Application of Advanced Imaging to Prostate Cancer Diagnosis and Management: A Narrative Review of Current Practice and Unanswered Questions.

Major advances in prostate cancer diagnosis, staging, and management have occurred over the past decade, largely due to our improved understanding of the technical aspects and clinical applications of advanced imaging, specifically magnetic resonance imaging (MRI) and prostate-cancer-specific positron emission tomography (PET). Herein, we review the established utility of these important and exciting technologies, as well as areas of controversy and uncertainty that remain important areas for future study. There is strong evidence supporting the utility of MRI in guiding initial biopsy and assessing local disease. There is debate, however, regarding how to best use the imaging modality in risk stratification, treatment planning, and assessment of biochemical failure. Prostate-cancer-specific PET is a relatively new technology that provides great value to the evaluation of newly diagnosed, treated, and recurrent prostate cancer. However, its ideal use in treatment decision making, staging, recurrence detection, and surveillance necessitates further research. Continued study of both imaging modalities will allow for an improved understanding of their best utilization in improving cancer care.

Treatment modalities and survival outcomes in prostate cancer parenchymal brain metastasis.

BACKGROUND: Prostate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes. METHODS: We retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan-Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups. RESULTS: At the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate-specific antigen (PSA) was 2.2 (0.1-26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6-100.9). The median (IQR) primary Gleason score was 8 (7-9) and over a median (IQR) follow-up time of 2.2 (1.2-16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log-rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16-0.86, p = 0.022). CONCLUSIONS: In our single-institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

Cost effectiveness of treatment strategies for high risk prostate cancer.

BACKGROUND: Patients with high-risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost. METHODS: The authors compared quality-adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external-beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low-dose-rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479). RESULTS: Treatment strategies were compared using the incremental cost-effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost-effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost-effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost. CONCLUSIONS: EBRT with LDR brachytherapy boost may be a cost-effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high-value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost-effective care, despite no change in overall survival.

Local Therapies in Oligometastatic and Oligoprogressive Prostate Cancer.

Oligometastatic disease was originally defined by Hellman and Weichselbaum as an intermediate-state existing between locally confined and widely disseminated malignancy, whose natural history could be positively impacted with systemic and importantly local therapies such as radiation. Currently oligometastatic prostate cancer (OPCa) is defined clinically by lesion enumeration and several subgroups exist: de novo (synchronous) oligometastatic disease present at initial diagnosis, oligorecurrent (metachronous) disease arising after definitive therapy to the prostate, and oligoprogressive disease where isolated lesions progress in a background of otherwise stable disease. In this review we highlight current knowledge and the potential future of local therapies, such as radiation to the primary prostate and metastasis-directed therapy (MDT), in the disease management of OPCa for all 3 subgroups. In addition, we examine more recent studies classifying the patterns of failure and natural history of OPCa following treatment with local therapies. Finally, while current clinical definitions of OPCa dominate, we introduce studies attempting to elucidate a more biological definition of OPCa to allow for improved selection of patients to treat with local therapies and to better inform precision combination approaches with systemic therapy.

Oligometastatic prostatic cancer recurrence: role of salvage lymph node dissection (sLND) and radiation therapy-stereotactic body radiation therapy (RT-SBRT).

PURPOSE OF REVIEW: Metastases directed therapy (MDT) is an increasingly utilized modality in patients with oligometastatic prostate cancer (OMPC) recurrence. The purpose of our review is to discuss the recent literature on the safety and oncologic outcomes of this treatment approach. RECENT FINDINGS: Metastases directed therapy, in particular, stereotactic body radiation therapy (SBRT) and salvage lymph node dissection (sLND), has shown promising efficacy in patients with OMPC. Many case series report favorable outcomes with MDT as compared to hormonal deprivation therapy alone or surveillance. Of the few case series investigating the use of MDT as part of a multimodality approach in castrate-resistant OMPC, more favorable outcomes in comparison to the use of systemic treatment alone are reported. SUMMARY: With the recent advances in imaging techniques, particularly molecular imaging, management of OMPC has progressed rapidly in the last few years. The feasibility and benefits of MDT in OMPC have been demonstrated in prospective and retrospective series. Further prospective studies investigating the role of MDT to define optimal patient subgroups and management strategies are warranted.

Metastasis-Directed Therapy in Prostate Cancer. Why, When, and How?

Metastatic prostate cancer remains a life-limiting disease; while we have seen significant advances in systemic approaches which form the backbone of management, no curative paradigm yet exists. Metastasis-directed therapy (MDT) with stereotactic ablative radiotherapy (SABR) has emerged as a promising complementary technique for the management of low-volume metastatic prostate cancer. Herein we will review the rationale, potential benefits, and practical considerations associated with this approach.

Bittersweet tumor development and progression: Emerging roles of epithelial plasticity glycosylations.

Altered metabolism is one of the hallmarks of cancer. The best-known cancer metabolic anomaly is an increase in aerobic glycolysis, which generates ATP and other basic building blocks, such as nucleotides, lipids, and proteins to support tumor cell growth and survival. Epithelial plasticity (EP) programs such as the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are evolutionarily conserved processes that are essential for embryonic development. EP also plays an important role during tumor progression toward metastasis and treatment resistance, and new roles in the acceleration of tumorigenesis have been found. Recent evidence has linked EMT-related transcriptomic alterations with metabolic reprogramming in cancer cells, which include increased aerobic glycolysis. More recent studies have revealed a novel connection between EMT and altered glycosylation in tumor cells, in which EMT drives an increase in glucose uptake and flux into the hexosamine biosynthetic pathway (HBP). The HBP is a side-branch pathway from glycolysis which generates the end product uridine-5'-diphosphate-N-acetylglucosamine (UDP-GlcNAc). A key downstream utilization of UDP-GlcNAc is for the post-translational modification O-GlcNAcylation which involves the attachment of the GlcNAc moiety to Ser/Thr/Asn residues of proteins. Global changes in protein O-GlcNAcylation are emerging as a general characteristic of cancer cells. In our recent study, we demonstrated that the EMT-HBP-O-GlcNAcylation axis drives the O-GlcNAcylation of key proteins such as c-Myc, which previous studies have shown to suppress oncogene-induced senescence (OIS) and contribute to accelerated tumorigenesis. Here, we review the HBP and O-GlcNAcylation and their putative roles in driving EMT-related cancer processes with examples to illuminate potential new therapeutic targets for cancer.

