively, 234, 51, and 108 patients and 232, 36, and 128 patients were categorized into normal, normalized, and non-normalized CRP groups. In respective CRP groups, objective response rates [95% confidence interval (CI)] were 56.0% (49.4% to 62.4%), 66.7% (52.1% to 79.2%), and 45.4% (35.8% to 55.2%) with avelumab plus axitinib and 30.6% (24.7% to 37.0%), 41.7% (25.5% to 59.2%), and 19.5% (13.1% to 27.5%) with sunitinib; complete response rates were 3.8%, 11.8%, and 0.9% and 3.0%, 0%, and 1.6%, respectively. Median progression-free survival (95% CI) was 15.2 months (12.5-21.0 months), not reached (NR) [11.1 months-not estimable (NE)], and 7.0 months (5.6-9.9 months) with avelumab plus axitinib and 11.2 months (8.4-13.9 months), 11.2 months (6.7-13.8 months), and 4.2 months (2.8-5.6 months) with sunitinib; median OS (95% CI) was NR (42.2 months-NE), NR (30.4 months-NE), and 23.0 months (18.4-33.1 months) and NR (39.0 months-NE), 39.8 months (21.7-NE), and 19.1 months (16.3-25.3 months), respectively. Multivariate analyses demonstrated that normalized or non-normalized CRP levels were independent factors for the prediction of objective response rate or OS, respectively, with avelumab plus axitinib. CONCLUSIONS: In patients with aRCC, CRP levels at baseline and early after treatment may predict efficacy with avelumab plus axitinib.

Sequential therapies with sorafenib and sunitinib in advanced or metastatic renal cell carcinoma.

PURPOSE: To investigate whether patients with metastatic renal cell carcinoma benefit from sequential therapies with the tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib. PATIENTS AND METHODS: A total of 89 patients were treated in nine German centres between 2002 and 2009. The TKI sequence started as first-, second- or third-line therapy after prior chemo- or immunotherapy. When progression was diagnosed, treatment was switched to the second TKI until further progression. RESULTS: Overall progression-free survival (PFS) of patients receiving sunitinib followed by sorafenib shows no statistically significant difference to patients receiving sorafenib followed by sunitinib (15.4 months vs. 12.1 months). The secondary use of sorafenib resulted in a median PFS of 3.8 months if the TKI sequence had been started as a first-line treatment and of 3.5 months if the TKI sequence had been started second-line treatment. The secondary use of sunitinib resulted in a median PFS of 3.4 and 4.0 months, respectively. OS was 28.8 months for all patients, without a statistically significant difference between the two groups. CONCLUSIONS: This study endorses the notion of a clinical benefit of the sequential use of sorafenib and sunitinib and supports observations from previous studies. In terms of the optimal succession of the two TKIs, the study does not allow a definite answer.

Prostatic Artery Embolization: Influence of Cone-Beam Computed Tomography on Radiation Exposure, Procedure Time, and Contrast Media Use.

PURPOSE: To evaluate the effect of cone-beam computed tomography (CBCT) on radiation exposure, procedure time, and contrast media (CM) use in prostatic artery embolization (PAE). MATERIALS AND METHODS: Seventy-eight patients were enrolled in this retrospective, single-center study. All patients received PAE without (group A; n = 39) or with (group B; n = 39) CBCT. Total dose-area product (DAPtotal; Gycm2), total entrance skin dose (ESDtotal; mGy), and total effective dose (EDtotal; mSv) were primary outcomes. Number of digital subtraction angiography (DSA) series, CM use, fluoroscopy time, and procedure time were secondary outcomes. PAE in group A was performed by a single radiologist with 15 years experience, PAE in group B was conducted by four radiologists with 4 to 6 years experience. RESULTS: For groups A vs. B, respectively, median (IQR): DAPtotal 236.94 (186.7) vs. 281.20 (214.47) Gycm2(p = 0.345); EDtotal 25.82 (20.35) vs. 39.84 (23.75) mSv (p = < 0.001); ESDtotal 2833 (2278) vs. 2563 (3040) mGy(p = 0.818); number of DSA series 25 (15) vs. 23 (10)(p = 0.164); CM use 65 (30) vs. 114 (40) mL(p = < 0.001); fluoroscopy time 23 (20) vs. 28 (25) min(p = 0.265), and procedure time 70 (40) vs.120 (40) min(p = < 0.001). Bilateral PAE was achieved in 33/39 (84.6%) group A and 32/39 (82.05%) group B(p = 0.761), all other patients received unilateral PAE. There were no significant differences between clinical parameters and origins of the prostatic arteries (PA) (p = 0.206-1.00). CONCLUSION: Operators with extensive expertise on PAE may not benefit from addition of CBCT to DSA runs, whereas for operators with less expertise, CBCT when used alongside with DSA runs increased the overall radiation exposure.

