VOC-based detection of prostate cancer using an electronic nose and ion mobility spectrometry: A novel urine-based approach.

BACKGROUND: Many diseases leave behind specific metabolites which can be detected from breath and urine as volatile organic compounds (VOC). Our group previously described VOC-based methods for the detection of bladder cancer and urinary tract infections. This study investigated whether prostate cancer can be diagnosed from VOCs in urine headspace. METHODS: For this pilot study, mid-stream urine samples were collected from 56 patients with histologically confirmed prostate cancer. A control group was formed with 53 healthy male volunteers matched for age who had recently undergone a negative screening by prostate-specific antigen (PSA) and digital rectal exam. Headspace measurements were performed with the electronic nose Cyranose 320TM. Statistical comparison was performed using principal component analysis, calculating Mahalanobis distance, and linear discriminant analysis. Further measurements were carried out with ion mobility spectrometry (IMS) to compare detection accuracy and to identify potential individual analytes. Bonferroni correction was applied for multiple testing. RESULTS: The electronic nose yielded a sensitivity of 77% and specificity of 62%. Mahalanobis distance was 0.964, which is indicative of limited group separation. IMS identified a total of 38 individual analytical peaks, two of which showed significant differences between groups (p < 0.05). To discriminate between tumor and controls, a decision tree with nine steps was generated. This model led to a sensitivity of 98% and specificity of 100%. CONCLUSIONS: VOC-based detection of prostate cancer seems feasible in principle. While the first results with an electronic nose show some limitations, the approach can compete with other urine-based marker systems. However, it seems less reliable than PSA testing. IMS is more accurate than the electronic nose with promising sensitivity and specificity, which warrants further research. The individual relevant metabolites identified by IMS should further be characterized using gas chromatography/mass spectrometry to facilitate potential targeted rapid testing.

Pilot study for bladder cancer detection with volatile organic compounds using ion mobility spectrometry: a novel urine-based approach.

PURPOSE: Despite many efforts, no reliable urinary marker system has so far shown the potential to substitute cystoscopy. Measuring volatile organic compounds (VOCs) from urine is a promising alternative. VOCs are metabolic products which can be measured from the headspace of urine samples. Previous studies confirmed that the urine of bladder tumor patients has a different VOC profile than healthy controls. In this pilot study, the feasibility of discriminating VOCs from urine of bladder cancer patients from that of healthy control subjects was investigated. Aim of this study was to investigate whether VOC-based diagnosis of bladder cancer from urine samples is feasible using multicapillary column ion mobility spectrometry (MCC/IMS) and to identify potential molecular correlates to the relevant analytes. METHODS: Headspace measurements of urine samples of 30 patients with confirmed transitional cell carcinoma (TCC) and 30 healthy controls were performed using MCC/IMS. In the results of the measurements, peaks showing significant differences between both groups were identified and implemented into a decision tree with respect to achieve group separation. Molecular correlates were predicted using a pre-defined dataset. RESULTS: Eight peaks with significantly differing intensity were identified, 5 of which were highly significant. Using a six-step decision tree, MCC/IMS showed a sensitivity of 90% and specificity of 100% in group separation. CONCLUSION: VOC-based detection of bladder cancer is feasible. MCC/IMS is a suitable method for urine-based diagnosis and should be further validated. The molecular characteristics and metabolic background of the analytes require further workup.

Enhancing Human Papillomavirus Vaccination Rates through Better Knowledge? Insights from a Survey among German Medical Students.

INTRODUCTION: Vaccination against human papillomavirus (HPV) significantly reduces the risk for malignant diseases like cervix, anal, or penile cancer. However, although vaccination rates are rising, they are still too low mirroring a lack of disease awareness in the community. This study aims to evaluate knowledge about HPV vaccination as well as the vaccination rate among German medical students. MATERIAL AND METHODS: Medical students were surveyed during a German medical students' sports event. The self-designed survey on HPV vaccination consisted of 24 items. The data collection was anonymous. RESULTS: Among 974 participating medical students 64.9% (632) were women, 335 (34.4%) were male and 7 (0.7%) were nonbinary. Mean age was 23.1 ± 2.7 (± standard deviation; range 18-35) years. Respondents had studied mean 6.6 ± 3.3 (1-16) semesters and 39.4% (383) had completed medical education in urology. 613 (64%) respondents reported that HPV had been discussed during their studies. 7.6% (74) had never heard of HPV. In a multivariate model female gender, the knowledge about HPV, and having worked on the topic were significantly associated with being HPV-vaccinated. Older students were vaccinated less likely. CONCLUSIONS: Better knowledge and having worked on the topic of HPV were associated with a higher vaccination rate. However, even in this highly selected group the knowledge about HPV vaccination was low. Consequently, more information and awareness campaigns on HPV vaccination are needed in Germany to increase vaccination rates.

