Performance of clinical risk scores and prediction models to identify pathogenic germline variants in patients with advanced prostate cancer.

PURPOSE: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. METHODS: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. RESULTS: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. CONCLUSION: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

Prognostic Role of Preoperative Vascular Cell Adhesion Molecule-1 Plasma Levels in Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy.

BACKGROUND: Angiogenesis-related marker vascular cell adhesion molecule-1 (VCAM-1) has been shown to be elevated in urothelial carcinoma of the bladder (UCB), but its predictive/prognostic role has not been determined. Thus, this study aimed to investigate the predictive/prognostic role of VCAM-1 for patients who have UCB treated with radical cystectomy (RC). METHODS: The study enrolled 1036 patients with clinically non-metastatic advanced UCB who underwent RC, and plasma VCAM-1 was evaluated preoperatively. The correlation of plasma VCAM-1 with pathologic and survival outcomes was assessed using binominal logistic regression and multivariable Cox regression analyses. Discrimination was assessed using the area under the curve and concordance indices. The clinical net benefit was evaluated using decision curve analysis (DCA). RESULTS: Preoperative VCAM-1 was significantly elevated in patients with adverse pathologic features. Higher VCAM-1 levels were independently associated with increased risk of lymph-node-metastasis (LNM), ≥pT3 disease, and non-organ-confined disease (NOCD (p < 0.001 for each). Preoperative plasma VCAM-1 was independently associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) in pre- and postoperative multivariable models. Adding VCAM-1 to these predictive models improved their discriminatory ability to predict all outcomes by a significant margin. In the DCA, VCAM-1 addition to the reference models for prediction of LNM, NOCD, RFS, and CSS resulted in relevant improvement. CONCLUSIONS: Elevated plasma VCAM-1 was associated with biologically and clinically aggressive UCB disease features. After validation, preoperative VCAM-1 may serve as a biomarker to help identify patients likely to benefit from intensified/multimodal therapy. In addition, VCAM-1 improved the discriminatory power of predictive/prognostic models and can be used to refine personalized clinical decision-making.

Prognostic role of the systemic immune-inflammation index in upper tract urothelial carcinoma treated with radical nephroureterectomy: results from a large multicenter international collaboration.

PURPOSE: To investigate the prognostic role of the preoperative systemic immune-inflammation index (SII) in patients with upper tract urothelial carcinoma (UTUC) treated with radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively analyzed our multi-institutional database to identify 2492 patients. SII was calculated as platelet count × neutrophil/lymphocyte count and evaluated at a cutoff of 485. Logistic regression analyses were performed to investigate the association of SII with muscle-invasive and non-organ-confined (NOC) disease. Cox regression analyses were performed to investigate the association of SII with recurrence-free, cancer-specific, and overall survival (RFS/CSS/OS). RESULTS: Overall, 986 (41.6%) patients had an SII > 485. On univariable logistic regression analyses, SII > 485 was associated with a higher risk of muscle-invasive (P = 0.004) and NOC (P = 0.03) disease at RNU. On multivariable logistic regression, SII remained independently associated with muscle-invasive disease (P = 0.01). On univariable Cox regression analyses, SII > 485 was associated with shorter RFS (P = 0.002), CSS (P = 0.002) and OS (P = 0.004). On multivariable Cox regression analyses SII remained independently associated with survival outcomes (all P < 0.05). Addition of SII to the multivariable models improved their discrimination of the models for predicting muscle-invasive disease (P = 0.02). However, all area under the curve and C-indexes increased by < 0.02 and it did not improve net benefit on decision curve analysis. CONCLUSIONS: Preoperative altered SII is significantly associated with higher pathologic stages and worse survival outcomes in patients treated with RNU for UTUC. However, the SII appears to have relatively limited incremental additive value in clinical use. Further study of SII in prognosticating UTUC is warranted before routine use in clinical algorithms.

Visibility of significant prostate cancer on multiparametric magnetic resonance imaging (MRI)-do we still need contrast media?

