Characterization of actionable genetic alterations to guide targeted therapy for metastatic urothelial carcinoma.

407 Background: Genetic alterations predicting response to targeted therapy are an area of active interest in developing novel therapies for patients with metastatic urothelial carcinoma (mUC). With the objective of characterizing the frequency of actionable alterations (AA) and the evidence supporting targeted therapy for these AAs, we report our experience with next-generation sequencing in mUC. Methods: Patients with sequenced mUC lesions were identified from our prospectively-maintained database. All AAs with clinical or biologic evidence supporting the alteration as predicting response to targeted therapy were identified and stratified by Oncology Knowledge Base (OncoKB) level of evidence (table). The relationship between strength of evidence and administration of targeted therapy was examined. Results: Ninety-nine of 134 patients (74%) harbored at least one AA, with 162 total AAs identified. Twenty level 2B AAs were identified, reflecting the highest level evidence in this cohort, with ERBB2 amplification (9), TSC1/TSC2 (6), and BRCA1/BRCA2 mutations (3) most common. Twenty-eight level 3A, 51 level 3B, and 62 level 4 AAs were also identified. Seventeen patients received targeted therapy, which was administered with greater frequency among patients with level 3B or higher AAs (21% vs 3%). Conclusions: Most patients with mUC harbor at least one AA, suggesting multiple targeted therapeutic opportunities in mUC. These findings highlight the need for additional clinical trials and the role of genetic testing in identifying candidates for targeted therapy. [Table: see text]

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The role of angiogenic signatures in advanced urothelial carcinoma (aUC) treated with VEGF-targeted therapy

European Urology ◽

10.1016/s0302-2838(21)00843-5 ◽

2021 ◽

Vol 79 ◽

pp. S636

Author(s):

F.E. Jackson-Spence ◽

C. Ackerman ◽

M. Khan ◽

M. Grant ◽

G. Soosaipillai ◽

...

Keyword(s):

Targeted Therapy ◽

Urothelial Carcinoma ◽

Advanced Urothelial Carcinoma

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The role of radical cystectomy in patients with unresectable or regionally metastatic urothelial carcinoma of the bladder

Bladder cancer ◽

10.1002/9781118674826.ch17 ◽

2015 ◽

pp. 190-197

Author(s):

Scott Delacroix ◽

Nathan Lawrentschuk ◽

Ashish M. Kamat

Keyword(s):

Urothelial Carcinoma ◽

Radical Cystectomy ◽

Metastatic Urothelial Carcinoma ◽

Carcinoma Of The Bladder

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Current Strategies and Novel Therapeutic Approaches for Metastatic Urothelial Carcinoma

Cancers ◽

10.3390/cancers12061449 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1449 ◽

Cited By ~ 4

Author(s):

Veronica Mollica ◽

Alessandro Rizzo ◽

Rodolfo Montironi ◽

Liang Cheng ◽

Francesca Giunchi ◽

...

Keyword(s):

Medical Treatment ◽

Urothelial Carcinoma ◽

Checkpoint Inhibitors ◽

Cancer Control ◽

Parp Inhibitors ◽

Published Data ◽

Drug Conjugates ◽

Platinum Based Chemotherapy ◽

Metastatic Urothelial Carcinoma

Urothelial carcinoma (UC) is a frequent cause of cancer-related deaths worldwide. Metastatic UC has been historically associated with poor prognosis, with a median overall survival of approximately 15 months and a 5-year survival rate of 18%. Although platinum-based chemotherapy remains the mainstay of medical treatment for patients with metastatic UC, chemotherapy clinical trials produced modest benefit with short-lived, disappointing responses. In recent years, the better understanding of the role of immune system in cancer control has led to the development and approval of several immunotherapeutic approaches in UC therapy, where immune checkpoint inhibitors have been revolutionizing the treatment of metastatic UC. Because of a better tumor molecular profiling, FGFR inhibitors, PARP inhibitors, anti-HER2 agents, and antibody drug conjugates targeting Nectin-4 are also emerging as new therapeutic options. Moreover, a wide number of trials is ongoing with the aim to evaluate several other alterations and pathways as new potential targets in metastatic UC. In this review, we will discuss the recent advances and highlight future directions of the medical treatment of UC, with a particular focus on recently published data and ongoing active and recruiting trials.

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Are Virtual Particles Less Real?

Entropy ◽

10.3390/e21020141 ◽

2019 ◽

Vol 21 (2) ◽

pp. 141 ◽

Cited By ~ 3

Author(s):

Gregg Jaeger

Keyword(s):

Quantum Field ◽

Interacting Particles ◽

Virtual Particles ◽

Quantum Particles ◽

Action At A Distance ◽

Relationship Of ◽

The Relationship

The question of whether virtual quantum particles exist is considered here in light of previous critical analysis and under the assumption that there are particles in the world as described by quantum field theory. The relationship of the classification of particles to quantum-field-theoretic calculations and the diagrammatic aids that are often used in them is clarified. It is pointed out that the distinction between virtual particles and others and, therefore, judgments regarding their reality have been made on basis of these methods rather than on their physical characteristics. As such, it has obscured the question of their existence. It is here argued that the most influential arguments against the existence of virtual particles but not other particles fail because they either are arguments against the existence of particles in general rather than virtual particles per se, or are dependent on the imposition of classical intuitions on quantum systems, or are simply beside the point. Several reasons are then provided for considering virtual particles real, such as their descriptive, explanatory, and predictive value, and a clearer characterization of virtuality—one in terms of intermediate states—that also applies beyond perturbation theory is provided. It is also pointed out that in the role of force mediators, they serve to preclude action-at-a-distance between interacting particles. For these reasons, it is concluded that virtual particles are as real as other quantum particles.

