Efficacy of Elimination Diets in Eosinophilic Esophagitis: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) can be treated by proton pump inhibitors, topical corticosteroids, or dietary measures. This study systematically assessed the efficacy of 4 major dietary treatment regimens in EoE, updating the evidence presented in a meta-analysis from 2014. METHODS: Electronic databases such as PubMed, Scopus, and Web of Science, and other sources were searched up to September 2022 to identify studies on dietary treatment of EoE. Based on histologic remission criteria, the efficacy of these treatments was pooled and analyzed with respect to the type of dietary regimen: 6-food elimination diet (SFED), 4-food elimination diet (FFED), 1-food elimination diet (OFED), and a targeted elimination diet (TED). Clinical response rates, food sensitization, and efficacies for a pediatric subpopulation were calculated. Influencing variables on efficacies were estimated via meta-regression analyses. RESULTS: Thirty-four studies with 1762 patients met the inclusion criteria. The overall rate of histologic remission was 53.8% (95% CI, 48.0%-59.6%), and in the individual dietary groups was 61.3% (95% CI, 53.0%-69.3%) for SFED, 49.4% (95% CI, 32.5%-66.3%) for FFED, 51.4% (95% CI, 42.6%-60.1%) for OFED, and 45.7% (95% CI, 32.0%-59.7%) for TED. Dietary regimen and patient age did not significantly affect rates of histologic remission. The overall rate of clinical response was 80.8% (95% CI, 72.3%-88.2%), with response rates of 92.8% (95% CI, 81.2%-99.6%) for SFED, 74.1% (95% CI, 49.8%-92.6%) for FFED, 87.1% (95% CI, 58.4%-99.9%) for OFED, and 69.0% (95% CI, 50.2%85.3%) for TED. CONCLUSIONS: Dietary therapy is an effective treatment for EoE patients of any age. The current results could support a trend toward less-restrictive dietary regimens as a primary treatment option.

External validation of two mpMRI-risk calculators predicting risk of prostate cancer before biopsy.

PURPOSE: Risk calculators (RC) aim to improve prebiopsy risk stratification. Their latest versions now include multiparametric magnetic resonance imaging (mpMRI) findings. For their implementation into clinical practice, critical external validations are needed. METHODS: We retrospectively analyzed the patient data of 554 men who underwent ultrasound-guided targeted and systematic prostate biopsies at 2 centers. We validated the mpMRI-RCs of Radtke et al. (RC-R) and Alberts et al. (RC-A), previously shown to predict prostate cancer (PCa) and clinically significant PCa (csPCa). We assessed these RCs' prediction accuracy by analyzing the receiver-operating characteristics (ROC) curve and evaluated their clinical utility using Decision Curve Analysis (DCA), including Net-Benefit and Net-Reduction curves. RESULTS: We found that the Area Under the ROC Curve (AUC) for predicting PCa was 0.681 [confidence interval (CI) 95% 0.635-0.727] for RC-A. The AUCs for predicting csPCa were 0.635 (CI 95% 0.583-0.686) for RC-A and 0.676 (CI 95% 0.627-0.725) for RC-R. For example, at a risk threshold of 12%, RC-A needs to assess 334 and RC-R 500 patients to detect one additional true positive PCa or csPCa patient, respectively. At the same risk threshold of 12%, RC-A only needs to assess 6 and RC-R 16 patients to detect one additional true negative PCa or csPCa patient. CONCLUSION: The mpMRI-RCs, RC-R and RC-A, are robust and valuable tools for patient counseling. Although they do not improve PCa and csPCa detection rates by a clinically meaningful margin, they aid in avoiding unnecessary prostate biopsies. Their implementation could reduce overdiagnosis and reduce PCa screening morbidity.

Sex-specific hormone changes during immunotherapy and its influence on survival in metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is a highly vascularized and immunogenic tumor, being an ideal candidate for checkpoint blockade-based immunotherapy. Accordingly, checkpoint inhibitors have demonstrated clinical efficacy in patients with metastatic RCC (mRCC). Sex-specific differences in cancer immunotherapy may be explained by the interaction of sex hormone signaling, genetic and environmental factors, affecting the innate and adaptive immune response in men and women in different ways. The aim of this prospective study was to monitor for the first time changes in sex hormones including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio and 17-ß-estradiol (E2) in 22 mRCC patients (12 male and 10 female) receiving nivolumab therapy. In contrast to female patients, male patients showed a significant increase in E2 (p = 0.006) and LH/FSH ratio (p = 0.013) from the beginning of nivolumab therapy to week 12 of follow-up. Moreover, survival analysis revealed a significant negative association between LH/FSH ratio and progression-free survival (PFS) (p = 0.022) as well as between therapy response (p = 0.009) in males compared to females at interim evaluation (week 6/8). Our findings may therefore be the first reference to sex hormone changes during immunotherapy.