[Risk-adapted therapy for metastatic renal cell carcinoma]. / Risikoadaptierte Therapie des metastasierten Nierenzellkarzinoms.

Current pivotal phase 3 studies have permanently changed the first-line treatment landscape in metastatic renal cell carcinoma. These studies showed that immune checkpoint combinations were more efficacious than sunitinib, a previous standard of care. Nivolumab plus ipilimumab is characterized by a survival advantage, a high rate of complete response and durable remission in patients with intermediate and unfavorable prognosis. Despite frequent immune-mediated side effects, fewer symptoms and a better quality of life were observed compared to sunitinib. Pembrolizumab or avelumab plus axitinib were characterized by an improved PFS and a high response rate with a low rate of intrinsic resistance. In addition, a significant survival benefit was achieved with pembrolizumab plus axitinib. The side effect profile is driven by the "chronic" toxicity of axitinib, but there is additional risk of immune-mediated side effects of the PD-1/PD-L1 immune checkpoint inhibitors. The quality-of-life data published so far do not suggest any improvement compared to the previous standard sunitinib. The PD-1/PD-L1 immune-check-point inhibitors thus form the "backbone" of the first-line therapy of metastatic renal cell carcinoma. Monotherapy with VEGFR-TKI remains an option in cases with contraindications and possibly for subgroups with favorable prognosis.

[Promotion and support of successful training as a urologist by the Deutsche Gesellschaft für Urologie]. / Förderung und Unterstützung der erfolgreichen Ausbildung zum Urologen durch die Deutsche Gesellschaft für Urologie.

The Deutsche Gesellschaft für Urologie (DGU) has set itself the task of supporting medical assistants on their way to becoming specialists in urology. At the same time, urological junior researchers have been given the opportunity to become part of the urological community at an early stage through the so-called junior membership of the DGU. The working group "Young Urologists" of the DGU addresses in particular topics such as the development of concepts for the promotion of young talent, improvement of further education, models for better compatibility of leisure/family and work as well as the compatibility of clinical and scientific work. As part of the DGU Congress, urological assistants can actively contribute by submitting abstracts for lecture or poster sessions. On the other hand, seminars and forums also address topics relevant to further education. To ensure this, representatives of the assistants are members of the scientific program commission of the DGU congress. The aim of the Junior Academy is to accompany young urologists on their way to becoming a specialist with high-quality seminars. In addition, the Junior Academy offers personal support on the way to their targeted career goal. The Junior Academy has a large network that makes it possible to learn from the best. The established Ferdinand-Eisenberger Research Fellowships allow young researchers in urology to be exempted from their clinical routine for one year in order to intensify independent scientific work at a renowned research institution in Germany. AuF-Symposia (working group urological research) and workshops are also aimed at young scientists. Further funding projects, such as support for DFG applications, are unique to the society.

[Follow-up of renal cell carcinoma in a nonmetastatic stage]. / Nachsorge beim Nierenzellkarzinom im nicht fernmetastasierten Stadium.