Ex vivo chemical cytometric analysis of protein tyrosine phosphatase activity in single human airway epithelial cells.

We describe a novel method for the measurement of protein tyrosine phosphatase (PTP) activity in single human airway epithelial cells (hAECs) using capillary electrophoresis. This technique involved the microinjection of a fluorescent phosphopeptide that is hydrolyzed specifically by PTPs. Analyses in BEAS-2B immortalized bronchial epithelial cells showed rapid PTP-mediated dephosphorylation of the substrate (2.2 pmol min(-1) mg(-1)) that was blocked by pretreatment of the cells with the PTP inhibitors pervanadate, Zn(2+), and 1,2-naphthoquinone (76%, 69%, and 100% inhibition relative to PTP activity in untreated controls, respectively). These studies were then extended to a more physiologically relevant model system: primary hAECs cultured from bronchial brushings of living human subjects. In primary hAECs, dephosphorylation of the substrate occurred at a rate of 2.2 pmol min(-1) mg(-1) and was also effectively inhibited by preincubation of the cells with the inhibitors pervanadate, Zn(2+), and 1,2-naphthoquinone (91%, 88%, and 87% median PTP inhibition, respectively). Reporter proteolysis in single BEAS-2B cells occurred at a median rate of 43 fmol min(-1) mg(-1) resulting in a mean half-life of 20 min. The reporter displayed a similar median half-life of 28 min in these single primary cells. Finally, single viable epithelial cells (which were assayed for PTP activity immediately after collection by bronchial brushing of a human volunteer) showed dephosphorylation rates ranging from 0.34 to 36 pmol min(-1) mg(-1) (n = 6). These results demonstrate the utility and applicability of this technique for the ex vivo quantification of PTP activity in small, heterogeneous, human cells and tissues.

Chemoproteomic discovery of AADACL1 as a regulator of human platelet activation.

A comprehensive knowledge of the platelet proteome is necessary for understanding thrombosis and for envisioning antiplatelet therapies. To discover other biochemical pathways in human platelets, we screened platelets with a carbamate library designed to interrogate the serine hydrolase subproteome and used competitive activity-based protein profiling to map the targets of active carbamates. We identified an inhibitor that targets arylacetamide deacetylase-like 1 (AADACL1), a lipid deacetylase originally identified in invasive cancers. Using this compound, along with highly selective second-generation inhibitors of AADACL1, metabolomics, and RNA interference, we show that AADACL1 regulates platelet aggregation, thrombus growth, RAP1 and PKC activation, lipid metabolism, and fibrinogen binding to platelets and megakaryocytes. These data provide evidence that AADACL1 regulates platelet and megakaryocyte activation and highlight the value of this chemoproteomic strategy for target discovery in platelets.

Measurement of protein tyrosine phosphatase activity in single cells by capillary electrophoresis.

A fluorescent peptide substrate was used to measure dephosphorylation by protein tyrosine phosphatases (PTP) in cell lysates and single cells and to investigate the effect of environmental toxins on PTP activity in these systems. Dephosphorylation of the substrate by PTPN1 and PTPN2 obeyed Michaelis-Menten kinetics, with KM values of 770 ± 250 and 290 ± 54 nM, respectively. Dose-response curves and IC50 values were determined for the inhibition of these two enzymes by the environmental toxins Zn(2+) and 1,2-naphthoquinone, as well as pervanadate. In A431 cell lysates, the reporter was a poor substrate for peptidases (degradation rate of 100 ± 8.2 fmol min(-1) mg(-1)) but an excellent substrate for phosphatases (dephosphorylation rate of 1.4 ± 0.3 nmol min(-1) mg(-1)). Zn(2+), 1,2-naphthoquinone, and pervanadate inhibited dephosphorylation of the reporter in cell lysates with IC50 values of 470 nM, 35 µM, and 100 nM, respectively. Dephosphorylation of the reporter, following loading into living single cells, occurred at rates of at least 2 pmol min(-1) mg(-1). When single cells were exposed to 1,2-naphthoquinone (50 µM), Zn(2+) (100 µM), and pervandate (1 mM), dephosphorylation was inhibited with median values and first and third quartile values of 41 (Q1 = 0%, Q3 = 96%), 50 (Q1 = 46%, Q3 = 74%), and 53% (Q1 = 36%, Q3 = 77%), respectively, demonstrating both the impact of these toxic exposures on cell signaling and the heterogeneity of response between cells. This approach will provide a valuable tool for the study of PTP dynamics, particularly in small, heterogeneous populations such as human biopsy specimens.

Catalytic, asymmetric, "interrupted" Feist-Bénary reactions.

Pyrimidine derivatives of the cinchona alkaloids function as excellent asymmetric catalysts for the "Interrupted" Feist-Bénary Reaction. This reaction produces highly substituted hydroxydihydrofurans from simple starting materials under mild conditions. The asymmetric reaction gives high enantioselectivities with unsubstituted bromoketones, and high enantio- and diastereoselectivities with substituted substrates. Mechanistic experiments suggest that the hydrobromide salt of the alkaloid derivative is the active catalyst for the reaction.