Lynch Syndrome: Its Impact on Urothelial Carcinoma.

Lynch syndrome, known as hereditary nonpolyposis colorectal cancer (HNPCC), is an autosomal-dominant familial cancer syndrome with an increased risk for urothelial cancer (UC). Mismatch repair (MMR) deficiency, due to pathogenic variants in MLH1, MSH2, MSH6, and PMS2, and microsatellite instability, are known for development of Lynch syndrome (LS) associated carcinogenesis. UC is the third most common cancer type in LS-associated tumors. The diversity of germline variants in the affected MMR genes and their following subsequent function loss might be responsible for the variation in cancer risk, suggesting an increased risk of developing UC in MSH2 mutation carriers. In this review, we will focus on LS-associated UC of the upper urinary tract (UUT) and bladder, their germline profiles, and outcomes compared to sporadic UC, the impact of genetic testing, as well as urological follow-up strategies in LS. In addition, we present a case of metastatic LS-associated UC of the UUT and bladder, achieving complete response during checkpoint inhibition since more than 2 years.

Organ-sparing surgery of penile cancer: higher rate of local recurrence yet no impact on overall survival.

PURPOSE: To report on the oncological outcome of organ-sparing surgery (OSS) compared to (total or partial) penectomy regarding recurrence patterns and survival in squamous cell carcinoma (SCC) of the penis. METHODS: This was a retrospective study of all patients with penile SCC and eligible follow-up data of at least 2 years at our institution. Patients with tumors staged ≥ pT1G2 underwent invasive lymph node (LN) staging by dynamic sentinel-node biopsy or modified inguinal lymphadenectomy. Radical inguinal lymphadenectomy was performed when LNs were palpable at diagnosis and in those with a positive LN status after invasive nodal staging. Follow-up visits were assessed, and local, regional and distant recurrences were defined and analyzed. RESULTS: 55 patients were identified with a mean follow-up of 63.7 months. Surgical management was OSS in 26 patients (47.2%) and partial or total penectomy in 29 cases (52.8%). Histopathological staging was: pTis (12.7%), pTa (16.3%), pT1a (18.2%), pT1b (5.5%), pT2 (29.1%) and pT3 (18.2%), respectively. Patients in the penectomy group were significantly older (mean 68 vs. 62 years; p = 0.026) with a higher rate of advanced tumor stage (≥ pT2: 44.8% vs. 11.5%; p = 0.002). The local recurrence rate was 42.3% (n = 11) following OSS compared to 10.3% (n = 3) after penectomy (p = 0.007). Kaplan-Meier curves showed no significant differences between the two groups regarding metastasis-free and overall survival. CONCLUSIONS: OSS is associated with a higher local recurrence rate compared to penectomy, yet it has no negative impact on overall and metastasis-free survival.

The influence of sex hormones on renal cell carcinoma.

Kidney cancer is a common malignancy that constitutes around 5% of all cancer cases. Males are twice as likely to acquire renal cell carcinoma (RCC) compared to females and experience a higher rate of mortality. These disparities indicate that sex hormone (SH)-dependent pathways may have an impact on the aetiology and pathophysiology of RCC. Examination of SH involvement in conventional signalling pathways, as well as genetics and genomics, especially the involvement of ribonucleic acid, reveal further insights into sex-related differences. An understanding of SHs and their influence on kidney cancer is essential to offer patients individualized medicine that would better meet their needs in terms of prevention, diagnosis and treatment. This review presents the understanding of sex-related differences in the clinical manifestation of kidney cancer patients and the underlying biological processes.

Individualised flow-controlled ventilation reduces applied mechanical power and improves ventilation efficiency in a porcine intra-abdominal hypertension model.

