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Robust biomarkers to predict response to immune checkpoint blockade (ICB) in metastatic urothelial carcinoma (mUC) are still in demand. Recently, early C-reactive protein (CRP) kinetics and especially the novel CRP flare-response phenomenon has been associated with immunotherapy response.We conducted a multicentre observational study comprising 154 patients with mUC treated with ICB to evaluate the predictive value of a previously described on-treatment CRP kinetics: CRP flare responders (at least doubling of baseline CRP within the first month after initiation of ICB followed by a decline below baseline within three months), CRP responders (decline in baseline CRP by ≥ 30% within three months without a prior flare) and the remaining patients as CRP non-responders. CRP kinetics groups were correlated with baseline parameters, PD-L1 status, progression-free survival (PFS) and overall survival (OS).Objective response was observed in 57.1% of CRP responders, 45.8% of CRP flare responders and 17.9% of CRP non-responders (P 0.001). CRP flare response was associated with prolonged PFS and OS (P 0.001). In multivariable Cox regression analysis, CRP flare responders showed a risk reduction of ∼70% for tumour progression and death compared to CRP non-responders. Subgroup analysis of CRP flare responders revealed that patients with a long-flare response (completed flare-response kinetics ≥6 weeks on-treatment) showed even more favourable outcomes following ICB (HR = 0.18, 95%-CI: 0.07-0.48, P 0.001).CRP (flare)response robustly predicts immunotherapy response and outcomes in mUC independent of PD-L1 status. Thus, early on-treatment CRP kinetics is a promising low-cost and easy-to-implement biomarker to optimise therapy monitoring in patients with mUC treated with ICB.

Supplementary Table 2. Baseline characteristics of the multicenter EV cohort.

Purpose:The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET).Experimental Design:Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts.Results:In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001).Conclusions:Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV.See related commentary by Aggen et al., p. 1377

Background Ionotropic glutamate receptors AMPAR and NMDAR modulate proliferation, invasion and radioresistance in glioblastoma (GB). Pharmacological targeting is difficult as many in vitro-effective agents are not suitable for in patient applications. We aimed to develop a method to test the well tolerated AMPAR- and NMDAR-antagonist xenon gas as radiosensitizer in GB. Methods We designed a diffusion-based system to perform the colony formation assay (CFA), the radiobiological gold standard, under xenon exposure. Stable and reproducible gas atmosphere was validated with oxygen and carbon dioxide as tracer gases. After checking for AMPAR and NMDAR expression via immunofluorescence staining we performed the CFA with the glioblastoma cell lines U87 and U251 as well as the non-glioblastoma derived cell line HeLa. Xenon was applied after irradiation and additionally tested in combination with NMDAR antagonist memantine. Results The gas exposure system proved compatible with the CFA and resulted in a stable atmosphere of 50% xenon. Glutamate receptor subunits were present in glioblastoma-derived and to a lesser extent in HeLa cells. Significant radiosensitization by xenon was shown in U251 and U87 at irradiation doses of 4–8 Gy and 2–8 Gy, respectively (p < .05). The effect was further enhanced by the addition of memantine, showing significant reduction in the surviving fraction already at 2 Gy for both glioblastoma cell lines (p < .05). Xenon did not increase the radiosensitivity of HeLa cells until a radiation dose of 8 Gy. Conclusion The developed system allows for testing of gaseous agents with CFA. As a proof of concept, we have, for the first time, unveiled radiosensitizing properties of xenon gas in glioblastoma.