OBJECTIVES: To assess the visibility of clinically significant prostate cancer (PCA) lesions on the sequences multiparametric MRI of the prostate (mpMRI) and to evaluate whether the addition of dynamic contrast-enhanced imaging (DCE) improves the overall visibility. METHODS: We retrospectively evaluated multiparametric MRI images of 119 lesions in 111 patients with biopsy-proven clinically significant PCA. Three readers assigned visual grading scores for visibility on each sequence, and a visual grading characteristic analysis was performed. Linear regression was used to explore which factors contributed to visibility in individual sequences. RESULTS: The visibility of lesions was significantly better with mpMRI when compared to biparametric MRI in visual grading characteristic (VGC) analysis, with an AUCVGC of 0.62 (95% CI 0.55-0.69; p < 0.001). This benefit was seen across all readers. Multivariable linear regression revealed that a location in the peripheral zone was associated with better visibility on T2-weighted imaging (T2w). A higher Prostate Imaging-Reporting and Data System (PI-RADS) score was associated with better visibility on both diffusion-weighted imaging (DWI) and DCE. Increased lesion size was associated with better visibility on all sequences. CONCLUSIONS: Visibility of clinically significant PCA is improved by using mpMRI. DCE and DWI images independently improve lesion visibility compared to T2w images alone. Further research into the potential of DCE to impact on clinical decision-making is suggested. KEY POINTS: • DCE and DWI images independently improve clinically significant prostate cancer lesion visibility compared to T2w images alone. • Multiparametric MRI (DCE, DWI, T2w) achieved significantly higher visibility scores than biparametric MRI (DWI, T2w). • Location in the transition zone is associated with poor visibility on T2w, while it did not affect visibility on DWI or DCE.

Dual immune check point blockade or immune check point-tyrosine kinase inhibitor combination: as a first-line treatment in metastatic renal cell carcinoma?

PURPOSE OF REVIEW: To discuss treatment decisions in the first-line setting of metastatic renal cell carcinoma (mRCC). RECENT FINDINGS: Immune check point inhibitor (ICI) combinations have replaced sunitinib as the standard of care in the first-line treatment of mRCC. Dual ICI treatment with nivolumab and ipilimumab was shown to significantly improve overall survival and objective response rates. Similarly, the ICI-tyrosine kinase inhibitor combinations pembrolizumab and axitinib and nivolumab and cabozantinib have demonstrated superiority in terms of overall survival, objective response rates and progression-free survival versus sunitinib. The lack of both comparative trials and predictive markers impedes individualized treatment decisions. Clinicians are left to make treatment choices based on clinical and biological factors. These factors may include differences in toxicity profiles, the rate of complete remission, a clinical situation that requires urgent tumor shrinkage, the presence of inflammation, histological or immune-histochemical features and others. SUMMARY: In the absence of comparative trials, clinical and biological factors may facilitate the choice between various treatment options in the first-line setting of mRCC. In addition, both the experience of the physician with a specific treatment together with patient's preferences and expectations of systemic therapy may be part of the decision-making process.

Overactive bladder symptoms in patients undergoing rigid and flexible cystoscopy.

PURPOSE: To evaluate overactive bladder (OAB) symptoms in patients undergoing diagnostic cystoscopy. Overall changes in the entire study population were assessed, as well as broken down by various subgroups. METHODS: A prospective multi-center study among consecutive 450 adults undergoing diagnostic cystoscopy was conducted. OAB-symptoms were evaluated with the validated eight-item OAB Screening Awareness Tool (OAB-V8) immediately before and on days 1, 4, and 7 after cystoscopy. Patients were distinguished between being OAB-negative and OAB-positive (< 8 and ≥ 8 sum-score, respectively). Average sum-scores and subdomains were evaluated. RESULTS: Before cystoscopy, 44.7% of patients were screened OAB-positive and 55.3% OAB-negative. Out of those being screened negative, development of de-novo OAB was noticed in 16.8%, declining to 8.1% on day 7 (p < 0.001). In patients being OAB-positive before cystoscopy, a decline of OAB-positivity was noted during follow-up (p < 0.001). No statistically significant differences were noted when broken down by gender (p = 0.92), age (p = 0.82) and type cystoscope (rigid vs. flexible, p = 0.38). Average sum-scores declined from 8.68 before cystoscopy to 6.9 during follow-up. Flexible cystoscopy was superior over rigid in four subdomains: uncomfortable urge to urinate (p = 0.04), sudden urge to urinate with little or no warning (p = 0.02), uncontrollable urge to urinate (p = 0.03), and urine loss associated with a strong desire to void (p = 0.009). CONCLUSION: OAB-symptoms are common in patients undergoing cystoscopy. Cystoscopy itself can cause de-novo OAB-symptoms. Controversially, a decline of OAB-symptoms was noted after cystoscopy when patients were screened OAB-positive before cystoscopy. Flexible scopes were superior in some subdomains.

