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Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behavior of cancer cells and their adaptation to the coevolving microenvironment and response to treatment. In alignment with this concept, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR). A comprehensive understanding of DDR mutation-associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for th.
Urothelial carcinoma is the most common type of carcinoma of the urinary bladder in the Western world. Currently TNM stage and WHO grade are the most important histopathologic parameters to classify patients into low- and high-risk groups and to decide appropriate treatment. However, as differentiating between stage Ta and T1 on surgical specimens is difficult and grade has only poor to fair reproducibility, these parameters do not precisely predict tumor recurrence or stage progression. As a consequence, patients undergo an intensive follow-up regimen and as such the treatment cost per patient for bladder cancer is one of the highest among all cancer types. Therefore, better prognostic and predictive markers are warranted. The aim of the p.
Introduction: Exceedingly little is known about the genomic difference between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We evaluated and compared genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end-stage disease. Methods: We performed whole-exome sequencing on 37 tumor samples from 7 patients with metastatic UC collected between 2015-2017 via rapid autopsy, with matched primary and metastatic tumor samples. Inter- and intrapatient analyses of mutational burden, mutational signatures, predicted deleterious mutations (somatic single nucleotide variations [sSNV] and insertions-deletions), and somatic copy alterations (sCNV) were conducted. Results: We inves.
Treating BCR-ABL–positive chronic myeloid leukemia remains impeded by the development of clinical resistance to imatinib. It has been demonstrated that berberine, a plant alkaloid, has activity against imatinib-resistant BCR-ABL mutants by inducing autophagic degradation of BCR-ABL, thereby preventing the acquisition of drug-resistant mutations. See related article by Yin et al., p. 4040.
Background: FGFR inhibition is a promising and clinically proven therapeutic approach in a number of solid tumors where genetic alterations of FGFR drive oncogenesis. PRN1371 is a highly selective oral, irreversible inhibitor of FGFR1-4 that exhibits high potency in cancer cell lines harboring FGFR alterations, including mutations and fusions. Methods: Part A of this phase 1 open-label, multicenter clinical trial explored ascending doses of PRN1371 in adult patients with advanced solid tumors who had received at least one prior treatment for recurrent, metastatic, and/or locally advanced disease, and for whom no standard therapy options were anticipated to result in a durable remission. The primary objectives were to investigate the safety
Background: FGFR3 mutations (mutFGFR3) are present in up to 20-35% of metastatic bladder (mUC) and upper tract urothelial cancer, respectively. Early data suggest that these tumors respond better to FGFR inhibition as compared with immunotherapy. Methods: Patients who failed prior treatment for mUC were treated with vofatamab, an antibody targeting both wild-type (wtFGFR3) and mutFGFR3. Patients were treated with a loading dose of vofatamab 25 mg/kg with a biopsy pre- and post-treatment, followed by combination therapy with pembrolizumab to cohorts of patients with and without mutFGFR3. We performed gene expression profiling on paired biopsies from patients enrolled to date. Results: We performed whole-transcriptome RNAseq on 17 matched tum.
Introduction and Objective: Cisplatin is an important chemotherapeutic agent against metastatic bladder cancer, but resistance often limits its usage. With the recent recognition of lipid metabolic alterations in bladder cancers, we studied the metabolic implications of cisplatin resistance using cisplatin-sensitive (T24S) and -resistant (T24R) bladder cancer cells. Methods: To test whether there should be differences in metabolism and metabolism-associated pathways between cisplatin-sensitive and resistant bladder cancer cells, we applied the live metabolomics approach that we recently developed to isogenic bladder cancer cell lines T24S (cisplatin sensitive) and T24R (cisplatin resistant). The metabolites generated from 13C-glucose tracer.
The addition of cisplatin-based neoadjuvant chemotherapy prior to radical cystectomy provides a modest overall survival benefit for patients with muscle-invasive bladder cancer (MIBC). Moreover, the extent of pathologic response at cystectomy correlates with survival, and patients who achieve a complete pathologic response following neoadjuvant chemotherapy have significantly improved survival compared to patients with residual MIBC. Clinical features alone are unable to predict which patients will respond to neoadjuvant chemotherapy, and there is an urgent clinical need to identify genomic biomarkers to guide neoadjuvant therapy for MIBC. The Cancer Genome Atlas (TCGA) and related efforts have defined the genomic landscape of MIBC and have.