BACKGROUND: Aim of this study was to evaluate feasibility and effects of individualised flow-controlled ventilation (FCV), based on compliance guided pressure settings, compared to standard of pressure-controlled ventilation (PCV) in a porcine intra-abdominal hypertension (IAH) model. The primary aim of this study was to investigate oxygenation. Secondary aims were to assess respiratory and metabolic variables and lung tissue aeration. METHODS: Pigs were randomly assigned to FCV (n = 9) and PCV (n = 9). IAH was induced by insufflation of air into the abdomen to induce IAH grades ranging from 0 to 3. At each IAH grade FCV was undertaken using compliance guided pressure settings, or PCV (n = 9) was undertaken with the positive end-expiratory pressure titrated for maximum compliance and the peak pressure set to achieve a tidal volume of 7 ml/kg. Gas exchange, ventilator settings and derived formulas were recorded at two timepoints for each grade of IAH. Lung aeration was assessed by a computed tomography scan at IAH grade 3. RESULTS: All 18 pigs (median weight 54 kg [IQR 51-67]) completed the observation period of 4 h. Oxygenation was comparable at each IAH grade, but a significantly lower minute volume was required to secure normocapnia in FCV at all IAH grades (7.6 vs. 14.4, MD - 6.8 (95% CI - 8.5 to - 5.2) l/min; p < 0.001). There was also a significant reduction of applied mechanical power being most evident at IAH grade 3 (25.9 vs. 57.6, MD - 31.7 (95% CI - 39.7 to - 23.7) J/min; p < 0.001). Analysis of Hounsfield unit distribution of the computed tomography scans revealed a significant reduction in non- (5 vs. 8, MD - 3 (95% CI - 6 to 0) %; p = 0.032) and poorly-aerated lung tissue (7 vs. 15, MD - 6 (95% CI - 13 to - 3) %, p = 0.002) for FCV. Concomitantly, normally-aerated lung tissue was significantly increased (84 vs. 76, MD 8 (95% CI 2 to 15) %; p = 0.011). CONCLUSIONS: Individualised FCV showed similar oxygenation but required a significantly lower minute volume for CO2-removal, which led to a remarkable reduction of applied mechanical power. Additionally, there was a shift from non- and poorly-aerated lung tissue to normally-aerated lung tissue in FCV compared to PCV.

Optimization of postoperative surveillance protocols in upper tract urothelial cancer: A retrospective cohort study.

Upper tract urothelial carcinoma (UTUC) is an aggressive disease that is managed by radical or organ-sparing surgery. High recurrence rates require early detection and strict follow-up (FU) protocols. Recommendations are assigned to a low level of evidence. Our aim was to identify time-to-tumor recurrence, analyze the temporal relation to recommended FU regimens, and provide a critical proposal for further surveillance. This retrospective study included 54 patients receiving radical nephroureterectomy (RNU) in high-risk UTUC and 14 patients assigned to kidney-sparing surgery (KSS) with low-risk disease. FU surveillance protocols consisted of close intervals irrespective of the received type of surgery. In total, 68 patients were included with a median FU of 23 months. Mean overall survival (OS) was significantly shorter in RNU compared to KSS (P = .027). Recurrence in the bladder and/or upper urinary tract (UUT) was 57.1% in KSS and 38.9% after RNU (P = .241). Mean recurrence-free survival (RFS) was significantly shorter in RNU patients compared to KSS (22.4 vs. 47.9 months, P = .013), and 76.2% of the recurrences in the RNU group occurred in the first postoperative year. UUT recurrence was diagnosed after a median of 3.0 (RNU) and 25.0 (KSS) months. There was a frequent onset of metastases in the RNU group, with 85.7% in the first year compared to the KSS group with 50%. Multivariable regression analysis showed that the tumor stage was the parameter independently related to OS (P = .002), RFS (P = .008), and metastasis-free survival (MFS, P = .002). In conclusion, surveillance of UTUC should be adapted to real-time occurrence patterns. Strict imaging protocols are recommended in the first two years irrespective of the method of surgery. As recurrence is equally distributed over the years after KSS, cystoscopy should be offered regularly for five years and diagnostic URS for three years. After RNU, cystoscopies should be decreased to yearly intervals after year three. Contralateral UUT should also be examined after RNU.

CXCR3 Expression Is Associated with Advanced Tumor Stage and Grade Influencing Survival after Surgery of Localised Renal Cell Carcinoma.

