Inflammatory Myofibroblastic Tumor: A Case Study

AbstractInflammatory myofibroblastic tumor (IMT) is a rare benign lesion found in many locations throughout the body and genitourinary tract. Endoscopically and radiographically, these solid lesions cannot be distinguished from malignant bladder tumors. We present the case of a 21-year-old woman who presented with painful obstructive and irritative voiding symptoms of short duration. After extensive preoperative evaluation failed to reveal a definitive diagnosis, the patient underwent partial cystectomy. Final pathology revealed IMT. A high index of suspicion is required for diagnosis of IMT as it is often difficult to distinguish from its malignant counterparts

Synthesis and Biological Evaluation of Novobiocin Core Analogues as Hsp90 Inhibitors

Development of heat shock protein 90 (Hsp90) C‐terminal inhibitors has emerged as an exciting strategy for the treatment of cancer. Previous efforts have focused on modifications to the natural products novobiocin and coumermycin. Moreover, variations in both the sugar and amide moieties have been extensively studied, whereas replacements for the coumarin core have received less attention. Herein, 24 cores were synthesized with varying distances and angles between the sugar and amide moieties. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity, were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Angle of attack: The distance and angle between the N‐methylpiperidine and the biaryl side chain was analyzed in an effort to develop more potent Hsp90 C‐terminal inhibitors. Compounds that exhibited good anti‐proliferative activity against multiple cancer cell lines and Hsp90 inhibitory activity were those that placed the sugar and amide moieties between 7.7 and 12.1 Å apart along with angles of 180°.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/1/chem201504955_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/2/chem201504955.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136281/3/chem201504955-sup-0001-misc_information.pd

ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer

PURPOSE: Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). METHODS: ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival. RESULTS: As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events. CONCLUSION: Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer

© 2020 Elsevier Ltd. All rights reserved. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence http://creativecommons.org/licenses/by-nc-nd/4.0/.Objective: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC). Methods: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses. Results: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75–1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71–1.58, P = 0.77). Conclusion: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.Peer reviewedFinal Accepted Versio

Development and characterization of a novel C-terminal inhibitor of Hsp90 in androgen dependent and independent prostate cancer cells

Background: The molecular chaperone, heat shock protein 90 (Hsp90) has been shown to be overexpressed in a number of cancers, including prostate cancer, making it an important target for drug discovery. Unfortunately, results with N-terminal inhibitors from initial clinical trials have been disappointing, as toxicity and resistance resulting from induction of the heat shock response (HSR) has led to both scheduling and administration concerns. Therefore, Hsp90 inhibitors that do not induce the heat shock response represent a promising new direction for the treatment of prostate cancer. Herein, the development of a C-terminal Hsp90 inhibitor, KU174, is described, which demonstrates anti-cancer activity in prostate cancer cells in the absence of a HSR and describe a novel approach to characterize Hsp90 inhibition in cancer cells.Methods: PC3-MM2 and LNCaP-LN3 cells were used in both direct and indirect in vitro Hsp90 inhibition assays (DARTS, Surface Plasmon Resonance, co-immunoprecipitation, luciferase, Western blot, anti-proliferative, cytotoxicity and size exclusion chromatography) to characterize the effects of KU174 in prostate cancer cells. Pilot in vivo efficacy studies were also conducted with KU174 in PC3-MM2 xenograft studies.Results: KU174 exhibits robust anti-proliferative and cytotoxic activity along with client protein degradation and disruption of Hsp90 native complexes without induction of a HSR. Furthermore, KU174 demonstrates direct binding to the Hsp90 protein and Hsp90 complexes in cancer cells. In addition, in pilot in-vivo proof-of-concept studies KU174 demonstrates efficacy at 75 mg/kg in a PC3-MM2 rat tumor model.Conclusions: Overall, these findings suggest C-terminal Hsp90 inhibitors have potential as therapeutic agents for the treatment of prostate cancer.Peer reviewedBiochemistry and Molecular Biolog

Where are we with bladder preservation for muscle-invasive bladder cancer in 2017?

Introduction: In 2017, neoadjuvant, cisplatin-based chemotherapy followed by radical cystectomy (RC) is considered the gold standard therapy for muscle-invasive bladder based on randomized controlled trials. Across all tumor stages, this approach has been associated with the highest rates of disease-specific survival. However, RC is one of the most challenging procedures performed by urologic surgeons and carries with it significant risks of complications, hospital readmission, and even a small risk of mortality, in addition to lifestyle changes that can have long-term effects on well-being. For these reasons, bladder-sparing approaches are utilized in some highly selected patients. We reviewed the most recent evidence for bladder-sparing modalities for muscle-invasive urothelial bladder cancer and summarize those findings in this review article. Methods: We performed a PubMed literature review utilizing the key words “bladder preservation,” “trimodal therapy,” “muscle-invasive bladder cancer,” and “partial cystectomy” written in English, dating back to 1990. We excluded case reports. Results: Our search yielded more than 2000 articles which we screened. Some articles were then rejected due to inappropriate topic. In addition, we reviewed the most recent American Urological Association, National Comprehensive Cancer Network (NCCN), and European guidelines on muscle-invasive bladder cancer. We identified fifty relevant articles which are summarized in this text. In some rare instances, recommendations are based on expert opinion. Conclusions: Bladder preservation is often considered for quality of life considerations or in the setting of multiple medical comorbidities, and this remains oncologically appropriate even in 2016 in highly selected patients with muscle-invasive urothelial carcinoma of the bladder

Near-Miss Diagnoses of Solitary Bladder Tumors Highlight the Importance of Immunohistochemical Staining

We report three cases of prostate adenocarcinoma appearing as bladder masses and misdiagnosed as muscle-invasive bladder cancer (MIBC). Patients were referred for consideration for radical cystectomy after initial pathological diagnosis suggested poorly differentiated bladder cancer. Pathological review of tissue samples and subsequent immunohistochemical (IHC) staining confirmed advanced prostatic adenocarcinoma. Systemic therapy for prostate cancer was then initiated. These cases highlight the importance of patient history, physical exam, and IHC staining in consideration of a bladder mass, as these patients may have been subject to undue morbidity and surgical intervention without accurate pathologic diagnosis