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Einleitung: Eine Lymphopenie ist mit schlechterem Immunstatus bei Krebspatienten assoziiert, was die Karzinomentstehung und -progression fördern kann. Rezente Arbeiten implizierten in dieser Situation ein schlechteres Outcome bei Patienten mit metastasiertem klarzelligem Nierenzellkarzinom (mccRCC).[zum vollständigen Text gelangen Sie über die oben angegebene URL], 44. gemeinsamen Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts (p &lt, 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort (n = 175, hazard ratio: 4.3, 95% confidence interval: 1.45&ndash, 12.75, p = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort (n = 530, hazard ratio: 2.19, 95% confidence interval: 1.59&ndash, 3.03, p &le, 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration (p &lt, 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A R = 0.19, p &lt, 0.0001, for LAMC2 R = 0.13, p = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis.

Einleitung: Laut den Leitlinien der Europäischen Gesellschaft für Urologie ist bei einem Prostatakarzinom ab einer präoperativen Wahrscheinlichkeit von 5% für das Vorliegen einer Lymphknotenmetastasierung eine Lymphadenektomie im Rahmen der radikalen Prostatektomie indiziert.[zum vollständigen Text gelangen Sie über die oben angegebene URL], 44. gemeinsamen Tagung der Bayerischen Urologenvereinigung und der Österreichischen Gesellschaft für Urologie und Andrologie

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

BACKGROUND: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

Background: Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. Methods: Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. Results: Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. Conclusions: These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

Table S1. Summary of patient characteristics of the DIAMOND cohort. Table S2. Summary of patient characteristics of the MonReC cohort. Table S3. Summary of filters applied to somatic single nucleotide variants (SNV) calls from Mutect2, for mutation calling of DIAMOND tissue samples. Table S4. Genes targeted for open reading frame sequencing. Table S5. Summary of samples with detected ctDNA at baseline of the MonReC cohort. Table S6. Mutations identified in tissue of in VHL, PTEN, TP53, SETD2, PBRM1, and BAP1 of patients subsequently analyzed with INVAR-TAPAS (n = 29). Table S7. Mutations identified at baseline in the MonReC cohort using a QIASeq custom panel targeting 10 frequently mutated genes in RCC. Fig. S1. Clinical records of select DIAMOND patients. Fig. S2. Schematic explaining the INVAR-TAPAS approach. Fig. S3. Summary of SCNA observed in matched tumor tissue from select DIAMOND patients. Fig. S4. tMAD - interrogation of plasma and urine data. Fig. S5. Assessment of SCNA landscape of matched tumor tissue supports their classification as oncocytoma. Fig. S6. Improved detection of SCNA by in silico size selection. Fig. S7. Comparison of the distribution of ichorCNA tumor fraction and tMAD score at baseline, and assessment of ichorCNA scores between cancer types from the MonReC cohort. Fig. S8. Summary of tumor tissue WES of the DIAMOND patients. Fig. S9. Tumor heterogeneity in RCC. Fig. 10. Summary of global ctDNA levels relative to informative reads in INVAR-TAPAS data from patient plasma and urine. Fig. S11. Correlation of tumor size and ctDNA detection. Fig. S12. Correlation of venous tumor thrombus and cell proliferation rates with ctDNA detection. Fig. S13. Confirmation of pathological classification as oncocytoma. Fig. S14. Application of a fragmentation feature based random forest model to predict patients with detected ctDNA. Fig. S15. Summary of ctDNA detection in all patients and all biofluids. Fig. S16. Comparison of z-score distribution at baseline, during treatment and when progression occurred. Fig. S17. Longitudinal monitoring of mutations detected with the QIAseq custom panel and ichorCNA tumor fractions. Fig. S18. Comparison of imaging data and ctDNA levels (as predicted by INVAR.TAPAS and tMAD). Fig. S19. Comparison of SCNA landscape of matched tumor tissue, normal adjacent tissue, and longitudinal plasma samples from DIAMOND patient 5634. Fig. S20. Comparison of imaging data and ctDNA levels (as predicted by INVAR.TAPAS and tMAD). Fig. S21. Tumor map of patient 5842. Fig. S22. Comparison between mAF and mutation representation in tumor lesions. Fig. S23. Representation of private mutations in the baseline plasma and USN samples of patient 5842. Fig. S24. Representation of mutations private to tumor regions in plasma and urine. Fig. S25. Distribution of mAF of patient specific mutations in plasma and urine from patient 5842. Fig. S26. Assessment of tumor heterogeneity representation in plasma from patient 5634.

BACKGROUND:Cell-free tumor-derived DNA (ctDNA) allows non-invasive monitoring of cancers, but its utility in renal cell cancer (RCC) has not been established. METHODS:Here, a combination of untargeted and targeted sequencing methods, applied to two independent cohorts of patients (n = 91) with various renal tumor subtypes, were used to determine ctDNA content in plasma and urine. RESULTS:Our data revealed lower plasma ctDNA levels in RCC relative to other cancers of similar size and stage, with untargeted detection in 27.5% of patients from both cohorts. A sensitive personalized approach, applied to plasma and urine from select patients (n = 22) improved detection to ~ 50%, including in patients with early-stage disease and even benign lesions. Detection in plasma, but not urine, was more frequent amongst patients with larger tumors and in those patients with venous tumor thrombus. With data from one extensively characterized patient, we observed that plasma and, for the first time, urine ctDNA may better represent tumor heterogeneity than a single tissue biopsy. Furthermore, in a subset of patients (n = 16), longitudinal sampling revealed that ctDNA can track disease course and may pre-empt radiological identification of minimal residual disease or disease progression on systemic therapy. Additional datasets will be required to validate these findings. CONCLUSIONS:These data highlight RCC as a ctDNA-low malignancy. The biological reasons for this are yet to be determined. Nonetheless, our findings indicate potential clinical utility in the management of patients with renal tumors, provided improvement in isolation and detection approaches.