BACKGROUND: Surgery is the standard treatment in localized renal cell carcinoma (RCC). Pembrolizumab is now approved for adjuvant therapy in high-risk patients. However, inhomogeneity of studies gives ambiguity which patient benefit most from adjuvant therapy. A high infiltration of CD8+ T cells is known to be linked with poor prognosis in RCC. CXCR3 is a key player of CD8+ T cell differentiation and infiltration. We aimed to evaluate CXCR3 as a potential marker for predicting recurrence. METHODS: CXCR3 and immune cell subsets (CD4, CD8, CD68 and FoXP3) were measured on RCC samples by multiplex immunofluorescence (mIF) staining. Cellular localization of CXCR3 was evaluated using single-cell RNA analysis on a publicly available dataset. RESULTS: Tumor samples of 42 RCC patients were analyzed, from which 59.5% were classified as clear-cell RCC and of which 20 had recurrence. Single-cell RNA analysis revealed that CXCR3 was predominantly expressed in intratumoral T cells and dendritic cells. CXCR3 expression was higher in advanced tumors stages (p = 0.0044) and grade (p = 0.0518), correlating significantly with a higher CD8+ T cell expression (p < 0.001). Patients with CXCR3high RCCs had also a significant shorter RFS compared to CXCR3low (median: 78 vs. 147 months, p = 0.0213). In addition, also tumor stage pT3/4 (p < 0.0001) as well as grade G3/4 (p = 0.0008) negatively influenced RFS. CONCLUSION: CXCR3high cell density was associated with high T cell infiltration and advanced tumor stage, worsening RFS in surgically resected RCC patients. Beside its prognostic value, CXCR3 might be a predictive biomarker to guide therapy decision for adjuvant therapy in localized RCC.

Sex hormones influence survival of patients with metastatic urothelial carcinoma undergoing immune checkpoint therapy.

INTRODUCTION: Clinical trials investigating efficacy of immune checkpoint inhibitors (ICI) revealed sex-specific divergent outcomes in urothelial cancer (UC), suggesting that sex hormones might play an important role in gender-specific dimorphisms of response upon ICI. However, further clinical investigations are still needed to understand the influence of sex hormones in UC. The aim of this study was to get further insights on the prognostic and predictive value of sex hormone levels in patients with metastatic UC (mUC) who underwent ICI. MATERIAL AND METHODS: Sex hormone levels of patients with mUC including luteinizing hormone (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, prolactin, testosterone and 17ß-estradiol (E2) were evaluated at baseline and during ICI at 6/8 weeks and 12/14 weeks. RESULTS: Twenty-eight patients (10 women, 18 men) with a median age of 70 years were included. Metastatic disease was confirmed in 21 patients (75%) after radical cystectomy while seven patients showed mUC at first diagnosis. Twelve patients (42.8%) received first line and 16 patients second line pembrolizumab. The objective response rate (ORR) was 39% (CR in 7%). The median progression-free survival (PFS) and overall survival (OS) was 5.5 and 20 months. Focusing on changes of sex hormone levels during ICI, a significant increase in FSH levels and decrease of the LH/FSH ratio was noticed in responders (p = 0.035), yet without sex-specific significance. When adjusted for sex and treatment line, a significant increase of FSH levels was confirmed in men during second line pembrolizumab. Focusing on baseline levels, LH/FSH ratio was significantly higher in female responders (p = 0.043) compared to non-responders. In women, increased LH levels and LH/FSH ratio were associated with better PFS (p = 0.014 for LH, p = 0.016 for LH/FSH ratio) and OS (p = 0.026 and p = 0.018). In male patients, increased E2 levels were linked with improved PFS (p < 0.001) and OS (p = 0.039). CONCLUSION: Increased LH and LH/FSH values in women as well as high E2 levels in men were significant predictors of better survival. Elevated LH/FSH ratio was predictive of better response to ICI in women. These results show first clinical evidence of the potential role of sex hormones as prognostic and predictive biomarker in mUC. Further prospective analyses are needed to corroborate our findings.