Background: Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC). Patients and methods: Medical records of patients with documented mRCC treated by immuno-oncology combinations were reviewed at 47 institutions from 16 countries. Patients were assessed for overall survival (OS), progression-free survival (OS), and overall clinical benefit (OCB), defined as the sum of the rate of partial/complete responses and stable disease. Univariate and multivariate analyses were used to explore the association of variables of interest with survival. Results: A total of 675 patients were included; BMI was >25 kg/m2 in 345 patients (51%) and was associated with improved OS (55.7 vs. 28.4 months, P < .001). The OCB of patients with BMI >25 kg/m2 versus those with BMI ≤25 kg/m2 was significantly higher only in patients with nonclear cell histology (81% vs. 65%, P = .011), and patients with liver metastases (76% vs. 58%, P = .007), Neutrophil to lymphocyte ratio >4 (77% vs 62%, P = .022) or treated by nivolumab plus ipilimumab (77% vs. 64%, P=.044). In the BMI ≤25 kg/m2 subgroup, significant differences were found between patients with NLR >4 versus ≤4 (62% vs. 82%, P = .002) and patients treated by IO+IO versus IO+TKIs combinations (64% vs. 83%, P = .002). Conclusion: Our study suggests that the prognostic significance and the association of BMI with treatment outcome varies across clinico-pathological mRCC subgroups.

Aim Less than a dozen cases of psoas abscesses in pregnancy have been described in the literature. We reviewed the literature when treating a patient with a psoas abscess after ipsilateral double J-ureteral stent placement (in the following: “double J-stent”) due to infected hydronephrosis. Methods In January 2022, this review was searched using the Pubmed/MEDLINE database and the mesh terms “Psoas Abscess” AND “Pregnancy”. Studies were included in any language and of all years, describing a psoas abscess during pregnancy. When patients did not have a psoas abscess, the abscess occurred after pregnancy, or when there was no full text available, the article was excluded. Main results Ten case reports about patients with psoas abscesses during pregnancy were included. The classical symptomatic triad of psoas muscle abscess included lower back pain, limping and persistent fever with daily spikes. However, in most cases, not all three symptoms can be found. Especially, fever is absent in more than half of the patients. Psoas abscesses are described between 13 and 39 weeks of gestation. Primary psoas abscesses with haematogenous spread are more common during pregnancy than secondary with spread per continuitatem. In the literature, the main reasons for psoas abscess are spinal tuberculosis, drug abuse or underlying diseases such as Crohn’s disease. It is not uncommon for the definite cause to be unclear. Regarding the patient's symptoms, pyelonephritis is often considered a possible aetiology. In general, the main treatment options include antibiotic treatment and abscess drainage. There is no higher caesarean section rate, and no negative outcome for the foetus has been described. Case presentation In our patient, a 38-year-old obese Caucasian woman, who had received a left double J-stent for infected hydronephrosis at 15 weeks of gestation, we successfully treated a psoas abscess of 20 × 10 cm with a sonographically assisted abscess drainage and antibiotics. The further course of pregnancy and the elective repeat caesarean section at 38 + 0 weeks of gestation were without any problems. Double J-stent placement and laser stone lithotripsy during puerperium were performed because of recurrent urolithiasis. Conclusions Although rare, psoas abscesses can occur during pregnancy, and it has often been treated surgically in the past. A psoas abscess as a complication after infected hydronephrosis and intervention during pregnancy has never been reported in the literature. Even for obese patients, minimally invasive therapy may be a treatment option that has rarely been reported in the literature.

Purpose: The antibody–drug conjugate enfortumab vedotin (EV) releases a cytotoxic agent into tumor cells via binding to the membrane receptor NECTIN-4. EV was recently approved for patients with metastatic urothelial carcinoma (mUC) without prior assessment of the tumor receptor status as ubiquitous NECTIN-4 expression is assumed. Our objective was to determine the prevalence of membranous NECTIN-4 protein expression in primary tumors (PRIM) and patient-matched distant metastases (MET). Experimental Design: Membranous NECTIN-4 protein expression was measured (H-score) by IHC in PRIM and corresponding MET (N = 137) and in a multicenter EV-treated cohort (N = 47). Progression-free survival (PFS) after initiation of EV treatment was assessed for the NECTIN-4–negative/weak (H-score 0–99) versus moderate/strong (H-score 100–300) subgroup. The specificity of the NECTIN-4 IHC staining protocol was validated by establishing CRISPR-Cas9–induced polyclonal NECTIN-4 knockouts. Results: In our cohort, membranous NECTIN-4 expression significantly decreased during metastatic spread (Wilcoxon matched pairs P < 0.001; median H-score = 40; interquartile range, 0–140), with 39.4% of MET lacking membranous NECTIN-4 expression. In our multicenter EV cohort, absence or weak membranous NECTIN-4 expression (34.0% of the cohort) was associated with a significantly shortened PFS on EV (log-rank P < 0.001). Conclusions: Membranous NECTIN-4 expression is frequently decreased or absent in mUC tissue. Of note, the clinical benefit of EV strongly depends on membranous NECTIN-4 expression. Thus, our results are of highest clinical relevance and argue for a critical reconsideration of the current practice and suggest that the NECTIN-4 receptor status should be determined (ideally in a metastatic/progressive lesion) before initiation of EV. See related commentary by Aggen et al., p. 1377