Postoperative follow-up care after curative surgery or ablative treatment is the standard of care in patients with nonmetastatic renal cell carcinoma. The goal is to identify and treat postoperative complications and local recurrences early on. Follow-up investigations and their relevance are widely acknowledged and validated and patients undergoing follow-up seem to benefit from a longer survival in nonmetastatic renal cell carcinoma. Hence there is no consensus on a standardized follow-up strategy. The most disputed question is around the frequency of the investigations and the duration of the follow-up. Without an evidence-based follow-up protocol, urologists should carry out an individualized, potentially lifelong follow-up regimen, which also includes the patients' needs and perspectives.

[Value of lymphadenectomy for limited nodal recurrence of prostate cancer after local therapy with curative intent]. / Lymphadenektomie beim limitierten Lymphknotenrezidiv des Prostatakarzinoms nach kurativer Lokaltherapie.

After local therapy for prostate cancer, presumably isolated nodal recurrence is being detected in increasing numbers of patients by modern imaging techniques, especially by positron emission tomography (PET). The question arises whether lymphadenectomy may delay tumor progression.Conclusions concerning the value of PET/computed tomography, perioperative complications, and oncological outcome were derived from available studies and our own experiences. Six studies reported on 83 patients who underwent lymphadenectomy for suspected nodal recurrence. In cases with histological confirmation, no patient was cured.Hence, nodal recurrence in prostate cancer most likely represents a systemic affection instead of locally limited disease. If a drop in the prostate-specific antigen level occurs after lymphadenectomy, it can be assumed that the progression-free period is expected to be less than 12 months.The available data on oncological outcomes of this procedure are insufficient. Therefore, lymphadenectomy for nodal recurrence of prostate cancer remains an unproven approach.

[Molecular genetic markers for prostate cancer. Evidence in fine needle biopsies for improved confirmation of the diagnosis]. / Molekulargenetische Marker des Prostatakarzinoms. Nachweis in Feinnadelbiopsien zur besseren Diagnoseabsicherung.

Selected transcript markers as well as their combinations were analyzed on minimal prostate tissue specimens with regard to their diagnostic potential. Artificial prostate biopsies from RPE explants were used for evaluation and optimization of the techniques used followed by application to diagnostic prostate needle core biopsies. Minimal prostate specimens were cryopreserved and processed with standardized methods. The RNA amount of a half of each biopsy was sufficient for the analysis of 11 marker genes and one reference gene (TBP) using quantitative PCR assays.The relative transcript amounts obtained were included in several analyses including calculations for each single marker gene like median overexpression rate as well as marker combinations. Two optimized mathematical models based on relative expression levels of EZH2, hepsin, PCA3, prostein, and TRPM8 were evaluated with regard to their diagnostic potential. Compared to single marker analyses these models show higher sensitivity and specificity for prostate cancer detection.Thus biomolecular prostate cancer identification may represent a suitable diagnostic tool to supplement conventional techniques on prostate biopsies. Furthermore, an extension of this approach to PCa prognosis and the transfer to urine samples appear very promising.

[Treatment with PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors : Immune-mediated side effects]. / Therapie mit PD-1/PD-L1- und CTLA-4-Immun-Checkpoint-Inhibitoren : Immunvermittelte Nebenwirkungen.

Immune checkpoint inhibitors are a new standard therapy for advanced or metastatic urothelial as well as renal cell carcinoma. Atezolizumab and Pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with transitional call cancer in the 1st line setting; both antibodies and Nivolumab may also be used after platinum based prior therapy. Regarding renal cell carcinoma approval for 1st line treatment with the combination of Nivolumab and Ipilimumab for patients at intermediate or high risk (IMDC) is currently expected. Furthermore, Nivolumab is approved for renal cell carcinoma after prior therapy. With the widespread use of immune checkpoint inhibitors understanding immune related adverse events gets paramount importance. In particular, combination therapy of Nivolumab and Ipilimumab is not only characterized by improving efficacy but also by a higher rate of adverse events. Most frequently rash and pruitus, endocrine events, colitis/diarrhea, hepatitis and pneumonia are observed. However, any organ system may be affected by immune related adverse events. Differential diagnosis between immune related or other (e. g. infectious) causes of organ dysfunction may be difficult. Early diagnosis and initiation of therapy is important to avoid deleterious outcomes. The use of corticosteroids generally leads to rapid resolution of symptoms; further immunosuppressive agents (MMF, infliximab) are rarely needed. Regarding endocrine adverse events permanent hormonal replacement of hormones is frequently needed. In particular in consequence of pneumonitis fatal outcomes have been observed.

