Search

The increasing availability of genomic sequencing of tumor tissue in oncology provided valuable insights into tumor evolution and offered clinicians the unprecedented opportunity to tailor therapies on each individual patient, according to the treatment-impacting alterations identified in the tumor cells. In addition to the characterization of somatic alterations in tumor samples, the identification of germline (i.e., constitutional) pathogenic variants can provide additional information to guide informed and personalized therapeutic planning for patients and to enable risk-based screening protocols for at-risk relatives. In genitourinary malignancies, only a few associations between germline mutations and cancer risk and behavior have been thoroughly investigated (e.g., alterations in DNA repair genes in prostate cancer or mutations in Lynch syndrome genes in upper tract urothelial carcinoma). To achieve a wider use of both tumor genomic and germline genetic testing, an integrative approach led by scientific societies is necessary to involve physicians, patients and advocacy groups, to develop a shared strategy to advance the field and provide value-based and reproducible standards of care for patients and their families.

A 41-yr-old, otherwise healthy, premenopausal woman presented at our uro-oncology clinic with a diagnosis of muscle-invasive bladder cancer following a transurethral resection of the bladder performed at another center. After a thorough discussion with the patient, she was enrolled in the phase II PURE-01 trial (NCT02736266), testing three cycles of neoadjuvant pembrolizumab (200mg) every 3 wk before radical cystectomy. Before treatment, imaging studies were obtained as per the protocol using computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT, and multiparametric magnetic resonance imaging of the bladder, defining a clinically localized T2N0M0 stage. As per the protocol, potential biomarkers were assessed, including PD-L1 expression (84% combined positive score), tumor mutational burden (16.67 mut/Mb), and genomic profiling (FoundationONE assay; somatic mutation in TP53, EZH2, APC, TERT, CDKN1A, CDKN1B, and ARID1Agenes, and truncation in BRCA2gene). After immunotherapy, the patient underwent a robot-assisted radical cystectomy with extended pelvic lymph node dissection. The final pathology report revealed absence of residual disease (ie, pathological complete response, ypT0ypN0). During follow-up, the only relevant and permanent immune-mediated adverse event was hypothyroidism secondary to an autoimmune thyroiditis. It appeared 2 mo after radical cystectomy and it was managed successfully with hormonal replacement therapy. Two years after treatment, the patient is asymptomatic and free from disease recurrence.

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher’s exact test, and logistic regression analyses to analyze the associations between the various FGFR3alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3GAs or high FGFR3signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time.

Halogenated and alkylated BODIPY derivatives are reported as suitable candidates for their use as photosensitizers in photodynamic therapy due to their efficient intersystem crossing (ISC) between states of different spin multiplicities. Spin–orbit couplings (SOCs) are evaluated using an effective one-electron spin–orbit Hamiltonian for brominated and alkylated BODIPY derivatives to investigate the quantitative effect of alkyl and bromine substituents on ISC. BODIPY derivatives containing bromine atoms have been found to have significantly stronger SOCs than alkylated BODIPY derivatives outside the Frank–Condon region while they are nearly the same at local minima. Based on calculated time-dependent density functional theory (TD-DFT) vertical excitation energies and SOCs, excited-state dynamics of three BODIPY derivatives were further explored with TD-DFT surface hopping molecular dynamics employing a simple accelerated approach. Derivatives containing bromine atoms have been found to have very similar lifetimes, which are much shorter than those of the derivatives possessing just the alkyl moieties. However, both bromine atoms and alkyl moieties reduce the HOMO/LUMO gap, thus assisting the derivatives to behave as efficient photosensitizers.

Data on the impact of human papillomavirus (HPV) infection status and outcomes for perioperative treatments for patients with lymph node–involved penile squamous-cell carcinoma (PSCC) are lacking.

Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT1/a/isypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT1/a/isypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders.

This paper assesses the impact on capital requirements of the Fundamental Review of the Trading Book (FRTB) based on a stylised financial portfolio sensible to the risk factors affected by the review. Our results show the order of magnitude of the increase across the two regulations and the two possible approaches: the standard approach and the internal model approach. We further disentangle the components of the expected increase implied by the FRTB. The most interesting result emerges for the internal model approach, whereby the increase in the capital charge is attributable not only to the change in the risk measure and the inclusion of longer liquidity horizons, but most importantly to the dampening of the diversification benefit.

