7 research outputs found
Testicular, Spermatic Cord, and Scrotal Soft Tissue Sarcomas: Treatment Outcomes and Patterns of Failure
Introduction. Paratesticular sarcomas are defined as tumors that arise within the scrotum and include the subsites of epididymis, spermatic cord, and tunica vaginalis and represent the most common type of GU sarcoma. The mainstay of treatment is often surgical resection, combined with histology specific chemotherapy and radiotherapy. Due to the rare nature of the disease, there are limited data to guide management. We present our single-institution retrospective experience regarding the management and treatment of paratesticular sarcomas. Materials and Methods. We queried our oncology registry database for patients treated for testicular, spermatic cord, and scrotal soft tissue sarcomas between 1971 and 2017. Patients in this series had pathological confirmation of a sarcoma diagnosis by a sarcoma-specialized pathologist. Only patients with localized disease were included in this analysis with the exception of patients with a diagnosis of rhabdomyosarcoma where patients with both localized and metastatic disease were included on this study. Results. A total of 34 patients were included in this retrospective analysis. The median was 24 (range, 5â78), and the median tumor size was 6.25âcm. Twenty-six patients had localized disease (76.6%) at the time of diagnosis. A predominance of patients had tumors involving the spermatic cord (45.5%), and the most common histology was rhabdomyosarcoma (35.3%), leiomyosarcoma (26.5%), and well-differentiated liposarcoma (23.5%). The median follow-up was 71.0 months (range, 2.5â534.4 months). A total of 7 patients experienced an isolated local failure (20.6%), four patients developed distant metastatic disease (11.8%), and one patient (2.9%) with synovial sarcoma of the spermatic cord experienced a regional recurrence. The median progression-free survival (PFS) was 99.6 months, 95% CI (45.8â534.3 months), with a three-year PFS rate of 71%, 95% CI (53%â83%), and a 5-year PFS rate of 64% (range, 46%â78%). We did not find any statistically significant associations based on surgery type (p=0.15), the use of chemotherapy, (p=0.36), or final margin status (p=0.21). Two patients who were treated with preoperative radiotherapy had significant wound healing complication with chronic sinus tracts, though these patients did not experience a local recurrence. Conclusions. We provide a characterization of the natural history and treatment patterns of paratesticular sarcomas. While effective at reducing a local recurrence, preoperative radiotherapy was associated with significant toxicity. As a result, we prefer the use of postoperative radiotherapy in patients as clinically indicated. We did not find any specific treatment patterns associated with an improvement in clinical outcomes
Treatment recommendations to cancer patients in the context of FDA guidance for next generation sequencing
Abstract Background Regulatory approval of next generation sequencing (NGS) by the FDA is advancing the use of genomic-based precision medicine for the therapeutic management of cancer as standard care. Recent FDA guidance for the classification of genomic variants based on clinical evidence to aid clinicians in understanding the actionability of identified variants provided by comprehensive NGS panels has also been set forth. In this retrospective analysis, we interpreted and applied the FDA variant classification guidance to comprehensive NGS testing performed for advanced cancer patients and assessed oncologist agreement with NGS test treatment recommendations. Methods NGS comprehensive genomic profiling was performed in a CLIA certified lab (657 completed tests for 646 patients treated at Roswell Park Comprehensive Cancer Center) between June 2016 and June 2017. Physician treatment recommendations made within 120âdays post-test were gathered from tested patientsâ medical records and classified as targeted therapy, precision medicine clinical trial, immunotherapy, hormonal therapy, chemotherapy/radiation, surgery, transplant, or non-therapeutic (hospice, surveillance, or palliative care). Agreement between NGS test report targeted therapy recommendations based on the FDA variant classification and physician targeted therapy treatment recommendations were evaluated. Results Excluding variants contraindicating targeted therapy (i.e., KRAS or NRAS mutations), at least one variant with FDA level 1 companion diagnostic supporting evidence as the most actionable was identified in 14% of tests, with physicians most frequently recommending targeted therapy (48%) for patients with these results. This stands in contrast to physicians recommending targeted therapy based on test results with FDA level 2 (practice guideline) or FDA level 3 (clinical trial or off label) evidence as the most actionable result (11 and 4%, respectively). Conclusions We found an appropriate âdose-responseâ relationship between the strength of clinical evidence supporting biomarker-directed targeted therapy based on application of FDA guidance for NGS test variant classification, and subsequent treatment recommendations made by treating physicians. In view of recent changes at FDA, it is paramount to define regulatory grounds and medical policy coverage for NGS testing based on this guidance
Identification of [<sup>18</sup>F]TRACK, a Fluorine-18-Labeled Tropomyosin Receptor Kinase (Trk) Inhibitor for PET Imaging
Changes in expression and dysfunctional
signaling of TrkA/B/C receptors and oncogenic Trk fusion proteins
are found in neurological diseases and cancers. Here, we describe
the development of a first <sup>18</sup>F-labeled optimized lead suitable
for in vivo imaging of Trk,
[<sup>18</sup>F]ÂTRACK, which is radiosynthesized with ease from a
nonactivated aryl precursor concurrently combining largely reduced
P-gp liability and improved brain kinetics compared to previous leads
while displaying high on-target affinity and human kinome selectivity
A Kinome-Wide Selective Radiolabeled TrkB/C Inhibitor for in Vitro and in Vivo Neuroimaging: Synthesis, Preclinical Evaluation, and First-in-Human
The
proto-oncogenes <i>NTRK1/2/3</i> encode the tropomyosin
receptor kinases TrkA/B/C which play pivotal roles in neurobiology
and cancer. We describe herein the discovery of [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> ([<sup>11</sup>C]-(<i>R</i>)-IPMICF16),
a first-in-class positron emission tomography (PET) TrkB/C-targeting
radiolabeled kinase inhibitor lead. Relying on extensive human kinome
vetting, we show that (<i>R</i>)-<b>3</b> is the most
potent and most selective TrkB/C inhibitor characterized to date.
It is demonstrated that [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> readily crosses the bloodâbrain barrier (BBB) in
rodents and selectively binds to TrkB/C receptors in vivo, as evidenced
by entrectinib blocking studies. Substantial TrkB/C-specific binding
in human brain tissue is observed in vitro, with specific reduction in the hippocampus of Alzheimerâs disease (AD) versus healthy brains. We additionally provide preliminary translational data regarding the brain disposition of [<sup>11</sup>C]-(<i>R</i>)-<b>3</b> in primates including first-in-human assessment. These results illustrate for the first time the use of a kinome-wide selective radioactive chemical probe for endogenous kinase PET neuroimaging in human