Immune checkpoint inhibition in muscle-invasive and locally advanced bladder cancer.

PURPOSE OF REVIEW: Immune-checkpoint inhibitors (CPIs) have been implemented in the treatment algorithm of metastatic urothelial cancer as they have shown higher and more sustained responses compared with conventional second-line chemotherapy. Recently, several clinical trials have reported on CPIs in earlier disease stages such as muscle-invasive bladder cancer (MIBC). This review summarizes ongoing clinical trials and results from early phase clinical trials in muscle invasive and locally advanced bladder cancer. RECENT FINDINGS: In phase II clinical trials, neoadjuvant use of CPIs as mono and combination therapy, in patients with MIBC planned for radical cystectomy, has shown promising pathological complete response rates. Whether this will translate in survival benefit remains to be assessed. Combination of CPIs and conventional chemotherapy or other targeted agents promises to increase the efficacy of perioperative systemic therapy with potentially additive toxicities. Recently, preclinical models of combined trimodal therapy with CPIs delivered the proof of principle leading to several ongoing trials in this setting. SUMMARY: First results of clinical trials evaluating CPIs in MIBC demonstrate very promising results that warrant further investigation as they could revolutionize management of MIBC in the near future. The trend and hope are toward higher rates of safe and sustained bladder preservation.

The role of taxane-based chemotherapy in the treatment of prostate cancer.

PURPOSE OF REVIEW: Indications for chemotherapy have increased in prostate cancer (PCA), many of which are shared with new hormonal agents (NHA). With no head to head comparison available, defining the optimal sequence and identifying biomarkers to predict response, has been a focus of intense research in PCA. We aim to summarize the best currently available evidence in all stages of disease to help guide therapy. RECENT FINDINGS: In metastatic castration-resistant prostate cancer, Cabazitaxel has shown improved radiographic progression-free survival over another NHA after Docetaxel and one NHA. For hormone sensitive PCA (mHSPC) multiple meta-analyses have shown combination therapy with Docetaxel or an NHA to be superior to androgen deprivation therapy alone, yet no clear benefit over each other. For peri-interventional chemotherapy with local therapy, there is currently only one positive prospective trial, for very high-risk disease. SUMMARY: Cabazitaxel is underutilized and should be used earlier. NHAs should not be used in succession as there is significant cross resistance. Combination therapy should be used in mHSPC, yet there is no clear benefit for any combination. Peri-interventional chemotherapy might have a benefit for a small group of patients with very high-risk disease, yet this must be carefully evaluated, and side effects must be taken into account.

An update on systemic therapy for penile cancer.

PURPOSE OF REVIEW: Whereas substantial advances have been made in systemic tumour therapy in the past decade, the prognosis of advanced squamous cell carcinoma (SCC) of the penis remains disproportionally poor. In this review, we aimed to present an update on systemic therapy of penile SCC highlighting the most recent data and future perspectives. RECENT FINDINGS: Lymph node metastases play a key role in treating and assessing the prognosis of patients with penile SCC. Data show longer overall survival with the use of adjuvant chemotherapy in patients with pelvic lymph node metastases and recent analyses lead to the development of a nomogramm predicting overall survival in connection with the use of perioperative chemotherapy. There are two pathways in the pathogenesis of penile cancer, including human papilloma virus related and unrelated, leading to many possible novel therapeutic targets. Other targeted therapies have been evaluated, which show promising results with the use of tyrosine kinase inhibitors. SUMMARY: Chemotherapy has shown moderate activity in advanced stages of the disease, however, the ideal timing of chemotherapy in patients with lymph node metastases is not entirely clear. Potential targets for future therapies exist, and are already being tested in other malignancies. Owing to the rarity of this condition, a robust evidence is lacking and it is of great importance to pursue further research to unveil several aspects of this disease, particularly in patients with recurrence, lymph node metastases or metastatic disease.

Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer.

OBJECTIVES: A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients. METHODS AND MATERIALS: A systematic medline/pubmed© literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC. RESULTS: Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers. CONCLUSIONS: PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.

Biomarkers for immunotherapy in urological cancers.

PURPOSE OF REVIEW: Immunotherapies for urological malignancies have made tremendous progress by targeting immune checkpoints and have been implemented in clinical practice nowadays. Though siginifcant number of patients does not respond to immunotherapy. Biomarkers could help to predict response to treatment, but are still under investigation. We reviewed the literature to identify relevant biomarkers in patient treated with immunotherapy. RECENT FINDINGS: A comprehensive search of PubMed through has been performed to identify important relevant publications from 2016 to 2017 on biomarkers for immunotherapies in urological cancers including reported clinical trials. In addition, abstracts of relevant oncological scientific meetings from 2017 have been implemented. SUMMARY: Checkpoint inhibitors have shown substantial improvement in the treatment of metastatic RCC and metastatic and locally advanced urothelial cancer. There is an unmet need for the development of predictive biomarkers in order to identify patients who are more likely to respond to therapy.

Sarcopenia as a Predictive Factor for Response to Upfront Cisplatin-Based Chemotherapy in Patients with Muscle-Invasive Urothelial Bladder Cancer.

PURPOSE: We hypothesized sarcopenia as predictive factor as a response to upfront chemotherapy of muscle-invasive urothelial bladder cancer (MIBC). METHODS: We retrospectively studied 30 patients who received upfront cisplatin-based chemotherapy for MIBC (pT2-4 N0/+ M0) before planned radical cystectomy. Skeletal muscle index (SMI) was calculated by CT at study baseline and following completion of chemotherapy. Patients were stratified according to the presence of sarcopenia. Endpoints included clinical and pathological response. RESULTS: Sixteen of the 30 patients (53.3%) had sarcopenia at baseline. The median SMI was 51.2 cm2/m2 (IQR 45.6-57.9). Throughout the course of chemotherapy, 22 patients (73.3%) experienced a decline in SMI, which ranged from 1 to 20% (median decline 3%, p < 0.01). All 16 patients with baseline sarcopenia persisted, while 5 of 14 patients (35.7%) without baseline sarcopenia became sarcopenic (p = 0.06). None of the clinical variables were predictive of clinical or pathological response, including SMI (p = 0.78 and p = 0.59), sarcopenia (p = 0.65 and p = 0.16) and SMI kinetics (p = 0.54 and p = 0.77). CONCLUSION: Sarcopenia is present in a considerable proportion of patients with MIBC undergoing upfront cisplatin-based chemotherapy before planned RC. SMI decreases during treatment, but neither baseline SMI nor its kinetics is associated with response to chemotherapy.

Anxiety and depression analyses of patients undergoing diagnostic cystoscopy.

PURPOSE: To prospectively assess anxiety and depression in patients undergoing diagnostic cystoscopy. METHODS: Patients presenting for outpatient diagnostic cystoscopy were recruited from four European urological departments. Anxiety and depression were assessed with the 'Hospital Anxiety and Depression Scale' (HADS) before cystoscopy and after 1 week. Statistical analyses, including the Chi-square test, univariate, and multivariate logistic regression analyses, were carried out with SPSS v. 21 (IBM Corp., Armonk, NY). RESULTS: Prior to cystoscopy, 30.2 % of patients were anxious and 24.8 % depressive (n = 442). In the post-examination period, anxiety declined to 24.5 %, while depression was unchanged (24.4 %). Pre-cystoscopy anxiety was significantly more common in women (41.8 vs. 24.5 %, p < 0.0001), patients aged <65 years (34.9 vs. 25.9 %, p = 0.04), and in those being examined with rigid cystoscopes (35.7 vs. 23.9 %, p = 0.007). In multivariate regression analyses, female gender (OR 2.6, p < 0.0001), <65 years of age (OR 1.7, p = 0.03), and coexistence of depression (OR 7.8, p < 0.0001) were independently associated with elevated pre-cystoscopy anxiety. Anxious (OR 2.1, p = 0.03) and depressive (OR 2.1, p = 0.01) patients had higher odds of experiencing moderate or severe pain during cystoscopy. Bladder cancer diagnosis did not significantly change patient's anxiety (p = 0.23) or depression (p = 0.7) during the 1 week of follow-up. CONCLUSIONS: Women, patients aged <65 years, depressive patients and those being examined with rigid devices had higher rates of anxiety prior to cystoscopy. Anxious and depressive patients experienced more pain during cystoscopy. Bladder cancer diagnosis seems to have a minor effect on anxiety and depression during the first week after diagnosis.

