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.

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.

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.

Nomograms including the UBC® Rapid test to detect primary bladder cancer based on a multicentre dataset.

OBJECTIVES: To evaluate the clinical utility of the urinary bladder cancer antigen test UBC® Rapid for the diagnosis of bladder cancer (BC) and to develop and validate nomograms to identify patients at high risk of primary BC. PATIENTS AND METHODS: Data from 1787 patients from 13 participating centres, who were tested between 2012 and 2020, including 763 patients with BC, were analysed. Urine samples were analysed with the UBC® Rapid test. The nomograms were developed using data from 320 patients and externally validated using data from 274 patients. The diagnostic accuracy of the UBC® Rapid test was evaluated using receiver-operating characteristic curve analysis. Brier scores and calibration curves were chosen for the validation. Biopsy-proven BC was predicted using multivariate logistic regression. RESULTS: The sensitivity, specificity, and area under the curve for the UBC® Rapid test were 46.4%, 75.5% and 0.61 (95% confidence interval [CI] 0.58-0.64) for low-grade (LG) BC, and 70.5%, 75.5% and 0.73 (95% CI 0.70-0.76) for high-grade (HG) BC, respectively. Age, UBC® Rapid test results, smoking status and haematuria were identified as independent predictors of primary BC. After external validation, nomograms based on these predictors resulted in areas under the curve of 0.79 (95% CI 0.72-0.87) and 0.95 (95% CI: 0.92-0.98) for predicting LG-BC and HG-BC, respectively, showing excellent calibration associated with a higher net benefit than the UBC® Rapid test alone for low and medium risk levels in decision curve analysis. The R Shiny app allows the results to be explored interactively and can be accessed at www.blucab-index.net. CONCLUSION: The UBC® Rapid test alone has limited clinical utility for predicting the presence of BC. However, its combined use with BC risk factors including age, smoking status and haematuria provides a fast, highly accurate and non-invasive tool for screening patients for primary LG-BC and especially primary HG-BC.

Seasonal Variations in the Diagnosis of Testicular Germ Cell Tumors: A National Cancer Registry Study in Austria.

We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr-Sep) and an increase during the winter months (Oct-Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct-Dec (p = 0.008) and Jan-Mar (p < 0.001) was significantly higher compared to the months of Jul-Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.

A presumed extragonadal germ cell tumor that turned out to be a gastric cancer-a case report.

A solely retroperitoneal mass in males in combination with elevated serum Alpha-Fetoprotein (AFP) and beta-human choriogonadotropin (ß-HCG) levels is highly indicative of a metastatic testicular cancer. Although testicular cancers are rare, they represent the most common diagnosed cancer in males between 14 and 40 years. However, in cases without evidence of a primary testicular tumor, the rare diagnosis of a retroperitoneal extragonadal germ cell tumor (EGCT) must be assumed. Here, we describe the first published case of a 66-year-old man presenting with this typical clinical picture and the diagnosis of an AFP and ß-HCG producing advanced gastric cancer with retroperitoneal lymph node metastases mimicking a primary retroperitoneal EGCT. The final diagnosis was only made by gastroscopy performed after a CT-guided retroperitoneal lymph node biopsy revealed an adenocarcinoma, suggesting an upper gastrointestinal tract primary origin. However, a specific initial anamnesis and also in the primary staging, including a full-body CT-scan there was no hint for another primary tumor. Only the slightly unusual extension of the retroperitoneal mass up to the ligamentum hepatoduodenale and the pylorus, as well as the atypical age made us question our initial diagnosis. This extraordinary case is of special clinical interest to all practising physicians and once again highlights the importance of keeping rare differential diagnosis such as AFP-producing gastrointestinal tumors in mind.

The "COVID-19 Pandemic Gap" and Its Influence on Oncologic Outcomes of Bladder Cancer.

Coronavirus-19 (COVID-19)-induced effects on deferred diagnosis and treatment of bladder cancer (BC) patients are currently not clarified. The aim of this study was to evaluate outcomes of the COVID-19 pandemic by considering its effects on tumor stage and grade, and to create feasible clinical triage decisions. A retrospective single-center analysis of all patients who underwent diagnostic and surgical procedures due to BC, during January 2019 and December 2020, was performed. Due to COVID-19 lockdowns, significantly fewer (diagnostic and therapeutic) endoscopic procedures were performed in the first 6 months of 2020 compared to 2019 (p = 0.002). In patients with a primary diagnosis of BC, a significant increase of high-grade tumors (p < 0.001), as well as advanced tumor stages (p = 0.014), were noticed during 2020 in comparison to 2019. On the contrary, patients with recurrent BC undergoing risk-adapted surveillance, depending on previous tumor histology, showed no adverse outcomes regarding tumor stage and grade when comparing the pre COVID-19 era with 2020. Thus, more awareness in clinical urologic practice is mandatory to avoid adverse consequences, with increased rates of advanced and aggressive tumors in patients with primary BC. In recurrent BC, an individual risk stratification in order to avoid worse outcomes during the COVID-19 pandemic seems to be justified.

