Economic Evaluation of Transperineal versus Transrectal Devices for Local Anaesthetic Prostate Biopsies.

BACKGROUND: Biopsy of the prostate for suspected cancer is usually performed transrectally under local anaesthesia in the outpatient clinic setting. As this involves piercing the bowel wall, the procedure is associated with a risk of infection. Recently, devices that facilitate transperineal biopsy approaches have been developed that avoid piercing the bowel and so should reduce the risk of infection. OBJECTIVE: The aim of this study was to estimate the cost effectiveness of transperineal versus transrectal ultrasound-guided local anaesthesia procedures for prostate biopsy from the perspective of the UK NHS and to estimate the value of further research in the area. METHODS: a) Decision tree and Markov model synthesising all relevant evidence estimating the life-time costs and QALYs accrued from each biopsy mode. b) Value of information analysis to predict the return from further research and thus guide future research efforts. RESULTS: Transperineal biopsy yields an ICER below £20,000 per QALY gained at a per-procedure device acquisition cost below £81, or £41 for cost-neutrality. These results are driven by differences in consumables cost, reduced cost of treating infections, and QALY gains associated with reduced infections. There is value in future research on the diagnostic accuracy of transperineal versus transrectal biopsies and the incidence of iatrogenic infection and sepsis; consideration should be given to enriching the patient population with men with intermediate-risk disease. CONCLUSIONS: Transperineal biopsy devices may be cost effective compared with transrectal biopsy at per-procedure acquisition costs below £81 and cost-neutral if under £41. Future research is required to confirm or refute these findings, particularly randomised comparisons of the diagnostic accuracy and infection risks between the methods.

Cost-Utility Analysis of Anterior Vertebral Body Tethering versus Spinal Fusion in Idiopathic Scoliosis from a US Integrated Healthcare Delivery System Perspective.

PURPOSE: Anterior vertebral body tethering (VBT) is a non-fusion, minimally invasive, growth-modulating procedure with some early positive clinical outcomes reported in pediatric patients with idiopathic scoliosis (IS). VBT offers potential health-related quality of life (HRQoL) benefits over spinal fusion in allowing patients to retain a greater range of motion after surgery. We conducted an early cost-utility analysis (CUA) to compare VBT with fusion as a first-choice surgical treatment for skeletally immature patients (age >10 years) with moderate to severe IS, who have failed nonoperative management, from a US integrated healthcare delivery system perspective. PATIENTS AND METHODS: The CUA uses a Markov state transition model, capturing a 15-year period following index surgery. Transition probabilities, including revision risk and subsequent fusion, were based on published surgical outcomes and an ongoing VBT observational study (NCT02897453). Patients were assigned utilities derived from published patient-reported outcomes (PROs; SRS-22r mapped to EQ-5D) following fusion and the above VBT study. Index and revision procedure costs were included. Probabilistic (PSA) and deterministic sensitivity analyses (DSA) were performed. RESULTS: VBT was associated with higher costs but also higher quality-adjusted life years (QALYs) than fusion (incremental costs: $45,546; QALYs gained: 0.54). The subsequent incremental cost-effectiveness ratio for VBT vs fusion was $84,391/QALY gained. Mean PSA results were similar to the base case, indicating that results were generally robust to uncertainty. The DSA indicated that results were most sensitive to variations in utility values. CONCLUSION: This is the first CUA comparing VBT with fusion in pediatric patients with IS and suggests that VBT may be a cost-effective alternative to fusion in the US, given recommended willingness-to-pay thresholds ($100,000-$150,000). The results rely on HRQoL benefits for VBT compared with fusion. For improved model accuracy, further analyses with longer-term PROs for VBT, and comparative effectiveness studies, would be needed.

MEIS-mediated suppression of human prostate cancer growth and metastasis through HOXB13-dependent regulation of proteoglycans.

The molecular roles of HOX transcriptional activity in human prostate epithelial cells remain unclear, impeding the implementation of new treatment strategies for cancer prevention and therapy. MEIS proteins are transcription factors that bind and direct HOX protein activity. MEIS proteins are putative tumor suppressors that are frequently silenced in aggressive forms of prostate cancer. Here we show that MEIS1 expression is sufficient to decrease proliferation and metastasis of prostate cancer cells in vitro and in vivo murine xenograft models. HOXB13 deletion demonstrates that the tumor-suppressive activity of MEIS1 is dependent on HOXB13. Integration of ChIP-seq and RNA-seq data revealed direct and HOXB13-dependent regulation of proteoglycans including decorin (DCN) as a mechanism of MEIS1-driven tumor suppression. These results define and underscore the importance of MEIS1-HOXB13 transcriptional regulation in suppressing prostate cancer progression and provide a mechanistic framework for the investigation of HOXB13 mutants and oncogenic cofactors when MEIS1/2 are silenced.

