Prostate cancer is the most prevalent non-skin cancer in men and is the leading cause of cancer-related death. Early detection of prostate cancer is largely determined by a widely used prostate ...specific antigen (PSA) blood test and biopsy is performed for definitive diagnosis. Prostate cancer is asymptomatic in the early stage of the disease, comprises of diverse clinico-pathologic and progression features, and is characterized by a large subset of the indolent cancer type. Therefore, it is critical to develop an individualized approach for early detection, disease stratification (indolent vs. aggressive), and prediction of treatment response for prostate cancer. There has been remarkable progress in prostate cancer biomarker discovery, largely through advancements in genomic technologies. A rich array of prostate cancer diagnostic and prognostic tests has emerged for serum (4K, phi), urine (Progensa,
, ExoDx, SelectMDx), and tumor tissue (ConfirmMDx, Prolaris, Oncoytype DX, Decipher). The development of these assays has created new opportunities for improving prostate cancer diagnosis, prognosis, and treatment decisions. While opening exciting opportunities, these developments also pose unique challenges in terms of selecting and incorporating these assays into the continuum of prostate cancer patient care.
Long noncoding RNAs (IncRNAs) have been implicated in a variety of physiological and pathological processes, including cancer. In prostate cancer, prostate cancer gene expression marker 1 (PCGEM1) is ...an androgen-induced prostate-specific IncRNA whose overexpression is highly associated with prostate tumors. PCGEM1's tumorigenie potential has been recently shown to be in part due to its ability to activate androgen receptor (AR). Here, we report a novel function of PCGEM1 that provides growth advantages for cancer cells by regulating tumor metabolism via c-Myc activation. PCGEM1 promotes glucose uptake for aerobic glycolysis, coupling with the pentose phosphate shunt to facilitate biosynthesis of nucleotide and lipid, and generates NADPH for redox homeostasis. We show that PCGEM1 regulates metabolism at a transcriptional level that affects multiple metabolic pathways, including glucose and g Iutamine metabolism, the pentose phosphate pathway, nucleotide and fatty acid biosynthesis, and the tricarboxylic acid cycle. The PCGEM1-mediated gene regulation takes place in part through AR activation, but predominantly through c-Myc activation, regardless of hormone or AR status. Significantly, PCGEM1 binds directly to target promoters, physically interacts with c-Myc, promotes chromatin recruitment of c-Myc, and enhances its transactivation activity. We also identified a c-Myc binding domain on PCGEM1 that contributes to the PCGEM1-dependent c-Myc activation and target induction. Together, our data uncover PCGEM1 as a key transcriptional regulator of central metabolic pathways in prostate cancer cells. By being a coactivator for both c-Myc and AR, PCGEM1 reprograms the androgen network and the central metabolism in a tumor-specific way, making it a promising target for therapeutic intervention.
Purpose
Magnetic resonance imaging (MRI) is commonly used in treatment planning for stereotactic radiosurgery (SRS) of trigeminal neuralgia (TN). With current MRI techniques, the delineation of the ...trigeminal nerve root entry zone (REZ) may be degraded due to poor contrast and artifacts. The purpose of this work is to develop an MRI technique with better delineation of the trigeminal nerve REZ to improve SRS treatment planning for TN.
Methods
A spiral fluid‐attenuated inversion recovery (FLAIR) MRI technique was developed to improve image quality by improving tissue contrast, fluid suppression, artifact reduction, and signal‐to‐noise ratio (SNR). A concomitant‐phase compensation method based on spiral gradient waveforms was implemented to minimize artifacts due to magnetic field change induced by the metal frame used in Gamma Knife treatment planning. The image quality of spiral FLAIR was assessed in four healthy volunteers. The geometric accuracy was quantitatively evaluated by registering spiral FLAIR to computed tomography (CT) images and comparing it with existing MRI techniques.
Results
The spiral FLAIR technique demonstrated better delineation of the trigeminal nerve REZ, improved tissue contrast of the brain stem, and minimized flow artifacts, compared to steady‐state free precession (SSFP) MRI. Spiral FLAIR also improved fluid suppression, SNR, and artifacts, which contributed to better delineation of the trigeminal nerve REZ compared to conventional Cartesian FLAIR. The measured mean (± standard deviation) distance between spiral FLAIR and CT images is 0.98 ± 0.56 mm, comparable to 0.40 ± 0.26 mm in 3T T1 spoiled gradient echo (T1‐SPGR), 0.59 ± 0.25 mm in 3T SSFP, 0.66 ± 0.38 mm in 1.5T T1‐SPGR, and 0.61 ± 0.25 mm in 1.5T Cartesian FLAIR.
Conclusion
A spiral FLAIR technique with improved image quality and good geometric accuracy provides a potential alternative for treatment planning in SRS for TN patients.
Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer and the second leading cause of male cancer deaths in the United States. Among African American (AA) men, CaP is the most ...prevalent malignancy, with disproportionately higher incidence and mortality rates. Even after discounting the influence of socioeconomic factors, the effect of molecular and genetic factors on racial disparity of CaP is evident. Earlier studies on the molecular basis for CaP disparity have focused on the influence of heritable mutations and single-nucleotide polymorphisms (SNPs). Most CaP susceptibility alleles identified based on genome-wide association studies (GWAS) were common, low-penetrance variants. Germline CaP-associated mutations that are highly penetrant, such as those found in
and
, are usually rare. More recently, genomic studies enabled by Next-Gen Sequencing (NGS) technologies have focused on the identification of somatic mutations that contribute to CaP tumorigenesis. These studies confirmed the high prevalence of
gene fusions and
deletions among Caucasian Americans and identified novel somatic alterations in
and
genes in early stages of CaP. Individuals with African ancestry and other minorities are often underrepresented in these large-scale genomic studies, which are performed primarily using tumors from men of European ancestry. The insufficient number of specimens from AA men and other minority populations, together with the heterogeneity in the molecular etiology of CaP across populations, challenge the generalizability of findings from these projects. Efforts to close this gap by sequencing larger numbers of tumor specimens from more diverse populations, although still at an early stage, have discovered distinct genomic alterations. These research findings can have a direct impact on the diagnosis of CaP, the stratification of patients for treatment, and can help to address the disparity in incidence and mortality of CaP. This review examines the progress of understanding in CaP genetics and genomics and highlight the need to increase the representation from minority populations.
ERG, an ETS family transcription factor, is known to be expressed in endothelial cells, and oncogenic ERG gene fusions occur in subsets of prostatic carcinoma, acute myeloid leukemia, and Ewing ...sarcoma. In this study, we immunohistochemically investigated nuclear ERG expression using a new monoclonal antibody, CPDR ERG-MAb, that is highly specific for detecting ERG protein and ERG-expressing prostate carcinomas. A broad range of vascular endothelial (n = 250), other mesenchymal (n = 973), and epithelial tumors (n = 657) was examined to determine the use of ERG immunohistochemistry in surgical pathology. Only immunostains with ERG-positive normal endothelia (internal control) were considered valid, and only nuclear staining was considered to be positive. In adult tissues, ERG was restricted to endothelial cells and to a subset of bone marrow precursors, but early fetal mesenchyme and subpopulations of fetal cartilage were also positive. In vascular tumors, ERG was expressed in endothelia of all hemangiomas and lymphangiomas, and typically extensively expressed in 96 of 100 angiosarcomas, 42 of 43 epithelioid hemangioendotheliomas, and all 26 Kaposi sarcomas. Among nonvascular mesenchymal tumors, only blastic extramedullary myeloid tumors (7 of 10) and rare Ewing sarcomas (2 of 29) were positive. Among epithelial tumors, 30 of 66 prostatic adenocarcinomas showed focal-to-extensive ERG positivity, with no immunoreactivity in the normal prostate. Other carcinomas and epithelial tumors (n = 643) were ERG negative, with the exception of 1 of 42 large cell undifferentiated pulmonary carcinomas and 1 of 27 mesotheliomas, each of which showed focal nuclear ERG positivity. On the basis of the above observations, ERG is a highly specific new marker for benign and malignant vascular tumors. Among epithelial tumors, ERG shows a great promise as a marker to identify prostatic carcinoma in both primary and metastatic settings.
Background
Methods for accurate absolute dose (AD) calibration are essential for the proper functioning of radiotherapy treatment machines. Many systems do not conform to TG‐51 calibration standards, ...and modifications are required. TG‐21 calibration is also a viable methodology for these situations with the appropriate setup, equipment, and factors. It has been shown that both these methods result in minimal errors. A similar approach has been taken in calibrating the dose for a recent vault‐free radiosurgery system.
Purpose
To evaluate modified TG‐21 and TG‐51 protocols for AD calibrations of the ZAP‐X radiosurgery system using ion chambers, film, and thermoluminescent dosimeters (TLDs).
Methods
The current treatment planning system for ZAP‐X requires AD calibration at dmax (7 mm) and 450 mm source‐to‐axis distance. Both ND,w60CoGy/C$N_{D,w}^{{60}Co} {Gy/C} $ and Nx R/C calibration coefficients were provided by an accredited dosimetry calibration laboratory for a physikalisch technische werkstatten (PTW) 31010 chamber (0.125 cc). The vendor provides an f‐bracket that can be mounted on the collimator. Various phantoms can then be attached to the f‐bracket. A custom acrylic phantom was designed based on recommendations from TG‐21 and technical report series‐398 that places the chamber at 500 mm from the source with a depth of 44‐mm acrylic and 456‐mm SSD. Nx along with other TG‐21 parameters was used to calculate the AD. Measurements using a PTW MP3‐XS water tank and the same chamber were used to calculate AD using ND,w60Co$N_{D,w}^{{60}Co}$ and TG‐51 factors. Dose verification was performed using Gafchromic film and 3rd party TLDs.