Adoption of Lutetium-177 PSMA radioligand therapy for metastatic castration resistant prostate cancer: a total population analysis in Germany from 2016 to 2020.

PURPOSE: This study is to investigate the adoption and current trends of Lutetium-177 PSMA RLT for mCRPC in Germany. METHODS: We analyzed data from the reimbursement.INFO tool based on German hospitals' quality reports for Lutetium-177 PSMA RLT from 2016 to 2020 and from the nationwide German hospital billing database (Destatis) for general therapy with open radionuclides in combination with prostate cancer from 2006 to 2020. For validation of these billing data, we included the 177Lu-PSMA RLT cycles from two participating institutions from 2016 to 2020. For detection of trends over time we applied linear regression models. RESULTS: General therapy with open radionuclides increased from 2006 to 2020. We identified a total of 12,553 177Lu-PSMA RLT cycles. The number of 177Lu-PSMA RLTs steadily increased from a total of 1026 therapies in 2016 to 3328 therapies in 2020 (+ 576 RLT/year; p < 0.005). In 2016, 25 departments of nuclear medicine offered this treatment, which increased to 44 nuclear medicine departments in 2020. In 2016, 16% of nuclear medicine departments (4/25) performed more than 100 177Lu-PSMA RLTs, which increased to 36% (16/44) in 2020 (p < 0.005). In 2016, 88% (22/25) of 177Lu-PSMA RLTs were performed at a university hospital, which decreased to 70% (31/44) in 2020. The proportion of patients older than 65 years receiving 177Lu-PSMA RLT increased from 78% in 2016 to 81% in 2020. CONCLUSION: Treatment of mCRPC with 177Lu-PSMA RLT has been rapidly increasing in Germany in the recent years providing an additional therapy option. This development is remarkable, because of outstanding formal EMA approval.

Focal Therapy for Renal Cancer: Comparative Trends in the USA and Germany from 2006 to 2020 and Analysis of the German Health Care Landscape.

INTRODUCTION: The aim of the study was to investigate trends of FT for in-patient treatment of renal RCC in the USA and Germany. METHODS: We analyzed the SEER database for the USA and the nationwide German hospital billing database each from 2006 to 2019 for a RCC diagnosis in combination with FT, radical nephrectomy, and partial nephrectomy. FT was defined as radiofrequency ablation (RFA) or cryotherapy. Linear regression analysis was performed to detect changes over time. RESULTS: For the USA, we included 7,318 FT cases. The share of FT increased from 2.4% in 2006 to 6.4% in 2019 (p < 0.001). For Germany, we identified 2,920 FT cases. The share of FT increased from 0.7% in 2006 to 2.0% in 2019 (p < 0.001). The number of RFAs in the USA steadily increased by 227% from a total of 93 in 2006 to 304 in 2019 while the number of cryotherapies in the USA steadily increased by 289% from a total of 127 in 2006 to 494 in 2019 (p < 0.001). The number of RFAs in Germany increased by 344% from a total of 59 in 2006 to 262 in 2019 (p < 0.001) while the number of cryotherapies steadily increased by 43% from a total of 54 in 2006 to 77 in 2019 (p < 0.001). In Germany, RFA is significantly more performed than cryotherapy while in the USA cryotherapy is more frequently applied. CONCLUSION: We observed a constant increase of FT in the USA and Germany for RCC in-patient treatment with a higher share in the USA.

End-of-life wishes and care planning for patients with advanced skin cancer.