Background: The methylation status of Septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) in circulating cell-free DNA (ccfDNA) are validated pan-cancer biomarkers. The present proof-of-concept study aimed to investigate the potential and dynamics of quantitative SEPT9 and SHOX2 methylation in prostate cancer (PCa) patient tissue and ccfDNA during prostate biopsy as a diagnostic tool. Methods: The methylation patterns of SEPT9 and SHOX2 in prostate tissue were analyzed using The Cancer Genome Atlas data set (n = 498 PCa and n = 50 normal adjacent prostate tissue (NAT)). Next, dynamic changes of ccfDNA methylation were quantified in prospectively enrolled patients undergoing prostate biopsy (n = 72), local treatment for PCa (n = 7; radical prostatectomy and radiotherapy) as well as systemic treatment for PCa (n = 6; chemotherapy and 177-Lu-PSMA-therapy). Biomarker levels were correlated with clinicopathological parameters. Results: SEPT9 and SHOX2 were hypermethylated in PCa tissue (p < 0.001) and allowed discrimination of PCa and non-tumor prostate tissue (mSEPT9: AUC 0.87, 95%CI [0.82–0.92]; mSHOX2: AUC 0.89, 95%CI 0.84–0.94). SHOX2 methylation and mRNA levels were significantly higher in PCa tissue and increased with tumor stage and grade, as well as in patients suffering from biochemical recurrence following radical prostatectomy. SEPT9 and SHOX2 ccfDNA methylation allowed distinguishing patients with localized and metastatic disease (p < 0.001 for both). In addition, methylation levels increased shortly after prostate biopsy only in patients with PCa (ΔmSEPT9: p < 0.001 and ΔmSHOX2: p = 0.001). Conclusions: The early dynamics of methylated SEPT9 and SHOX2 in ccfDNA allow differentiation between PCa patients and patients without PCa and is a promising marker for tumor monitoring in the metastatic stage to determine tumor burden under systemic therapy.

Simple Summary With the introduction of immune checkpoint inhibitors (ICI) in recent years, the treatment landscape of metastatic urothelial cancer has undergone a substantial transformation. Nevertheless, disease progression after prior platinum-based chemotherapy and ICI pretreatment remains a challenging clinical situation with little evidence for following therapeutic options. The aim of this multicenter analysis was to examine the efficacy of the vinca alkaloid vinflunine after previous ICI therapy. In our cohort, post-ICI patients showed an overall response rate (ORR) of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and the clinical benefit rate (CBR) was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Our analysis demonstrates the clinical activity of vinflunine in a third- or later-line post-ICI setting, and the therapeutic benefit may be considerably higher than demonstrated in previous studies. Abstract Background: Immune checkpoint inhibitors (ICI) are standard of care in patients with metastatic urothelial carcinoma (mUC) ineligible for cisplatin, and as second-line therapy after platinum-based chemotherapy. To date, few data exist about the efficacy of the former second-line chemotherapeutic agent vinflunine after the failure of sequential platinum-based chemotherapy and ICI treatment. The aim of this analysis was to examine the efficacy of vinflunine in a post-ICI third- or later-line setting. Methods: In this retrospective German multicenter study, data of mUC patients treated with vinflunine were reviewed in six centers between February 2010 and December 2021. All of the 105 included patients had radiologic progression after first-line platinum-based chemotherapy. The objective was to describe the efficacy of vinflunine in terms of overall response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and progression-free survival (PFS) for post-ICI and ICI-naïve patients, respectively. Results: In our cohort, 61 patients (58.1%) had preceding immunotherapy before vinflunine administration, and 44 patients (41.9%) were ICI-naïve. Patients with ICI pretreatment showed an ORR of 22.4% compared to 15.6% within ICI-naïve patients (p = 0.451), and CBR was 51.0% vs. 25.0% (p = 0.020), respectively. Post-ICI patients showed longer OS (8.78 vs. 5.72 months; p = 0.467) and longer PFS (3.09 vs. 2.14 months; p = 0.105). Conclusion: This analysis supports the sequential use of vinflunine in post-ICI patients since the vinca-alkaloid retains a measurable clinical activity in these heavily pretreated patients. The therapeutic benefit may be higher than demonstrated in previous studies.