Comprehensive characterization of the urinary and urothelium-bound microbiomes in bladder cancer (BCa) and healthy state is essential to understand how these local microbiomes may play a role in BCa tumorigenesis and response to therapy, as well as to explain sex-based differences in BCa pathobiology. Performing 16 s rDNA microbiome analysis on 166 samples (urine and paired bladder tissues) from therapy-naïve BCa patients undergoing radical cystectomy and healthy controls, we defined (1) sex-specific microbiome differences in the urine and bladder tissue, and (2) representativeness of the tissue microenvironment by the voided urinary microbiome. The genus Klebsiellawas more common in the urine of female BCa patients versus healthy controls, while no clinically relevant bacteria were found differently enriched in men. In tissues, the genus Burkholderiawas more abundant in the neoplastic versus the non-neoplastic tissue in both sexes, suggesting a potential role in BCa pathobiology. Lastly, we found that the urinary microbiome shares >80% of the bacterial families present in the paired bladder tissue, making the urinary microbiome a fair proxy of the tissue bacterial environment.

Nonurothelial carcinoma (UC) malignancies have traditionally been considered to have a more aggressive clinical course, and little is known about their response to neoadjuvant therapy. We examined the effect of neoadjuvant chemotherapy (NAC) on a large population of patients with bladder cancer (BCa) with different histologic variants (HVs).

Despite improvements in diagnosis and treatment approaches, prostate cancer remains a leading cause of cancer-related death in men. PC progresses through various stages, mostly driven by androgen receptor signaling. However, after androgen deprivation therapies, in a significant portion of patients, several different molecular mechanisms contribute to the development of castration-resistance. Delving deeply into the molecular landscape of castration-resistant prostate cancer, grasping the selective pressures exerted by therapies, and understanding the drivers of lineage plasticity is pivotal to prevent progression. Targeting genetic and epigenetic alterations that drive this transition will guide clinical management strategies and possibly prevent and/or treat lethal disease.

•Using clinical samples of urothelial carcinoma and paired non-neoplastic tissue, we identified a progressive increase of the re-arrangement of the collagen fibers topography from the beginning of the inflammatory process to the tumor onset and invasion.•In two preclinical models, we demonstrated that the re-arrangement of the topography of the collagen fibers created a ground that favors the onset of the tumor. Findings from this study are exploitable for identifying bladder areas at risk of tumor relapse.•Additionally, this study opens avenues for the intravesical instillation of adjuvant therapy that targets enzymes responsible for the linearization of collagen fibers.

Halogenated BODIPY derivatives are emerging as important candidates for photodynamic therapy of cancer cells due to their high triplet quantum yield. We probed fundamental photophysical properties and interactions with biological environments of such photosensitizers. To this end, we employed static TD-DFT quantum chemical calculations as well as TD-DFT surface hopping molecular dynamics on potential energy surfaces resulting from the eigenstates of the total electronic Hamiltonian including the spin–orbit (SO) coupling. Matrix elements of an effective one-electron spin–orbit Hamiltonian between singlet and triplet configuration interaction singles (CIS) auxiliary wave functions are calculated using a new code capable of dealing with singlets and both restricted and unrestricted triplets built up from up to three different and independent sets of (singlet, alpha, and beta) molecular orbitals. The interaction with a biological environment was addressed by using classical molecular dynamics (MD) in a scheme that implicitly accounts for electronically excited states. For the surface hopping trajectories, an accelerated MD approach was used, in which the SO couplings are scaled up, to make the calculations computationally feasible, and the lifetimes are extrapolated back to unscaled SO couplings. The lifetime of the first excited singlet state estimated by semiclassical surface hopping simulations is 139 ± 75 ps. Classical MD demonstrates that halogenated BODIPY in the ground state, in contrast to the unsubstituted one, is stable in the headgroup region of minimalistic cell membrane models, and while in the triplet state, the molecule relocates to the membrane interior ready for further steps of photodynamic therapy.