Muscle-invasive bladder cancer::staging and treatment

Horenblas, S. [Promotor]Rhijn, B.W.G. [Copromotor

Algorithms for Game Metrics

Simulation and bisimulation metrics for stochastic systems provide a quantitative generalization of the classical simulation and bisimulation relations. These metrics capture the similarity of states with respect to quantitative specifications written in the quantitative {\mu}-calculus and related probabilistic logics. We first show that the metrics provide a bound for the difference in long-run average and discounted average behavior across states, indicating that the metrics can be used both in system verification, and in performance evaluation. For turn-based games and MDPs, we provide a polynomial-time algorithm for the computation of the one-step metric distance between states. The algorithm is based on linear programming; it improves on the previous known exponential-time algorithm based on a reduction to the theory of reals. We then present PSPACE algorithms for both the decision problem and the problem of approximating the metric distance between two states, matching the best known algorithms for Markov chains. For the bisimulation kernel of the metric our algorithm works in time O(n^4) for both turn-based games and MDPs; improving the previously best known O(n^9\cdot log(n)) time algorithm for MDPs. For a concurrent game G, we show that computing the exact distance between states is at least as hard as computing the value of concurrent reachability games and the square-root-sum problem in computational geometry. We show that checking whether the metric distance is bounded by a rational r, can be done via a reduction to the theory of real closed fields, involving a formula with three quantifier alternations, yielding O(|G|^O(|G|^5)) time complexity, improving the previously known reduction, which yielded O(|G|^O(|G|^7)) time complexity. These algorithms can be iterated to approximate the metrics using binary search.Comment: 27 pages. Full version of the paper accepted at FSTTCS 200

Tumor Heterogeneity of Fibroblast Growth Factor Receptor 3 (FGFR3) Mutations in Invasive Bladder Cancer: Implications for Peri-Operative anti-FGFR3 Treatment

Background: Fibroblast growth factor receptor 3 (FGFR3) is an actionable target in bladder cancer. Preclinical studies show that anti-FGFR3 treatment slows down tumor growth, suggesting that this tyrosine kinase receptor is a candidate for personalized bladder cancer treatment, particularly in patients with mutated FGFR3. We addressed tumor heterogeneity in a large multicenter, multi-laboratory study, as this may have significant impact on therapeutic response. Patients: and methods We evaluated possible FGFR3 heterogeneity by the PCR-SNaPshot method in the superficial and deep compartments of tumors obtained by transurethral resection (TUR, n = 61) and in radical cystectomy (RC, n = 614) specimens and corresponding cancer-positive lymph nodes (LN+, n = 201).Results: We found FGFR3 mutations in 13/34 (38%) T1 and 8/27 (30%) ≥T2-TUR samples, with 100% concordance between superficial and deeper parts in T1-TUR samples. Of eight FGFR3 mutant ≥T2-TUR samples, only 4 (50%) displayed the mutation in the deeper part. We found 67/614 (11%) FGFR3 mutations in RC specimens. FGFR3 mutation was associated with pN0 (P < 0.001) at RC. In 10/201 (5%) LN+, an FGFR3 mutation was found, all concordant with the corresponding RC specimen. In the remaining 191 cases, RC and LN+ were both wild type.Conclusions: FGFR3 mutation status seems promising to guide decision-making on adjuvant anti-FGFR3 therapy as it appeared homogeneous in RC and LN+. Based on the results of TUR, the deep part of the tumor needs to be assessed if neoadjuvant anti-FGFR3 treatment is considered. We conclude that studies on the heterogeneity of actionable molecular targets should precede clinical trials with these drugs in the perioperative setting

Occult lymph node metastases in patients without residual muscle-invasive bladder cancer at radical cystectomy with or without neoadjuvant chemotherapy: a nationwide study of 5417 patients

Purpose Little is known about the prevalence of occult lymph node metastases (LNM) in muscle-invasive bladder cancer (MIBC) patients with pathological downstaging of the primary tumor. We aimed to estimate the prevalence of occult LNM in patients without residual MIBC at radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC) or neoadjuvant radiotherapy (NAR), and to assess overall survival (OS). Methods Patients with cT2-T4aN0M0 urothelial MIBC who underwent RC plus pelvic lymph node dissection (PLND) with curative intent between January 1995-December 2013 (retrospective Netherlands Cancer Registry (NCR) cohort) and November 2017-October 2019 (prospective NCR-BlaZIB cohort (acronym in Dutch: BlaaskankerZorg In Beeld; in English: Insight into bladder cancer care)) were identified from the nationwide NCR. The prevalence of occult LNM was calculated and OS of patients with y)pT2N0 vs. y)pT2N+ disease was estimated by the Kaplan-Meier method. Results In total, 4657 patients from the NCR cohort and 760 patients from the NCR-BlaZIB cohort were included. Of 1374 patients downstaged to y)pT2, 4.3% (N = 59) had occult LNM 4.1% (N = 49) of patients with cT2-disease and 5.6% (N = 10) with cT3-4a-disease. This was 4.0% (N = 44) in patients without NAC or NAR, 4.5% (N = 10) in patients with NAC, and 13.5% (N = 5) in patients with NAR but number of patients treated with NAR and downstaged disease was small. The prevalence of y)pT2N+ disease was 4.2% (N = 48) in the NCR cohort and 4.6% (N = 11) in the NCR-BlaZIB cohort. For patients with y)pT2N+ and y)pT2N0, median OS was 3.5 years (95% CI 2.5-8.9) versus 12.9 years (95% CI 11.7-14.0), respectively. Conclusion Occult LNM were found in 4.3% of patients with cT2-4aN0M0 MIBC with (near-) complete downstaging of the primary tumor following RC plus PLND. This was regardless of NAC or clinical T-stage. Patients with occult LNM showed considerable worse survival. These results can help in counseling patients for bladder-sparing treatments.Urolog