Urothelial carcinoma (UC) presents as aggressive disease with a greater incidence in men, yet a more aggressive course of disease in women. Patients with metastatic UC receive a chemotherapy regimen as the gold standard, based on an included platin substance. In the case of having contraindications to chemotherapy, checkpoint immunotherapy, priming the immune system to the tumor, is the treatment of choice. Furthermore, immunotherapy is used as second line therapy in progressive disease after chemotherapy and as maintenance therapy in stable tumor conditions after completing the chemotherapy regimen.Evidence shows that sex hormones of the hypothalamus­hypophysis axis influence development and course of UC. The sex hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate estrogen (E2) production with a negative feedback function on the LH and FSH secretion. High levels of E2 present with a protective effect against UC. Sex has furthermore shown to predict potential response to immunotherapy. This study therefore focused on monitoring and correlating changes of sex hormone levels in 28 patients during therapy with checkpoint inhibitors.This first study assessing changes in sex hormones and the influence of baseline sex hormone values on survival in UC shows that responders to immunotherapy had significantly increased FSH levels. FSH furthermore increased in male patients receiving second line immunotherapy. High values of LH and a high LH/FSH ratio at baseline correlated with better overall survival in female patients. High E2 levels were indicative of better survival in male patients. The study results represent first suggestive prognostic and predictive results to the response of immunotherapy in UC.

Targeting c-Met to Improve Immune Checkpoint Inhibition in Metastatic Renal Cell Carcinoma.

c-Met inhibition has direct antitumor effects on proliferation, angiogenesis, and metastasis, and indirect antitumor effects via prevention of the induction of immunosuppressive mechanisms (PD-L1, TGFß, IDO1). c-Met inhibition is key to overcome resistance to immune checkpoint inhibition and to maximize the efficacy of immunotherapy.

Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma.

Fumarate hydratase (FH) - deficient renal cell carcinoma (FHdRCC) is a rare aggressive subtype of RCC caused by a germline or sporadic loss-of-function mutation in the FH gene. Here, we summarize how FH deficiency results in the accumulation of fumarate, which in turn leads to activation of hypoxia-inducible factor (HIF) through inhibition of prolyl hydroxylases. HIF promotes tumorigenesis by orchestrating a metabolic switch to glycolysis even under normoxia, a phenomenon well-known as the Warburg effect. HIF activates the transcription of many genes, including vascular endothelial growth factor (VEGF). Crosstalk between HIF and epidermal growth factor receptor (EGFR) has also been described as a tumor-promoting mechanism. In this review we discuss therapeutic options for FHdRCC with a focus on anti-angiogenesis and EGFR-blockade. We also address potential targets that arise within the metabolic escape routes taken by FH-deficient cells for cell growth and survival.

Multiparametric ultrasound in torsion of the testicular appendages: a reliable diagnostic tool?

AIM: Torsion of the testicular appendages represents the most common cause of an acute scrotum in prepubertal boys. Its sonographic appearances on gray-scale US and color Doppler US have already been presented in several studies. The aim of this analysis was to expand those already established techniques with strain elastography and thus present typical features of this entity on multiparametric US. MATERIAL AND METHODS: Retrospective analysis of all patients presented to the urological department with an acute scrotum between January 2018 and July 2020 identified eleven patients 6-17 years old (mean, 11.1 years), discharged with the diagnosis torsion of the testicular appendages that were examined with a high-end ultrasound device. Results: On gray-scale US all patients showed a round lesion with heterogenous echotexture adjacent to the upper pole of the testis/epididymis with a diameter of 4 to 11.1 mm (mean, 7.7 mm). Scrotal skin thickening and a concomitant hydrocele were found in 9 (81.8%) and 7 (63.6%) cases, respectively. On color Doppler images, all torsed appendages were avascular and in 9 (81.8%) patients we observed hyperemia of the adjacent epididymis. Strain elastography showed increased tissue stiffness in all documented images. CONCLUSION: Torsion of the testicular appendages has a set of features on multiparametric US. Awareness of this features can facilitate diagnosis of torsion of the testicular appendages and reduce unnecessary surgicalscrotal exploration or unwarranted antibiotic treatment.

HUS1 as a Potential Therapeutic Target in Urothelial Cancer.

Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based DNA adducts and to repair chemotherapy-induced DNA lesions by various DNA repair proteins. The Rad9-Rad1-HUS1 complex that is loaded onto DNA at sites of damage is involved in checkpoint activation as well as DNA repair. Here, we addressed for the first time the potential influence of HUS1 expression in urothelial carcinogenesis (using two human basal urothelial cancer cell lines UM-UC-3 and HT1197) and its role as a potential therapeutic target for predicting responses to platinum-based chemotherapy. Specific inhibition of HUS1 expression in both cell lines was achieved by specific siRNA and validated by Western blot. In order to define the possible importance of HUS1 in the regulation of cellular proliferation, parental and resistant cells were treated with increasing concentrations of either control or HUS1 siRNA. HUS1 protein expression was observed in both human basal urothelial cancer cell lines UM-UC-3 and HT1197. In cisplatin-sensitive cells, knock-down of HUS1 inhibited cellular proliferation in the presence of cisplatin. On the contrary, knock-down of HUS1 in resistant cells did not result in a re-sensitization to cisplatin. Finally, RNAseq data from the Cancer Genome Atlas provided evidence that HUS1 expression is a significant prognostic factor for poor survival in UC patients. In summary, HUS1 may acts as an oncogene in UC and might be a key determinant of the cellular response to cisplatin-based chemotherapy.