BACKGROUND: Patients with advanced or metastatic skin cancer have a limited life expectancy and the majority die as a result of the tumor despite modern treatment options. The preferences of these patients concerning care during their last phase of life are currently unknown. PATIENTS AND METHODS: 150 patients with advanced skin cancer (AJCC/UICC stage III or IV) were interviewed using a structured questionnaire. RESULTS: 75% of the respondents wished to die in their domestic environment, although a more advanced tumor stage and increased reflection upon end-of-life care lead away from this wish. However, only 42% reported having communicated this wish to someone else. 55% of the respondents had completed advance directives, while younger patients did this significantly less often (95% CI: 0.11-0.56; p  =  0.001). The majority of patients (62%) would like to have discussions about possibilities for end-of-life care with the attending dermato-oncologist. CONCLUSIONS: Although the moment of death is unpredictable, early initiation of end-of-life advance care planning appears prudent. The attending dermato-oncologists should take the initiative to raise the subject with their patients during routine control visits. In this context, it may be useful to present available care options to patients and relatives and to design strategies for the event of deteriorating health.

Alternative- and focal therapy trends for prostate cancer: a total population analysis of in-patient treatments in Germany from 2006 to 2019.

PURPOSE: Focal therapy (FT) offers an alternative approach for prostate cancer (PCa) treatment in selected patients. However, little is known on its actual establishment in health care reality. PATIENTS AND METHODS: We defined FT as high-intensity focused ultrasound (HIFU), hyperthermia ablation, cryotherapy, transurethral ultrasound ablation (TULSA) or vascular-targeted photodynamic therapy (VTP) TOOKAD®. We analyzed the nationwide German hospital billing database for a PCa diagnosis in combination with FT. For analyses on the hospital level, we used the reimbursement.INFO tool based on hospitals' quality reports. The study period was 2006 to 2019. RESULTS: We identified 23,677 cases of FT from 2006 to 2019. Considering all PCa cases with surgery, radiotherapy or FT, the share of FT was stable at 4%. The annual caseload of FT increased to a maximum of 2653 cases in 2008 (p < 0.001) and then decreased to 1182 cases in 2014 (p < 0.001). Since 2015, the cases of FT remained on a plateau around 1400 cases per year. The share of HIFU was stable at 92-96% from 2006 to 2017 and decreased thereafter to 75% in 2019 (p = 0.015). In 2019, VTP-TOOKAD® increased to 11.5% and TULSA to 6%. In 2006, 21% (62/299) of urological departments performed FT and 20 departments reached > 20 FT procedures. In 2019, 16% (58/368) of urological departments performed FT and 7 departments reached > 20 FT. In 2019, 25 urological departments offered FT other than HIFU: 5 centers hyperthermia ablation, 11 centers VTP TOOKAD®, 3 centers cryotherapy, 6 centers TULSA. CONCLUSION: The FT development in Germany followed the Gartner hype cycle. While HIFU treatment is the most commonly performed FT, the share of newer FT modalities such as VTP-TOOKAD® and TULSA is remarkably increasing.

Urolithiasis in Germany: Trends from the National DRG Database.

INTRODUCTION: Urolithiasis is a common disease leading to a high socioeconomic burden due to treatment costs and sickness leave. The aim of this study was to evaluate recent trends in the incidence of urolithiasis in Germany and in the use of therapeutic interventions. METHODS: Treatment data for all in-patient hospital episodes for urolithiasis between 2005 and 2016 were extracted from the national DRG statistics at DESTATIS and analysed with regard to the corresponding procedures according to the OPS code. RESULTS: Incidence for urolithiasis was stable at around 120,000 cases per year during the observation period with a male:female ratio of 2:1. Rising numbers were noted for patients >80 years. Nevertheless, the number of coded procedures rose significantly with a marked disproportionate transition from extracorporeal shock wave lithotripsy towards ureterorenoscopy. Percutaneous nephrolithotomy was performed more frequently on a smaller scale. DISCUSSION/CONCLUSION: While the global incidence of urolithiasis is still rising, Germany, as other Western countries, has reached a plateau. There is a remarkable trend towards invasive treatment of even asymptomatic kidney stones. Besides the effects on individual patients with increased risk for complications, this results in a higher monetary burden to the health care system and society.

Trends in urological stone disease: a 5-year update of hospital episode statistics.