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.

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.

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 in Testicular Tumor: Is This the Right Approach for Lesions ≤ 20 mm?

Background: This study was conducted in order to analyze factors predicting malignancy in patients undergoing organ-sparing surgery (OSS) for small testicular lesions. Methods: Patients with small (£20 mm) marker-negative clinical stage I testicular tumors were managed by OSS with tumor enucleation and frozen section examination (FSE) for the past 15 years at our institution. Benign and malignant cases were compared, focusing on preoperative and postoperative lesion sizes. Results: Eighty-nine patients were enrolled in this retrospective study. Ten (11.2%) of them were treated for synchronous bilateral tumors. Sixty-seven (67.7%) of ninety-nine lesions were benign, confirming a high concordance rate (98%) between FSE and final histology. Patients with benign tumors were significantly older than patients with malignant tumors (p = 0.026), and benign tumors were detected more frequently during urologic work-up of hormone disorders (p = 0.001). Preoperative tumor size was a strong predictor of malignancy (area under the curve (AUC) = 0.726; p < 0.001). According to the Youden index, the best cutoff to predict tumor dignity was 13.5 mm, resulting in a sensitivity and specificity of 53% and 85%, respectively. No cases of local recurrence or distant metastasis were confirmed after a median follow-up of 42 months. Conclusion: Our findings are consistent with previous reports, supporting an OSS approach in small testicular tumors whenever possible. Most tumors ≤ 20 mm were benign, and in the case of malignancy, OSS with FSE and consecutive orchiectomy is oncologically safe due to the high concordance rate of FSE and final histology, thus preventing a two-stage procedure.

Real-World Evidence Data on Metastatic Renal-Cell Carcinoma Treatment in Austria: The RELACS Study.

BACKGROUND: Treatment decisions in routine clinical practice are based on reports of clinical trials, which represent highly selected populations. Limited studies reported real-world evidences representing routine clinical practices in patients with renal-cell carcinoma (RCC) in Europe. The aim of this retrospective, noninterventional chart review was to collect data on the treatment landscape for patients with advanced/metastatic RCC in routine clinical practice in a broader patient population in Austria. PATIENTS AND METHODS: Patients with advanced/metastatic RCC receiving systemic treatment between June 2010 and June 2016 across 12 centers in Austria were included. Parameters were entered into an electronic case report form from the participating sites via the application Hermesoft electronic data capture system. Progression-free survival (PFS) and overall survival (OS) were the 2 primary end points. RESULTS: The median PFS and OS were 12 months and 44 months, respectively (first-line PFS was 14 months for pazopanib and 13 months for sunitinib; first-line OS was 44 months for pazopanib and 48 months for sunitinib). Factors influencing the OS were sex, with female patients at a significantly higher risk than male patients (hazard ratio = 1.719), Eastern Cooperative Oncology Group performance status > 0 increased the risk twice (hazard ratio = 2.048), and number of metastases > 3 before the first line doubled the risk compared to metastases (hazard ratio = 2.064). CONCLUSION: OS in this retrospective chart review was considerably longer than the previous reports in real-world patients, underlining the benefit of current RCC treatment options in routine clinical practice.

Adenomatoid tumor of the testis mimicking malignant testicular cancer on multiparametric ultrasound.

BACKGROUND: Adenomatoid tumor is one of the most common histological subtypes of paratesticular cancer arising from the epididymis. In very rare cases, these tumors appear as intratesticular lesions originating in the tunica albuginea, representing a diagnostic challenge. CASE PRESENTATION: We present a case of a 51-year-old man with a small (0.9 cm) hyperechoic lesion of the left testicle mimicking testicular cancer on multiparametric ultrasound. The lesion was localized in the peripheral zone, confirming vascularization and increased stiffness on contrast-enhanced ultrasound and real-time elastography. Preoperative tumor markers and hormone levels were within normal ranges. Staging computed tomography was negative. Organ-sparing surgery with tumor enucleation and frozen section analysis was performed, confirming testicular adenomatoid tumor. CONCLUSION: Currently, no typical ultrasound features can definitively distinguish intratesticular adenomatoid tumors from malignant testicular masses. Thus, a surgical approach is almost always considered in such a case for both diagnostic and therapeutic purposes.

Increased accuracy of a novel mRNA-based urine test for bladder cancer surveillance.