Clinical parameters for the prediction of occult lymph node metastasis in patients with negative PSMA-PET.

BACKGROUND: Depending on the risk of LN metastasis ePLND at RP is recommended. As ePLND has potential side effects, and diagnostics have improved substantially, our objective was to evaluate the performance of the Briganti 2019 nomogram in a contemporary cohort with preoperative negative PSMA-PET. METHODS: Patients with intermediate- and high-risk prostate cancer (CaP), undergoing RP and ePND at our center with preoperative negative [68Ga]Ga-PSMA-11 PET were included. The Accuracy of the nomogram was assessed using ROC analysis. The association of clinical parameters with the presence of LN metastasis was assessed using logistic regression. Specimen of prostate and LNs in patients with false negative PSMA-PET were additionally stained for AR and PSMA expression and assessed by IHC. RESULTS: The study included 108 patients, 28% intermediate- and 72% high-risk. Twelve patients harbored occult LN metastasis. Accuracy of the nomogram was 0.62. [68Ga]Ga-PSMA-11 PET showed a NPV of 89%. IHC showed expression of PSMA and AR in the primary and LN metastasis in all patients. On logistic regression analysis only DRE (OR 2.72; 95%CI 1.01-7.35; P = 0.05) and percentage of cores with significant CaP (OR 1.29; 95%CI 1.05-1.60; P = 0.02) showed a significant association with LN metastasis. CONCLUSION: The currently used nomogram is suboptimal in detecting patients with occult LNM. While the cut-off value to perform ePLND can be increased slightly following a negative PSMA-PET scan, more accurate methods of identifying these patients are needed. Whether ePLND can have a therapeutic benefit, as opposed to a diagnostic only, needs to be re-evaluated in the PSMA-PET era.

Treatment Patterns and Real-World Outcomes for Locally Advanced or Metastatic Urothelial Cancer in the Era of Immunotherapy.

BACKGROUND AND OBJECTIVE: There are limited data on real-world outcomes for patients with advanced or metastatic urothelial cancer (mUC) since immune checkpoint inhibitors (ICIs) became available. Our objective was to analyze outcomes for patients with mUC since ICIs became available. METHODS: We performed a retrospective analysis of 131 patients with mUC attending the outpatient clinic of a single tertiary care center who received systemic therapy between June 2017 and July 2021 with follow-up up to December 2022. Summary and descriptive statistics were calculated for categorical and continuous variables. The Kaplan-Meier method was applied to calculate survival, and a Cox proportional-hazards model was used to explore associations between clinical variables and outcomes. KEY FINDINGS AND LIMITATIONS: The median patient age was 68 yr (range 35-90). The first systemic therapy administered was platinum-based in 79% of cases and ICI-based in 21%. Some 61% of the cohort received a second systemic treatment, with 75% of these an ICI. Median overall survival for the entire cohort was 24 mo (interquartile range 9-35). Patients on ICI therapy for ≥6 mo had median overall survival of 59 mo (95% confidence interval 39 mo-not reached). Metastatic sites on initiation of ICI therapy and C-reactive protein kinetics were prognostic in patients receiving ICIs. Limitations include the retrospective design and inherent selection bias. CONCLUSIONS AND CLINICAL IMPLICATIONS: More than 60% of patients with mUC received second-line treatment, and 75% of these received an ICI. Patients staying on immunotherapy for more than 6 mo have substantially better outcomes in comparison to patients with less time on immunotherapy and historical cohorts. PATIENT SUMMARY: We looked at the lines of therapy and outcomes for patients with advanced or metastatic cancer of the urinary tract, starting from when immunotherapy drugs called immune checkpoint inhibitors (ICIs) became available. We found that 60% of patients have received second-line therapy, which is a double the rate in comparison to historical groups of patients. Patients with long-term ICI therapy (>6 months) had significantly better outcomes, with a median survival of more than 3 years.