OBJECTIVE: To provide a 5-year follow-on update on the changes in prevalence and treatment of upper urinary tract (UUT) stone disease in England. METHODS: Data from the Hospital Episode Statistics (HES) website (http://www.hesonline.nhs.uk) were extracted, summarised, analysed, and presented. RESULTS: The total number of UUT stone hospital episodes increased slightly from 83 050 in 2009-2010 to 86 742 in 2014-2015 (4.4% increase). The use of shockwave lithotripsy (SWL) for treating all UUT stones remained stable over the 5-year study period following a significant increase in previous years. There was a 49.6% increase in the number of ureteroscopic stone treatments from 12 062 in 2009-2010 to 18 055 in 2014-2015. Increase in ureterorenoscopy (flexible ureteroscopy) showed the most rapid increase from 3 267 to 6 631 cases in the 5-year study period (103% increase). The gap between the total number of ureteroscopies and SWL treatments continues to narrow. Open stone surgery continued to decline with only 30 reported cases in 2014-2015. Due to the continued rapid increase in the number of ureteroscopies performed, treatment for stone disease has continued to increase significantly in comparison to other urological activity. CONCLUSION: This study provides an update on the changing landscape of the management of UUT stones in England. It shows a sustained high prevalence of stone disease commensurate with levels in other developed countries. This study reveals a trend in the last 5 years to surgically intervene on a higher proportion of patients with stones. As in other countries, there is a significant increase in the use of ureteroscopy (particularly intrarenal flexible ureteroscopy) in England. These data have important implications for work-force planning, training, service delivery, and research in the field of urolithiasis.

Assessing blood platelets as RNA biomarker source for prostate cancer.

CONTEXT: Blood platelets may offer as RNA biomarker source for cancer as recently described for an oncogenic transcript in glioma patients and for PCA3 in prostate cancer (PCa) patients. OBJECTIVE: Here, we elaborated on this aspect for PCa. MATERIALS AND METHODS: PCA3 and other PCa-associated RNA markers were measured in platelets of PCa patients (cases) and healthy subjects (controls) in comparison to PCa cell lines by relative quantitative RT-PCR. RESULTS: The RNA markers displayed heterogeneous expression patterns in cell lines and platelets, however, without significant differences between cases and controls. DISCUSSION AND CONCLUSION: The data do not support platelets as a profitable RNA source for early detection of PCa. Nonetheless, certain PCa-derived RNA markers in platelets may merit further investigation as potential prognostic biomarkers for PCa.

Lymphoceles Post-Radical Retropubic Prostatectomy: A Retrospective Evaluation of Epidemiology, Risk Factors and Outcome.

INTRODUCTION: We aimed at evaluating the incidence of lymphoceles, a common complication after radical retropubic prostatectomy (RRP), at a high volume centre, define risk factors and assess the clinical outcome. MATERIALS AND METHODS: 454 patients receiving RRP and pelvic lymph node dissection were assessed for postoperative lymphoceles using the ultrasound method. Findings were correlated to clinical parameters from a database (age, BMI, initial PSA, number of lymph nodes removed, prostate weight, duration of surgery, hospital stay, duration of catheterisation) and possible unconventional risk factors using meteorological data. RESULTS: Overall, 15.4% developed a lymphocele, 2.6% had a symptomatic lymphocele requiring treatment. The mean size of the lymphoceles requiring treatment was significantly higher (400 vs. 115 ml). Patients with lymphocele stayed longer in hospital. No correlation could be found between the clinical parameters and the risk for lymphoceles. Functional results in terms of urinary continence were similar. The assessment of meteorological risk factors showed a correlation of lymphoceles with air humidity. CONCLUSION: Lymphoceles are common after RRP, but few cases require intervention. There is no reliable clinical predictor for the risk of lymphocele development. Data sets have been published suggesting several risk factors but may be subject to statistical error like in the case of the meteorological predictors in this study.

Anatomic locations of ureterovascular fistulae: a review of 532 patients in the literature and a new series of 8 patients.