Transabdominal urological sonography covers the organs kidney and urinary bladder as well as the retroperitoneal space. As a rapid and side-effect-free point-of-care diagnostic technique, it is used in a variety of ways in the majority of patient contacts. Numerous scientific data underscore the special value of ultrasound in the primary diagnosis of almost any pathology regarding the kidney or urinary tract: In cases of urothelial or renal carcinoma, urolithiasis and urinary flow disorders, ultrasound exams are performed before more invasive or complex diagnostics are indicated. Innovative techniques, in particular contrast-enhanced ultrasound, provide a glimpse of future possibilities and make it likely that the importance of sonography in urology will continue to increase. Appropriate education and training of all practicing urologists is therefore just as indispensable as documentation and archiving of image data.Die transabdominelle urologische Sonographie umfasst die Organe Niere und Harnblase sowie den retroperitonealen Raum. Als schnelle und nebenwirkungsfreie Point-of-care-Diagnostik wird sie vielfältig und bei nahezu jedem Patientenkontakt eingesetzt. Zahlreiche wissenschaftliche Daten untermauern den besonderen Stellenwert des Ultraschalls in der Primärdiagnostik nahezu aller Pathologien von Nieren und Harnwegen: Bei Urothel- oder Nierenkarzinom, Urolithiasis und Harnabflussstörungen erfolgt zunächst die sonographische Untersuchung, bevor eine invasivere oder aufwendigere Diagnostik indiziert wird. Innovative Verfahren, insbesondere der kontrastmittelverstärkte Ultraschall, geben dabei einen Ausblick auf zukünftige Möglichkeiten und machen eine weitere Aufwertung des Stellenwerts der Sonographie in der Urologie wahrscheinlich. Die entsprechende Aus- und Weiterbildung aller praktizierenden Urologen in ihrer Schlüsselrolle als Befundersteller ist daher ebenso unverzichtbar wie Dokumentation und Archivierung der Bilddaten.

Background: Impaired kidney function increases the risk of vascular events in stroke patients, when assessed by single measurements of serum creatinine and estimated glomerular filtration rate (eGFR). Whether repeated measurements improve risk prediction in acute stroke patients is unknown. Methods: The investigator-initiated, prospective, multicenter Systematic Monitoring for Detection of Atrial Fibrillation in Patients with Acute Ischemic Stroke study randomized 3,465 acute ischemic stroke patients without known AF to usual diagnostic procedures for detecting AF or an additive Holter-ECG. eGFR was estimated by the CKD-Epi formula. Dynamics of eGFR during hospitalization was categorized as “stable ≥60ml/min”, “rising” (by at least 15% from any baseline value), “falling” (by at least 15% and baseline eGFR≥60ml/min) and “stable Results: The dynamics of eGFR were available in 1,623 patients. In 1,001 (61.7%) eGFR was “stable≥60ml/min”, in 231 (6.7%) “rising”, in 74 (4.6%) “falling”, and in 317 (19.5%) “stable Conclusions: Hospitalized ischemic stroke patients with a falling eGFR (of at least 15%, baseline ≥60ml/min) are at similar risk for recurrent vascular events or death and at higher risk for death as stroke patients with constantly reduced kidney function. Repeated estimates of eGFR may therefore improve risk prediction.