Chemotherapy is superior to checkpoint inhibitors after radical surgery for urothelial carcinoma: a systematic review and network meta-analysis of oncologic and toxicity outcomes.

OBJECTIVE: To determine the oncologic and toxicity outcomes of adjuvant immunotherapy with immune checkpoint inhibitors (ICIs) compared to adjuvant chemotherapy in patients treated with radical surgery for urothelial carcinoma (UC). METHODS: We used the Bayesian approach in the network meta-analysis of different therapy regimens compared to observation or placebo. RESULTS: Nine studies comprised of 2,444 patients met the eligibility criteria. In bladder UC, chemotherapy, atezolizumab, and nivolumab did not improve disease progression compared to observation/placebo. In upper tract UC (UTUC), chemotherapy was significantly associated with a lower likelihood of disease progression compared to observation/placebo, while atezolizumab and nivolumab were not. Based on the analysis of the treatment ranking, adjuvant chemotherapy appeared as the best treatment approach in both bladder UC and UTUC. The risk of adverse events with ICIs was comparable to that of observation/placebo. CONCLUSION: Our analysis suggests a superior oncologic benefit to adjuvant chemotherapy over ICIs in patients treated with radical surgery for both bladder UC and UTUC.

Evaluation of APOBEC3 expression as prognostic marker in squamous cell carcinoma of the penis.

Squamous cell carcinoma of the penis (PSC) is a rare disease with limited information on the molecular events leading to malignant transformation. In a third of PSC cases, presence of human papilloma virus (HPV) is found. The APOBEC3 family of proteins is known to play a significant role in defense against HPV infection, but their role in PSC is largely unknown. In this study, we aim to assess mRNA expression levels of APOBEC3 family members in HPV+ and HPV- PSC to get insight into their association with clinicopathological features and to evaluate their prognostic impact. Expression levels of six APOBEC3 family members in tissue from 50 patients with PSC were determined by RT-PCR and correlated with clinical and histopathological features. Lower expression of APOBEC3A, APOBEC3B, and APOBEC3C was observed in advanced PSC stages. Except for APOBEC3D, HPV+ samples showed higher expression of APOBEC3s compared to HPV- samples. In univariate analyses, APOBEC3A and APOBEC3C expression tended to be associated with disease-free survival and APOBEC3A expression with overall survival; however, multivariable analyses failed to confirm these associations with outcome. More extensive external validation and functional laboratory studies are needed to evaluate further their role in PSC development and progression.

Comparison of two new generation pulse oximeters during emergency ambulance transportation.

OBJECTIVES: We wanted to test whether there is a difference between the total number and duration of malfunctions and a correlation between the oxygen saturation and pulse rate values of two new generation pulse oximeters (Masimo 'Radical 7' and Nellcor 'N 600') during emergency ambulance transportation. METHODS: Patients were monitored with two pulse oximeters ('Radical 7' and 'N 600') on different randomly selected fingers of the same hand during transportation. Data of both devices were recorded continuously by a laptop computer. RESULTS: Fifty-two patients with signs of peripheral vasoconstriction (including 22 patients with a blood pressure ≤100/60) were included. There were 0.21 ± 0.72 (0-4) malfunctions per patient lasting for a mean 113.55 ± 272.55 s in the 'Radical 7' and 0.13 ± 0.49 (0-3) malfunctions per patient with a mean duration of 301.0 ± 426.58 s in the 'N 600'. Oxygen saturation and pulse rate values correlated significantly [r² = 0.9608 (SpO2), r² = 0.9608 (pulse rate)] between the devices and showed a bias of -0.177770 (SpO2) and 0.310883 (pulse rate) with a standard deviation of 1.68367 (SpO2) and 4.46532 (pulse rate) in a Bland-Altman test. CONCLUSION: Although number and duration of malfunctions did not differ significantly between the devices, they showed a very low number of malfunctions even in hypotensive patients with peripheral vasoconstriction. Oxygen saturation correlated significantly in the two devices investigated at 49.409 time points. In addition, pulse rate also correlated significantly.