Do we need repeated CT imaging in uncomplicated blunt renal injuries? Experiences of a high-volume urological trauma centre.

BACKGROUND: Current guidelines recommend repeat computed tomography (CT) imaging in high-grade blunt renal injury within 48-96 h, yet diagnostic value and clinical significance remain controversial. The aim of this work was to determine the possible gain of CT re-imaging in uncomplicated patients with blunt renal trauma at 48 h after injury, presenting one of the largest case series. METHODS: A retrospective database of patients admitted to our centre with isolated blunt renal trauma due to sporting injuries was analysed for a period of 20 years (2000-2020). We included only patients who underwent repeat imaging at 48 h after trauma irrespective of AAST renal injury grading (grade 1-5) and initial management. The primary outcome was intervention rates after CT imaging at 48 h in uncomplicated patients versus CT scan at the time of clinical symptoms. RESULTS: A total of 280 patients (mean age: 37.8 years; 244 (87.1%) male) with repeat CT after 48 h were included. 150 (53.6%) patients were classified as low-grade (grade 1-3) and 130 (46.4%) as high-grade (grade 4-5) trauma. Immediate intervention at trauma was necessary in 59 (21.1%) patients with high-grade injuries: minimally invasive therapy in 48 (81.4%) and open surgery in 11 (18.6%) patients, respectively. In only 16 (5.7%) cases, intervention was performed based on CT re-imaging at 48 h (low-grade vs. high-grade: 3.3% vs. 8.5%; p = 0.075). On the contrary, intervention rate due to clinical symptoms was 12.5% (n = 35). Onset of clinical progress was on average (range) 5.3 (1-17) days post trauma. High-grade trauma (odds ratio [OR]grade 4 vs. grade 3, 14.62; p < 0.001; ORgrade 5 vs. grade 3, 22.88, p = 0.004) and intervention performed at the day of trauma (OR 3.22; p = 0.014) were powerful predictors of occurrence of clinical progress. CONCLUSION: Our data suggest that routine CT imaging 48 h post trauma can be safely omitted for patients with low- and high-grade blunt renal injury as long as they remain clinically stable. Patients with high-grade renal injury have the highest risk for clinical progress; thus, close surveillance should be considered especially in this group.

Expression of ADAM Proteases in Bladder Cancer Patients with BCG Failure: A Pilot Study.

Although Bacillus Calmette Guérin (BCG) remains a mainstay of adjuvant treatment in high-risk, non-muscle-invasive bladder cancer, BCG failure occurs in up to 40% of patients, with radical cystectomy (RC) as the inevitable therapeutic consequence. Current data suggest that PD-L1 immunosuppressive signaling is responsible for BCG failure, supporting the therapeutic rationale of combining checkpoint inhibitors with BCG. To address the immune cascade in 19 RC specimens obtained after BCG failure, we applied a small immunohistochemical (IHC) panel consisting of selected markers (PD-L1, GATA-3, a disintegrin and metalloproteinase (ADAM) proteases, IL-10/IL-10R). A modified quick score was used for IHC semi-quantification of these markers in tumor cells (TC) and immune cells (IC) within two different regions: muscle-invasive bladder cancer (MIBC) and primary/concurrent carcinoma in situ (CIS). Contrary to expectation, PD-L1 was consistently low, irrespective of tumor region and cell type. Intriguingly, expression of ADAM17, which has been reported to release membrane-bound PD-L1, was high in both tumor regions and cell types. Moreover, expression of GATA3, IL-10, and IL-10R was also increased, indicative of a generally immunosuppressive tumor microenvironment in BCG failure. ADAM10 expression was associated with advanced tumor disease at RC. Our findings raise the possibility that ADAM proteases may cleave PD-L1 from the surface of bladder TC and possibly also from IC. Therefore, IHC assessment of PD-L1 expression seems to be insufficient and should be supplemented by ADAM10/17 in patients with BCG failure.