INTRODUCTION: Ureterovascular fistula (UVF) is a rare but potentially life-threatening condition. Since its primary description by Moschkowitz in 1908, many case reports, studies and reviews have been written about this condition with the suggestive symptoms and risk factors repeatedly discussed. This study will be focusing on the different locations of 532 out of 605 fistulae published from 1908 up to 2022 besides eight new patients of our own. MATERIAL AND METHODS: A systematic review of the literature started using PubMed database searching for "ureteroarterial fistula", "arteriovascular fistula" and "uretero vascular fistula" was performed yielding 122, 62 and 188 results respectively. Those studies and the cited literature in each study were examined to include studies, which did not appear in the primary search. A total of 605 patients in 315 publications were gathered. Only studies mentioning new patients, a clear indication of the location of the UVF, the presence/absence of urinary diversion (UD) as well as the type of UD if present were included. Ten duplicates as well as studies lacking information regarding the UVF and/or the UD (seven publications with 63 patients) were excluded, with 298 publications including 532 external patients remaining. Eight internal cases were included with a total of 540 cases. RESULTS: From the 540 included cases, 384 patients (71.1%) had no UD compared to 156 patients (28.9%) with UD. Due to the anatomical ureteral course, the common iliac artery (CIA) was the most common vascular component of UVF, irrespective of the presence or absence of UD. Any dispute to whether the crossing point is the common or the external iliac artery (EIA) was settled for the CIA. Further common vascular components besides CIA include the aorta, EIA, internal iliac artery (IIA) including its branches and vascular bypasses including the anastomosis sites. Other unusual arterial localizations were stated under the "others" category. CONCLUSION: Identifying the location of the bleeding artery in UVF is critical and represents the most important step for successful management. We present the largest summary of described locations up to date including our own.

[Geriatric assessment - What should be done and considered before starting therapy of mHSPC and mCRPC?] / Geriatrisches Assessment ­ Was sollte vor Therapiebeginn des mHSPC und des mCRPC gemacht und bedacht werden?

The systemic treatment of prostate cancer nowadays is predominantly carried out with combination therapies. A range of aspects should be respected in older and comorbid patients, in order to avoid toxicities and to achieve a successful therapy alongside good quality of life. The definition of geriatric patients is not primarily based on chronological age but rather on the overall health condition and life expectancy. Comorbid patients > 70 years should undergo a three-step geriatric screening before treatment initiation. If the G8 screening and/or mini-COG shows abnormalities (taking into account nutrition, comorbidity/medication, mobility, and cognition), a simplified geriatric assessment is recommended. Patients can then be stratified into three groups (fit, vulnerable, frail). Only a few cases warrant a complete geriatric assessment. Treatable deficits in the above mentioned domains should be improved if possible. When choosing a systemic therapy, fit patients can be treated the same as non-geriatric patients. Vulnerable and frail patients are under a higher risk for toxicities, so special care should be taken. While the diverse substances of hormonal therapy are usually well tolerated (even though some substance-specific toxicities can occur), haematotoxic substances such as taxanes or olaparib can only be recommended in select cases. As falls - especially under hormonal therapy - are a common problem, osteoprotective therapy should especially be considered. Upon progression of the tumour disease, there should not be a reflex to simply switch to the next line of treatment, but an individual concept should be established together with the patient and his relatives, taking into account aspects of palliative care and patient needs and focussing on quality of life and also setting therapy limitations.

End-of-Life Care Preferences of Patients with Advanced Urological Malignancies: An Explorative Survey Study at a Tertiary Referral Center.

Background: Many people want to die at home, but it is often not possible because they do not share their wishes with family members. This study was conducted to find out the extent to which patients with advanced urological malignancies had wishes regarding their final stage of life, made arrangements accordingly, and communicated their wishes to relatives and health care professionals. Methods: We conducted a survey among advanced urological tumor patients during their clinic visit at a German university hospital using a 31-item questionnaire. Inclusion criteria were metastatic or irresectable prostate cancer, urothelial carcinoma, or renal cell carcinoma. Results: In total, 88 patients (76 male, 12 female) completed the questionnaire, and 62 of those respondents (70%) had received their tumor diagnosis within the past 5 years. Symptoms were reported by 80%, and 18% described five or more symptoms. The majority (88%) stated that they had thought about their preferred place of death but 58% had not informed anyone about it. The preference for a hospice as the place of death correlated statistically significantly with the absence of a domestic partnership (p = 0.001) or marriage (p < 0.001) and with a high number of symptoms (≥5; p = 0.009). However, 73% had not talked with their urological oncologist about care options in case their health deteriorated though 36% of those were interested in having a conversation about it. Conclusions: Our results showed that 9 out of 10 patients reflected on their preferred place of death but only a few discussed it with anyone. Based on this finding, physicians and healthcare staff should initiate discussions about early care planning so that patients in incurable situations can express their wishes regarding their preferred place of death.