Introduction and Objectives: Despite multiple resections and long-term chemo and immunotherapy, most non-muscle invasive bladder cancer patients suffer from recurrence or progression leading to cystectomy and a less favorable outcome. Possible reasons for that are incomplete resection and reimplantation of cancer cells, which could be prevented by improved resection and adjuvant therapy. Our objective was to develop a targeted drug for detection, fluorescence-guided resection, and deep-penetrating adjuvant photodynamic therapy of urothelial carcinoma (UC). The agent was based on upconversion nanoparticles (UCNP), which can carry a photosensitizer and can transform deep-penetrating near-infrared light into high-energy visible light, demanded.
Purpose: Machine-learning assisted histopathology using markers of basal and luminal differentiation was employed to profile the intratumoral heterogeneity of bladder cancer from cystectomy patients and predict disease-free survival in this high-risk patient population. Methods: Urothelial carcinomas are biologically heterogeneous and vary greatly in clinical progression as well as treatment response.
Bladder cancer can be divided into several major subtypes that include urothelial carcinoma, squamous cell carcinoma, adenocarcinoma and neuroendocrine carcinoma. Urothelial carcinoma, the most common form of bladder cancer, is further subdivided into numerous histologic variants based on distinct morphologic features. While histologic characterization remains the most important factor in diagnosis and patient management, emerging molecular data across bladder cancer subtypes and variants may potentially alter how bladder cancer is classified. Large scale -omic analytics have uncovered unique signatures within major bladder cancer subtypes. In addition, molecular groupings and unique single-gene alterations have been identified within uroth.
In recent years, we have witnessed an explosion in both therapeutic drug development and our understanding of the key biologic drivers and targets in bladder cancer. While new drug approvals have thus far been confined to metastatic patients, several promising agents have fully accrued key FDA registration studies in the BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) population. Initial early-response data in the carcinoma in situ (CIS) populations demonstrate clear signals of activity with long-term follow-up ongoing to assess response durability. Agents administered by either intravesical or systemic routes are among those being assessed. While urologists, medical oncologists, and radiation oncologists have long worked togeth.
Purpose:. The activating mutation AKT1 E17K occurs in approximately 7% of estrogen receptor–positive (ER + ) metastatic breast cancer (MBC). We report, from a multipart, first-in-human, phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of patients with AKT1 E17K -mutant ER + MBC. Patients and Methods:. Patients with an AKT1 E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST
The culture of cancer cells from urine samples is a simple, noninvasive technique that has the potential to advance the diagnosis, treatment, and monitoring of patients with bladder cancer, and the generation of such urine-derived cultures can provide both genetic and phenotypic data for precision medicine.
Background: Patients with advanced bladder cancer have limited therapeutic options, apart from cisplatin-based chemotherapy and use of immune checkpoint inhibitors (ICI). Median survival for patients with metastatic disease is 15 to 18 months. Hence there is a need for more effective therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated durable and complete responses with long-term survival of > 10 years in patients with metastatic melanoma. Previous attempts to generate TIL from bladder cancer showed some success; however, the process required an extended manufacturing time (35–50+ days). Iovance has developed a second-generation GMP manufacturing process (Gen 2) with a significantly reduced time to e.
Purpose:. Several groups have reported a prevalence of human cytomegalovirus (CMV) in glioblastoma close to 100%. Previously, we reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged survival in 50 patients with glioblastoma. Here, we present an updated retrospective analysis that includes an additional 52 patients. Experimental Design:. From December 2006 to November 2019, 102 patients with newly diagnosed glioblastoma received valganciclovir as an add-on to standard therapy. No additional toxicity was observed. Contemporary controls were 231 patients with glioblastoma who received similar baseline therapy. Results:. Patients with newly diagnosed glioblastoma receiving valganci.
Urothelial carcinoma (UC) arises from epithelial lining of pyelocaliceal cavities, ureter, bladder, and urethra and is the sixth most common cancer in the United States. UC of bladder (UCB) accounts for 90–95% of UCs, and upper tract UC (UTUC) is substantially less common (5–10%). Clinical implication is generally extrapolated to UTUC from biologic studies in UCB due to the rarity of this disease. Although UTUC and UCB share similar histologic appearances and some common gene alterations, UTUC exhibits distinct epidemiologic and clinical features. For example, UTUC patients tend to have high risk of tumor recurrence and poor prognosis compared with UCB, especially in advanced disease. These observations suggest that some unique molecular pa.
Background: Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes, improving prediction of clinical outcomes and treatment responses. FGFR3 alterations (mutations and translocations), observed in 20% of MIBCs, are found mainly in the luminal papillary subtype that respond poorly to chemo- and immunotherapy. Basal tumors represent 35% of MIBCs and were shown to be better responders to chemotherapy. Here, we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these main subtypes. Methods: Bladder tumors were obtained from pa.

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