Update on systemic treatment of upper tract urothelial carcinoma: a narrative review of the literature.

Urothelial cancer (UC) is most commonly found in the urinary bladder, but can also appear in the upper urinary tract, where it is associated with several disease-specific challenges affecting its diagnosis, clinical staging, surgical management, and systemic therapy. A significant number of patients experience extra-vesical disease recurrence despite radical nephroureterectomy (RNU), leading to inevitable demise. Over the last years, the therapeutic armamentarium of UC has expanded with several systemic treatment options entering clinical care and deliver the potential to support a more individualized treatment in the near future. Currently, novel targeted therapies are emerging, accompanied with extensive biomarker research, which leads to a better understanding of the disease and therefore, reshaping the treatment landscape continuously and decisively. Though, systemic treatment of UTUC comes along with certain challenges that are specific to the disease, e.g., loss of renal function after RNU, which might result in ineligibility for a cisplatin-based chemotherapy. In this narrative review, the current standard of systemic treatment of UC in the perioperative and metastatic treatment setting are reported, with focus on UTUC. In addition, molecular aspects of UTUC, as well as future directions and specific implications for treatment of patients diagnosed with UTUC are discussed.

First-line Immunotherapy-based Combinations for Metastatic Renal Cell Carcinoma: A Systematic Review and Network Meta-analysis.

CONTEXT: There have been substantial changes in the management of patients with metastatic renal cell carcinoma (mRCC) over the past decade, with upfront immunotherapy-based combinations replacing targeted therapies. A broad range of combinations have been approved, and comparisons of their efficacy and safety are needed to guide the optimal choice of first-line therapy. OBJECTIVE: To perform indirect comparisons of efficacy and safety of first-line immune checkpoint inhibitor (ICI)-based combination therapies for mRCC. EVIDENCE ACQUISITION: We searched multiple databases and abstracts of major scientific meetings up to February 2021 to identify phase III randomized controlled trials of patients receiving first-line ICI-based combination therapies for mRCC. Progression-free survival (PFS) and overall survival (OS) were the primary endpoints. The secondary endpoints included complete response rates (CRRs), objective response rates (ORRs), grade ≥3 treatment-related adverse events (TRAEs), and rates of treatment discontinuation due to adverse events (AEs). Subgroup network meta-analyses were performed based on patients' risk group categories and programmed death ligand 1 (PD-L1) expression status. EVIDENCE SYNTHESIS: Six trials were included in our network meta-analyses comprising 5121 patients. Nivolumab plus cabozantinib had the highest likelihood of providing the maximal OS (P score: 0.7573). Lenvatinib plus pembrolizumab demonstrated the highest likelihood of PFS (P score: 0.9906) and ORR (P score: 0.9564). CRRs were more likely to be associated with nivolumab plus ipilimumab (P score: 0.8682). In patients with ≥1% PD-L1 expression, the highest likelihood of better PFS was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab. Nivolumab plus ipilimumab was also associated with the lowest rates of grade ≥3 TRAEs; while the highest likelihood of AE-related treatment discontinuation was associated with lenvatinib plus pembrolizumab and nivolumab plus ipilimumab. CONCLUSIONS: Our network meta-analysis suggests that combinations of ICIs and tyrosine kinase inhibitors (TKIs) provide superior PFS, ORR, and OS to ICI-ICI combinations, regardless of the on International mRCC Database Consortium risk group. However, an ICI-ICI combination could be the optimal treatment for tumors with increased PD-L1 expression. The newly introduced ICI-TKI combinations, nivolumab plus cabozantinib and lenvatinib plus pembrolizumab, showed promising activity and are likely to have an important role in the mRCC treatment strategy. PATIENT SUMMARY: The use of immune checkpoint inhibitor (ICI)-based combinations (ICI plus tyrosine kinase inhibitor and ICI-ICI) improved oncological outcomes of metastatic renal cell carcinoma. Programmed death ligand 1 (PD-L1) expression status could help guide physicians and patients to select the appropriate treatment strategy.