Table S1. Summary of patient characteristics of the DIAMOND cohort. Table S2. Summary of patient characteristics of the MonReC cohort. Table S3. Summary of filters applied to somatic single nucleotide variants (SNV) calls from Mutect2, for mutation calling of DIAMOND tissue samples. Table S4. Genes targeted for open reading frame sequencing. Table S5. Summary of samples with detected ctDNA at baseline of the MonReC cohort. Table S6. Mutations identified in tissue of in VHL, PTEN, TP53, SETD2, PBRM1, and BAP1 of patients subsequently analyzed with INVAR-TAPAS (n = 29). Table S7. Mutations identified at baseline in the MonReC cohort using a QIASeq custom panel targeting 10 frequently mutated genes in RCC. Fig. S1. Clinical records of select DIAMOND patients. Fig. S2. Schematic explaining the INVAR-TAPAS approach. Fig. S3. Summary of SCNA observed in matched tumor tissue from select DIAMOND patients. Fig. S4. tMAD - interrogation of plasma and urine data. Fig. S5. Assessment of SCNA landscape of matched tumor tissue supports their classification as oncocytoma. Fig. S6. Improved detection of SCNA by in silico size selection. Fig. S7. Comparison of the distribution of ichorCNA tumor fraction and tMAD score at baseline, and assessment of ichorCNA scores between cancer types from the MonReC cohort. Fig. S8. Summary of tumor tissue WES of the DIAMOND patients. Fig. S9. Tumor heterogeneity in RCC. Fig. 10. Summary of global ctDNA levels relative to informative reads in INVAR-TAPAS data from patient plasma and urine. Fig. S11. Correlation of tumor size and ctDNA detection. Fig. S12. Correlation of venous tumor thrombus and cell proliferation rates with ctDNA detection. Fig. S13. Confirmation of pathological classification as oncocytoma. Fig. S14. Application of a fragmentation feature based random forest model to predict patients with detected ctDNA. Fig. S15. Summary of ctDNA detection in all patients and all biofluids. Fig. S16. Comparison of z-score distribution at baseline, during treatment and when progression occurred. Fig. S17. Longitudinal monitoring of mutations detected with the QIAseq custom panel and ichorCNA tumor fractions. Fig. S18. Comparison of imaging data and ctDNA levels (as predicted by INVAR.TAPAS and tMAD). Fig. S19. Comparison of SCNA landscape of matched tumor tissue, normal adjacent tissue, and longitudinal plasma samples from DIAMOND patient 5634. Fig. S20. Comparison of imaging data and ctDNA levels (as predicted by INVAR.TAPAS and tMAD). Fig. S21. Tumor map of patient 5842. Fig. S22. Comparison between mAF and mutation representation in tumor lesions. Fig. S23. Representation of private mutations in the baseline plasma and USN samples of patient 5842. Fig. S24. Representation of mutations private to tumor regions in plasma and urine. Fig. S25. Distribution of mAF of patient specific mutations in plasma and urine from patient 5842. Fig. S26. Assessment of tumor heterogeneity representation in plasma from patient 5634.

Contains fulltext : 294430.pdf (Publisher’s version ) (Open Access) BACKGROUND: Ta grade 3 (G3) non-muscle-invasive bladder cancer (NMIBC) is a relatively rare diagnosis with an ambiguous character owing to the presence of an aggressive G3 component together with the lower malignant potential of the Ta component. The European Association of Urology (EAU) NMIBC guidelines recently changed the risk stratification for Ta G3 from high risk to intermediate, high, or very high risk. However, prognostic studies on Ta G3 carcinomas are limited and inconclusive. OBJECTIVE: To evaluate the prognostic value of categorizing Ta G3 compared to Ta G2 and T1 G3 carcinomas. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data for 5170 primary Ta-T1 bladder tumors from 17 hospitals were analyzed. Transurethral resection of the tumor was performed between 1990 and 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to recurrence and time to progression were analyzed using cumulative incidence functions, log-rank tests, and multivariable Cox-regression models with interaction terms stratified by institution. RESULTS AND LIMITATIONS: Ta G3 represented 7.5% (387/5170) of Ta-T1 carcinomas of which 42% were classified as intermediate risk. Time to recurrence did not differ between Ta G3 and Ta G2 (p = 0.9) or T1 G3 (p = 0.4). Progression at 5 yr occurred for 3.6% (95% confidence interval [CI] 2.7-4.8%) of Ta G2, 13% (95% CI 9.3-17%) of Ta G3, and 20% (95% CI 17-23%) of T1 G3 carcinomas. Time to progression for Ta G3 was shorter than for Ta G2 (p