OBJECTIVES: To evaluate the diagnostic accuracy of the Xpert Bladder Cancer (BC) Monitor, compared with cystoscopy and cytology in the oncological follow-up of non-muscle-invasive bladder cancer (NMIBC). MATERIAL AND METHODS: A total of 140 patients with a history of NMIBC undergoing routine surveillance at our institution were enrolled prospectively in this study (ISRCTN study registry number 37210907). Urine cytology was evaluated according to the Paris classification system. In addition, urinary specimens were analysed using the Xpert BC Monitor, which measures five target mRNAs (ABL1, CRH, IGF2, UPK1B, ANXA10) using real-time PCR. Descriptive analysis, diagnostic accuracy including sensitivity, specificity, positive (PPV) and negative predictive value (NPV), receiver-operating characteristic curve, and area under the curve (AUC) were calculated. RESULTS: The overall sensitivity (0.84) and NPV (0.93) of the Xpert BC Monitor were significantly superior to those of bladder washing cytology (0.33 and 0.76; P < 0.001). Subgroup analyses confirmed the high sensitivity of the Xpert BC Monitor even in low-grade (0.77) and pTa (0.82) disease compared with barbotage cytology (low-grade: 0.13; pTa: 0.21). The overall specificity of the Xpert BC Monitor and barbotage cytology was similar (0.91 vs 0.94; P = 0.41). Combining the Xpert BC Monitor with barbotage cytology (AUC = 0.85) did not enhance diagnostic performance compared with the performance of the Xpert BC Monitor alone (AUC = 0.87). CONCLUSION: In this study, we report for the first time that the Xpert BC Monitor, a new mRNA-based urine test, outperforms cytology with regard to sensitivity and NPV, even in low-grade and pTa tumours, with no reduction of specificity.

Urinary UBC Rapid and NMP22 Test for Bladder Cancer Surveillance in Comparison to Urinary Cytology: Results from a Prospective Single-Center Study.

Background: Non-muscle invasive bladder cancer (NMIBC) is associated with high rates of recurrence, resulting in frequent follow-up cystoscopies. We evaluated the use of two point-of-care tests - the nuclear matrix protein 22 (NMP22) and urinary bladder cancer antigen (UBC) Rapid - compared to routine follow-up in patients with a previous history of NMIBC. Methods: 31 patients with cystoscopy-verified active bladder cancer, and 44 follow-up patients without disease as confirmed by cystoscopy were prospectively enrolled. All urine samples were analyzed by voided urine and bladder washing cytology, NMP22 and UBC rapid test (qualitatively and quantitatively). The best cutoff (highest Youden index; ≥6.7 ng/ml) for the quantitative UBC was determined by receiver operating characteristic curves. Results: Voided urine and barbotage cytology resulted in a sensitivity of 25.8% and 32.3%, and a specificity of 100% and 100%, while the NMP22 showed a sensitivity and specificity of 12.9% and 100%, respectively. The qualitative and quantitative UBC Rapid revealed a sensitivity of 61.3% and 64.5%, with a specificity of 77.3% and 81.8%. Barbotage cytology and qualitative UBC test proved to be the best dual combination with the highest overall sensitivity (77.4%). In contrast to barbotage cytology alone, sensitivity increased from 21.4% to 50% for detecting low-grade tumors, and from 43.8% to 100% for high-grade cancers, but reducing specificity from 100% to 77.3%. Conclusion: Compared to urinary cytology, UBC tests alone as well as UBC tests in combination with bladder washing cytology revealed higher sensitivities in detecting low- and high-grade tumors, but at the expense of a lower specificity. Thus, currently cystoscopy cannot be replaced by any of the evaluated methods.

Effect of Urinary Cytology for Detecting Recurrence in Remnant Urothelium After Radical Cystectomy: Insights From a 10-year Cytology Database.

BACKGROUND: We evaluated the diagnostic accuracy of urinary cytology (UCy) for detecting recurrence in the remnant urothelium (RRU) after radical cystectomy (RC) for urothelial cancer. PATIENTS AND METHODS: We conducted a 10-year retrospective analysis of a prospectively collected, single-center RC database comprising 177 patients who had undergone follow-up examinations at our department with ≥ 1 available postoperative UCy specimen. UCy specimens were classified using the Papanicolaou scheme. RESULTS: In total, 957 cytology specimens were collected. Negative UCy results were noted in 927 (96.8%), atypical urothelial cells in 19 (2.0%), and suspicious/positive for malignancy in 11 (1.2%) cases. RRU was diagnosed in 16 patients (9.1%) during a mean follow-up period of 37 months (range, 1-118 months). The mean interval from RC to RRU was 34.7 months. Only 2 of 11 positive UCy specimens (18.2%) were falsely positive, for an overall sensitivity and specificity of 56.3% and 98.8% for predicting RRU, respectively. Urethral recurrence was diagnosed by UCy alone before the patients had developed symptoms in 8 of 12 cases (66.7%). Patients with clinical symptoms at the diagnosis of RRU had poorer cancer-specific survival rates than those of asymptomatic patients, although this trend was not statistically significant (P = .496). Moreover, positive UCy findings were associated with significantly lower overall survival (P < .001) and cancer-specific survival (P = .04) compared with negative UCy findings. CONCLUSION: Our results underline the predictive value of UCy in the surveillance of the remnant urothelium, with early detection of urethral recurrence before the development of clinical symptoms.