A deep-learning workflow to predict upper tract urothelial carcinoma protein-based subtypes from H&E slides supporting the prioritization of patients for molecular testing.

Upper tract urothelial carcinoma (UTUC) is a rare and aggressive, yet understudied, urothelial carcinoma (UC). The more frequent UC of the bladder comprises several molecular subtypes, associated with different targeted therapies and overlapping with protein-based subtypes. However, if and how these findings extend to UTUC remains unclear. Artificial intelligence-based approaches could help elucidate UTUC's biology and extend access to targeted treatments to a wider patient audience. Here, UTUC protein-based subtypes were identified, and a deep-learning (DL) workflow was developed to predict them directly from routine histopathological H&E slides. Protein-based subtypes in a retrospective cohort of 163 invasive tumors were assigned by hierarchical clustering of the immunohistochemical expression of three luminal (FOXA1, GATA3, and CK20) and three basal (CD44, CK5, and CK14) markers. Cluster analysis identified distinctive luminal (N = 80) and basal (N = 42) subtypes. The luminal subtype mostly included pushing, papillary tumors, whereas the basal subtype diffusely infiltrating, non-papillary tumors. DL model building relied on a transfer-learning approach by fine-tuning a pre-trained ResNet50. Classification performance was measured via three-fold repeated cross-validation. A mean area under the receiver operating characteristic curve of 0.83 (95% CI: 0.67-0.99), 0.8 (95% CI: 0.62-0.99), and 0.81 (95% CI: 0.65-0.96) was reached in the three repetitions. High-confidence DL-based predicted subtypes showed significant associations (p < 0.001) with morphological features, i.e. tumor type, histological subtypes, and infiltration type. Furthermore, a significant association was found with programmed cell death ligand 1 (PD-L1) combined positive score (p < 0.001) and FGFR3 mutational status (p = 0.002), with high-confidence basal predictions containing a higher proportion of PD-L1 positive samples and high-confidence luminal predictions a higher proportion of FGFR3-mutated samples. Testing of the DL model on an independent cohort highlighted the importance to accommodate histological subtypes. Taken together, our DL workflow can predict protein-based UTUC subtypes, associated with the presence of targetable alterations, directly from H&E slides.

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Enfortumab Vedotin in Metastatic Urothelial Carcinoma: Survival and Safety in a European Multicenter Real-world Patient Cohort.

Background: Treatment options for patients with urothelial cancer (UC) refractory to platinum and immunotherapy are limited and survival is short. Enfortumab vedotin (EV) is a monoclonal anti-NECTIN4 antibody conjugated to monomethyl auristatin. It was recently approved because of superior survival in comparison to standard-of-care (SOC) chemotherapy. Real-world patients, however, often have worse characteristics than patients included in clinical trials. Objective: To analyze the efficacy and safety of EV in a cohort of real-world patients. Design setting and participants: Retrospective data were collected from 23 hospitals and private practices for patients with metastatic and previously treated UC who received EV either when reimbursed by their insurance company before European Medicines Agency (EMA) approval, within a compassionate use program, or as SOC treatment after EMA approval. Imaging and therapy management were in accordance with local standards. Outcome measurements and statistical analysis: Adverse events (AEs) were reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 criteria. Objective responses were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results and limitations: The median age for the 125 eligible patients was 66 yr (range 31-89). The Eastern Cooperative Oncology Group performance status (ECOG PS) was 0-1 for 76.0%, 2-4 for 13.6%, and unknown for 10.4% of patients. EV was administered in the fourth or later line for 44.8% of patients. The overall response rate was 41.6% (partial response 39.2%, complete response 2.4%). Median OS was 10.0 months (mo) (95% confidence interval 7.20-12.80) and median PFS was 5.0 mo (95% confidence interval 4.34-5.67). For patients with ECOG PS of 0-1, median OS was 14 mo. Any-grade AEs were observed in 67.2% and CTCAE grade ≥3 AEs in 30.4%. The most common AEs were peripheral sensory neuropathy and skin toxicity. Three fatal events (pneumonia, pneumonitis) occurred. Limitations include the retrospective design and short follow-up. Conclusions: Administration of EV for real-world patients was feasible with an acceptable toxicity profile. No new safety signals were reported. Antitumor activity in our cohort was comparable to data previously reported for trials. In summary, our results support the use of EV in patients with metastatic UC. Patient summary: Enfortumab vedotin is a medication that improved the survival of patients with bladder cancer in comparison to standard chemotherapy in clinical trials. However, patients included in clinical trials are highly selected and results for toxicities and improvements in survival do not always transfer to the real-world setting. We analyzed data for 125 patients who were treated with enfortumab vedotin. Our results are comparable to the outcomes from clinical trials regarding the safety and efficacy of this treatment.