[Tumor assessment in immune checkpoint inhibitor therapy : Tumor response, progression and pseudoprogression]. / Tumorassessment bei Immun-Checkpoint-Inhibitor-Therapie : Tumoransprechen, Progression und Pseudoprogression.

In contrast to chemotherapy, treatment with immune checkpoint inhibitors occasionally results in an unconventional pattern of response. Besides an early partial or complete response or tumor progression, a so-called pseudoprogression, a "mixed response" or late responses can also be observed. Treatment beyond radiographically defined progression may therefore be appropriate in selected cases. For these treatment decisions, the clinical evaluation of the patient (performance status, symptoms, etc.), the "dynamics" of the underlying malignancy, and the availability of other treatment options are of paramount importance. However, the time to initiate another treatment should not be missed by rapid progression. In PD-1 (programmed cell death protein 1) immune checkpoint inhibition in urothelial cancer after platinum-based chemotherapy, response or progression can be observed early at week 8 in the vast majority of the cases. In contrast, in second-line treatment of renal cell carcinoma around 25% of responses are seen late, at week 24 or later (occasionally after 1 year). Therefore, immune checkpoint inhibition should be continued for stable disease. At present, it remains unclear how long to continue therapy in cases with partial or complete remission.

[Adverse events of immune checkpoint inhibitors]. / Nebenwirkungen der Immun-Checkpoint-Inhibitoren.

After immune checkpoint inhibitor therapy was approved for renal cell carcinoma last year, this new immune therapy has spread to urology. Further approvals (atezolizumab, nivolumab, pembrolizumab) are expected in 2017 for metastatic urothelial carcinoma that has progressed following treatment with platinum-based chemotherapy. With expanding use of immune checkpoint inhibitors, experience in diagnosing and managing immune-mediated adverse events increases. Although of low incidence, grade 3/4 toxicities play a central role. Organs most common for immune-mediated adverse events are skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis), and endocrine organs (hyper-, hypothyroidism and hypophysitis). Diagnostic workup includes routine laboratory tests (including liver function tests) and may be supplemented with hormone values. In cases of pneumonitis or hypophysitis, imaging (high-resolution CT, MRI) can confirm diagnoses. Immune-mediated toxicities are treated with therapy interruption and administration of corticosteroids (and in individual cases additional immunosuppression). Dose modification is not intended!

[Radium-223 dichloride in patients with castration-refractory prostate cancer]. / Alpharadin-Therapie bei Patienten mit metastasiertem kastrationsrefraktärem Prostatakarzinom.

Since November 2013, the alpha emitter radium-223 dichloride (Alpharadin/Xofigo®) has been approved for the treatment of men with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. In the ASYMPCA clinical trial, radium-223 was shown to improve overall survival and to reduce the time to the first symptomatic skeletal event. The use of radium-223 was associated with a reduction of pain and an improvement of health-related quality of life compared to the placebo arm. The efficacy of radium-223 dichloride was not inhibited by the use of chemotherapy with docetaxel. Studies have demonstrated a longer overall survival (OS) in patients with a combined treatment of abiraterone or enzalutamide; however, until this data is validated in larger clinical trials, the combination of radium-223 and abiraterone/enzalutamide cannot be recommended. Patients who have received concomitant medication with denosumab appeared to have a longer OS compared to patients who did not. A second treatment cycle of radium-223 was not associated with any adverse events when compared to the outcomes reported in the ASLYMPCA trial. Here the median radiographic progression-free survival was 9 months.