Results
Measurements from TG‐51, TG‐21 (utilizing the custom acrylic phantom), film, and TLDs agreed to within ± 2%.
Conclusions
A modified TG‐51 AD calculation in water is preferred but may not be practical due to the difficulty in tank setup. The TG‐21 modified protocol using a custom acrylic phantom is an accurate alternative option for dose calibration. Both of these methods are within acceptable agreement and provide confidence in the system's AD calibration.
In prostate cancer, emerging data highlight the role of DNA damage repair genes (DDRGs) in aggressive forms of the disease. However, DDRG mutations in African American men are not yet fully defined. ...Here, we profile germline mutations in all known DDRGs (N = 276) using whole genome sequences from blood DNA of a matched cohort of patients with primary prostate cancer comprising of 300 African American and 300 European Ancestry prostate cancer patients, to determine whether the mutation status can enhance patient stratification for specific targeted therapies. Here, we show that only 13 of the 46 DDRGs identified with pathogenic/likely pathogenic mutations are present in both African American and European ancestry patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), which are potentially targetable, as well as PMS2 and BRCA1, are among the most frequently mutated DDRGs in African American, but not in European Ancestry patients.
Oncogenic activation of the ETS-related gene (
) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of the most validated and prevalent genomic alterations present in early stages of ...prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in
harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-2-Thiazolylazo-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature.
, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity-based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.
A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy.
.
Purpose
This study reports a single‐institution experience with beam data acquisition and film‐based validation for a novel self‐shielded sterotactic radiosurgery unit and investigates detector ...dependency on field output factors (OFs), off‐axis ratios (OARs), and percent depth dose (PDD) measurements within the context of small‐field dosimetry.
Methods
The delivery platform for this unit consists of a 2.7‐MV S‐band linear accelerator mounted on coupled gimbals that rotate around a common isocenter (source‐to‐axis distance SAD = 450 mm), allowing for more than 260 noncoplanar beam angles. Beam collimation is achieved via a tungsten collimator wheel with eight circular apertures ranging from 4 mm to 25 mm in diameter. Three diodes (PTW 60012 Diode E, PTW 60018 SRS Diode, and Sun Nuclear EDGE) and a synthetic diamond detector (PTW 60019 micro Diamond µD detector) were used for OAR, PDD, and OF measurements. OFs were also acquired with a PTW 31022 PinPoint ionization chamber. Beam scanning was performed using a 3D water tank at depths of 7, 50, 100, 200, and 250 mm with a source‐to‐surface distance of 450 mm. OFs were measured at the depth of maximum dose (dmax = 7 mm) with the SAD at 450 mm. Gafchromic EBT3 film was used to validate OF and profile measurements and as a reference detector for estimating correction factors for active detector OFs. Deviations in field size, penumbra, and PDDs across the different detectors were quantified.
Results
Relative OFs (ROFs) for the diodes were within 1.4% for all collimators except for 5 and 7.5 mm, for which SRS Diode measurements were higher by 1.6% and 2.6% versus Diode E. The µD ROFs were within 1.4% of the diode measurements. PinPoint ROFs were lower by >10% for the 4‐mm and 5‐mm collimators versus the Diode E and µD. Corrections to OFs using EBT3 film as a reference were within 1.2% for all diodes and the µD detector for collimators 10 mm and greater and within 2.0%, 2.8%, and 1.1% for the 7.5‐, 5‐, and 4‐mm collimators, respectively. The maximum difference in full width at half maximum (FWHM) between the Diode E and the other active detectors was for the 25‐mm collimator and was 0.09 mm (µD), 0.16 mm (SRS Diode), and 0.65 mm (EDGE). Differences seen in PDDs beyond the depth of dmax were <1% across the three diodes and the µD. FWHM and penumbra measurements made using EBT3 film were within 1.34% and 3.26%, respectively, of the processed profile data entered into the treatment planning system.
Conclusions
Minimal differences were seen in OAR and PDD measurements acquired with the diodes and the µD. ROFs measured with the three diodes were within 2.6% and within 1.4% versus the µD. Gafchromic Film measurements provided independent verification of the OAR and OF measurements. Estimated corrections to OFs using film as a reference were <1.6% for the Diode E, EDGE, and µD detector.
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