Rare, but Severe: Vasculitis and Checkpoint Inhibitors.

In the last years, immunotherapy has become a mainstay of cancer treatment. Owing to its increasing application in clinical practice, novel and rare, but severe, immune-related adverse events such as vasculitis are now being described more frequently. Vasculitis occurs as part of a primary immune disorder but might be induced additionally by substances such as checkpoint inhibitors, which boost the immune system, and thus can also appear as an immune-related adverse event. Several lines of evidence indicate that checkpoint proteins such as programmed death-1 (PD-1) play a major role in the pathophysiology of vasculitis. Such immune checkpoints serve to prevent autoimmunity and to maintain tolerance. We present a case of pronounced vasculitis in a patient with metastatic urothelial carcinoma who received pembrolizumab, and discuss potential pathomechanisms regarding how checkpoint inhibitors can mediate immune-related vascular toxicity. PATIENT SUMMARY: In this report, we looked at potential interactions between checkpoint inhibitors and immune-associated vascular adverse events. Immunotherapy-induced changes of the immune status can favor the occurrence of vascular disease, being fatal in most cases. We conclude that the risk of progressive vascular damage and identification of patients with pre-existing vascular disease should always be borne in mind when treating patients with immunotherapy.

Brunn's Cyst Inducing Persistent Lower Urinary Tract Symptoms in a Young Man: A Case Report.

Background: Lower urinary tract symptoms (LUTS) are mostly caused by hyperplasia of the prostate in the elderly generation or are the consequence of a urethral stricture in young men. Proliferated Brunn's cell nests forming cysts at the bladder neck can likewise result in similar symptoms and can, therefore, often be overlooked. Case Presentation: The case describes a 46-year-old man presenting with the typical LUTS of urgency and pathologic residual urine volume of 350 mL. Sonographic and cystoscopic diagnostics showed a cystic lesion located at the bladder neck, acting as a ball valve mechanism. Transurethral deroofing and resection of the cyst resulted in an immediate resolution of LUTS and a symptom-free patient with no residual urine at follow-up. Conclusion: The presence of a Brunn's cyst is rare but should be kept in mind as a differential diagnosis of LUTS in young men.

Effects of head-up vs. supine CPR on cerebral oxygenation and cerebral metabolism - a prospective, randomized porcine study.

BACKGROUND: Recent studies have shown that during cardiopulmonary resuscitation (CPR) head-up position (HUP) as compared to standard supine position (SUP) decreases intracranial pressure (ICP) and increases cerebral perfusion pressure (CPP). The impact of this manoeuvre on brain oxygenation and metabolism is not clear. We therefore investigated HUP as compared to SUP during basic life support (BLS) CPR for their effect on brain oxygenation and metabolism. METHODS: Twenty pigs were anaesthetized and instrumented. After 8 min of cardiac arrest (CA) pigs were randomized to either HUP or SUP and resuscitated mechanically for 20 min. Mean arterial pressure (MAP), ICP, CPP, cerebral regional oxygen saturation (rSO2) and brain tissue oxygen tension (PbtO2) were measured at baseline, after CA and every 5 min during CPR. Cerebral venous oxygen saturation (ScvO2) was measured at baseline, after CA and after 20 min of CPR. Cerebral microdialysis parameters, e.g. lactate/pyruvate ratio (L/P ratio) were taken at baseline and the end of the experiment. RESULTS: ICP was significantly lower in HUP compared to SUP animals after 5 min (18.0 ±â€¯4.5 vs. 24.1 ±â€¯5.2 mmHg; p = 0.033) and 20 min (12.0 ±â€¯3.4 vs. 17.8 ±â€¯4.3 mmHg; p = 0.023) of CPR. Accordingly, CPP was significantly higher in the HUP group after 5 min (11.2 ±â€¯9.5 vs. 1.0 ±â€¯9.2 mmHg; p = 0.045) and 20 min (3.4 ±â€¯6.4 vs. -3.8 ±â€¯2.8 mmHg; p = 0.023) of CPR. However, no difference was found in rSO2, PbtO2, ScvO2 and L/P ratio between groups after 20 min of CPR. CONCLUSION: In this animal model of BLS CPR, HUP as compared to SUP did not improve cerebral oxygenation or metabolism.