Frequency of microsatellite instability (MSI) in upper tract urothelial carcinoma: comparison of the Bethesda panel and the Idylla MSI assay in a consecutively collected, multi-institutional cohort.

AIMS: Upper tract urothelial carcinoma (UTUC) is a rare malignancy with a poor prognosis which occurs sporadically or in few cases results from a genetic disorder called Lynch syndrome. Recently, examination of microsatellite instability (MSI) has gained importance as a biomarker: MSI tumours are associated with a better response to immunomodulative therapies. Limited data are known about the prevalence of MSI in UTUC. New detection methods using the fully automated Idylla MSI Assay facilitate analysis of increased patient numbers. METHODS: We investigated the frequency of MSI in a multi-institutional cohort of 243 consecutively collected UTUC samples using standard methodology (Bethesda panel), along with immunohistochemistry of mismatch repair (MMR) proteins. The same tumour cohort was retested using the Idylla MSI Assay by Biocartis. RESULTS: Using standard methodology, 230/243 tumours were detected as microsatellite stable (MSS), 4/243 tumours as MSI and 9/243 samples as invalid. In comparison, the Idylla MSI Assay identified four additional tumours as MSS, equalling 234/243 tumours; 4/243 were classified as MSI and only 5/243 cases as invalid. At the immunohistochemical level, MSI results were supported in all available cases with a loss in MMR proteins. The overall concordance between the standard and the Idylla MSI Assay was 98.35%. Time to result differed between 3 hours for Idylla MSI Assay and 2 days with the standard methodology. CONCLUSION: Our data indicate a low incidence rate of MSI tumours in patients with UTUC. Furthermore, our findings highlight that Idylla MSI Assay can be applied as an alternative method of MSI analysis for UTUC.

Soluble PD-L1 in blood correlates positively with neutrophil and negatively with lymphocyte mRNA markers and implies adverse sepsis outcome.

Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.e., sPD-1 and sPD-L1, respectively) are recognized as possible sepsis biomarkers, their functional implications are yet to be elucidated. Our research assessed the correlation between sPD-1 and sPD-L1 and blood mRNA markers and sepsis outcome. Blood samples of septic patients of urogenital origin versus control patients (both groups: n = 18) were analyzed. Blood serum sPD-1 and sPD-L1 levels were determined using the enzyme-linked immunosorbent assay (ELISA). The whole blood mRNA concentrations of PD-1, PD-L1, neutrophil markers (CEACAM8 and MPO), and T-lymphocyte markers (TCRß, CD4 and CD8) were determined via reverse transcriptase quantitative PCR (RT-qPCR). sPD-L1 levels were significantly increased in septic patients when compared to the controls, whereas sPD-1 levels were unaltered. Patients with high sPD-L1 levels, as dichotomized to the median, had a significantly shorter survival rate than those with low sPD-L1 levels. The sensitivity/specificity characteristics of sPD-L1 proved significant for sepsis detection. Furthermore, sPD-L1 correlated with the mRNA concentrations of PD-L1, CEACAM, and MPO, as well as major inflammatory markers (C-reactive protein and procalcitonin). However, sPD-L1 negatively correlated with TCRß, CD4, and CD8 mRNAs. sPD-L1 was found to be significantly increased in septic patients. Notably, sPD-L1 correlated with PD-L1 mRNA and neutrophil markers and was indicative of adverse outcomes.