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Traumatic glioblastoma: commentary and suggested mechanism

Journal of International Medical Research ◽

10.1177/0300060518771265 ◽

2018 ◽

Vol 46 (6) ◽

pp. 2170-2176

Author(s):

Nissim Ohana ◽

Daniel Benharroch ◽

Dimitri Sheinis ◽

Abraham Cohen

Keyword(s):

Traumatic Brain Injury ◽

Transcription Factors ◽

Brain Injury ◽

Brain Injuries ◽

Hypoxia Inducible Factor ◽

Subsequent Development ◽

Factors Associated ◽

The Relationship

The role of head trauma in the development of glioblastoma is highly controversial and has been minimized since first put forward. This is not unexpected because skull injuries are overwhelmingly more common than glioblastoma. This paper presents a commentary based on the contributions of James Ewing, who established a major set of criteria for the recognition of an official relationship between trauma and cancer. Ewing’s criteria were very stringent. The scholars who succeeded Ewing have facilitated the characterization of traumatic brain injuries since the introduction of computed tomography and magnetic resonance imaging. Discussions of the various criteria that have since developed are now being conducted, and those of an unnecessarily limiting nature are being highlighted. Three transcription factors associated with traumatic brain injury have been identified: p53, hypoxia-inducible factor-1α, and c-MYC. A role for these three transcription factors in the relationship between traumatic brain injury and glioblastoma is suggested; this role may support a cause-and-effect link with the subsequent development of glioblastoma.

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Filament Fragmentation Phenomena

MRS Proceedings ◽

10.1557/proc-170-65 ◽

1989 ◽

Vol 170 ◽

Author(s):

Juan C. Figueroa ◽

Linda S. Schadler ◽

Campbell Laird

Keyword(s):

Strain Energy ◽

Stress Transfer ◽

Fiber Surface ◽

Yield Information ◽

The Matrix ◽

Two Parameters ◽

The Relationship

AbstractThe effect of fiber surface treatments on the relationship between the tensile strength of a filament and the shear strength of its interphase is one of the central issues facing composite materials technologists today. We demonstrate here that analysis of fragmentation phenomena in monofilament composites can simultaneously yield information about these two parameters. Characterization of shear stress transfer zones in non-critical fragments has led us to the determination of interphase strength.A phenomenological treatment that highlights the role of the matrix in the fragmentation process is presented here. This analysis considers issues such as the strain energy exchange between a failing fiber and the matrix, as well as interphase relaxation due to the viscoelastic nature of the matrix. Our observations of the fragmentation phenomena in AU4/polycarbonate monofilament composites indicate that the fiber/matrix interaction in this system is governed by micromechanical locking.

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Quantum potentiality revisited

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2016.0390 ◽

2017 ◽

Vol 375 (2106) ◽

pp. 20160390 ◽

Cited By ~ 6

Author(s):

Gregg Jaeger

Keyword(s):

Quantum System ◽

Careful Consideration ◽

Full Detail ◽

Natural Evolution ◽

Quantum Revolution ◽

The Relationship ◽

Physical Causation ◽

Common Character

Heisenberg offered an interpretation of the quantum state which made use of a quantitative version of an earlier notion, , of Aristotle by both referring to it using its Latin name, potentia , and identifying its qualitative aspect with . The relationship between this use and Aristotle's notion was not made by Heisenberg in full detail, beyond noting their common character: that of signifying the system's objective capacity to be found later to possess a property in actuality. For such actualization, Heisenberg required measurement to have taken place, an interaction with external systems that disrupts the otherwise independent, natural evolution of the quantum system. The notion of state actualization was later taken up by others, including Shimony, in the search for a law-like measurement process. Yet, the relation of quantum potentiality to Aristotle's original notion has been viewed as mainly terminological, even by those who used it thus. Here, I reconsider the relation of Heisenberg's notion to Aristotle's and show that it can be explicated in greater specificity than Heisenberg did. This is accomplished through the careful consideration of the role of potentia in physical causation and explanation, and done in order to provide a fuller understanding of this aspect of Heisenberg's approach to quantum mechanics. Most importantly, it is pointed out that Heisenberg's requirement of an external intervention during measurement that disrupts the otherwise independent, natural evolution of the quantum system is in accord with Aristotle's characterization of spontaneous causation. Thus, the need for a teleological understanding of the actualization of potentia, an often assumed requirement that has left this fundamental notion neglected, is seen to be spurious. This article is part of the themed issue ‘Second quantum revolution: foundational questions’.

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