Decisions regarding the treatment of patients with early-stage prostate cancer are often based on the risk that the cancer could grow and spread quickly. However, it is not always straightforward to predict how the cancer will behave. Studies from 2017 and 2018 found that samples of less aggressive prostate cancer have higher levels of a group of proteins called MEIS proteins. MEIS proteins help control the production of numerous other proteins, which could affect the behavior of prostate cancer cells in many ways. VanOpstall et al. ­ including some of the researchers that performed the 2017 and 2018 studies ­ have investigated how MEIS proteins affect prostate cancer. When prostate cancer cells are implanted into mice, they result in tumors. VanOpstall et al. found that tumors that produced MEIS proteins grew more slowly. Next, MEIS proteins were extracted from the prostate cancer cells and were found to interact with another protein called HOXB13, which regulates the activity of numerous genes. When the cells were genetically modified to prevent HOXB13 being produced, the protective effect of MEIS proteins was lost. MEIS proteins work with HOXB13 to regulate the production of several other proteins, in particular a protein called Decorin that can suppress tumors. When MEIS proteins and HOXB13 are present, the cell produces more Decorin and the tumors grow more slowly and are less likely to spread. VanOpstall et al. found that blocking Decorin production rendered MEIS proteins less able to slow the spread of prostate cancer. These results suggest that MEIS proteins and HOXB13 are needed to stop tumors from growing and spreading, and some of this ability is by prompting production of Decorin. This study explains how MEIS proteins can reduce prostate cancer growth, providing greater confidence in using them to determine whether aggressive treatment is needed. A greater understanding of this pathway for tumor suppression could also provide an opportunity for developing anti-cancer drugs.

MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease.

Purpose: Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored.Experimental Design: Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression.Results: These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the protumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFß2.Conclusions: These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression. Clin Cancer Res; 24(15); 3668-80. ©2018 AACR.

HOXB13 mutations and binding partners in prostate development and cancer: Function, clinical significance, and future directions.

The recent and exciting discovery of germline HOXB13 mutations in familial prostate cancer has brought HOX signaling to the forefront of prostate cancer research. An enhanced understanding of HOX signaling, and the co-factors regulating HOX protein specificity and transcriptional regulation, has the high potential to elucidate novel approaches to prevent, diagnose, stage, and treat prostate cancer. Toward our understanding of HOX biology in prostate development and prostate cancer, basic research in developmental model systems as well as other tumor sites provides a mechanistic framework to inform future studies in prostate biology. Here we describe our current understanding of HOX signaling in genitourinary development and cancer, current clinical data of HOXB13 mutations in multiple cancers including prostate cancer, and the role of HOX protein co-factors in development and cancer. These data highlight numerous gaps in our understanding of HOX function in the prostate, and present numerous potentially impactful mechanistic and clinical opportunities for future investigation.

Contribution of Caudal Müllerian Duct Mesenchyme to Prostate Development.

A fundamental understanding of prostate development and tissue homeostasis has the high potential to reveal mechanisms for prostate disease initiation and identify novel therapeutic approaches for disease prevention and treatment. Our current understanding of prostate lineage specification stems from the use of developmental model systems that rely upon the embryonic preprostatic urogenital sinus mesenchyme to induce the formation of mature prostate epithelial cells. It is unclear, however, how the urogenital sinus epithelium can derive both adult urethral glands and prostate epithelia. Furthermore, the vast disparity in disease initiation between these two glands highlights key developmental factors that predispose prostate epithelia to hyperplasia and cancer. In this study we demonstrate that the caudal Müllerian duct mesenchyme (CMDM) drives prostate epithelial differentiation and is a key determinant in cell lineage specification between urethral glands and prostate epithelia. Utilizing both human embryonic stem cells and mouse embryonic tissues, we document that the CMDM is capable of inducing the specification of androgen receptor, prostate-specific antigen, NKX3.1, and Hoxb13-positive prostate epithelial cells. These results help to explain key developmental differences between prostate and urethral gland differentiation, and implicate factors secreted by the caudal Müllerian duct as novel targets for prostate disease prevention and treatment.

Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.

Enzalutamide (MDV3100) is a second generation Androgen Receptor (AR) antagonist with proven efficacy in the treatment of castration resistant prostate cancer (CRPC). The majority of treated patients, however, develop resistance and disease progression and there is a critical need to identify novel targetable pathways mediating resistance. The purpose of this study was to develop and extensively characterize a series of enzalutamide-resistant prostate cancer cell lines. Four genetically distinct AR-positive and AR-pathway dependent prostate cancer cell lines (CWR-R1, LAPC-4, LNCaP, VCaP) were made resistant to enzalutamide by long-term culture (> 6 months) in enzalutamide. Extensive characterization of these lines documented divergent in vitro growth characteristics and AR pathway modulation. Enzalutamide-resistant LNCaP and CWR-R1 cells, but not LAPC-4 and VCAP cells, demonstrated increased castration-resistant and metastatic growth in vivo. Global gene expression analyses between short-term enzalutamide treated vs. enzalutamide-resistant cells identified both AR pathway and non-AR pathway associated changes that were restored upon acquisition of enzalutamide resistance. Further analyses revealed very few common gene expression changes between the four resistant cell lines. Thus, while AR-mediated pathways contribute in part to enzalutamide resistance, an unbiased approach across several cell lines demonstrates a greater contribution toward resistance via pleiotropic, non-AR mediated mechanisms.

Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer.

The function and clinical utility of stem cell markers in metastatic castration-resistant prostate cancer (mCRPC) remains unresolved, and their expression may confer important therapeutic opportunities for staging and therapy. In the adult human prostate, CD133 (PROM1) expression identifies infrequent prostate epithelial progenitor cells and putative cancer stem cells. Previous work demonstrated an association with CD133 and cancer cell proliferation using in vitro model systems. The primary objective here was to investigate the expression of CD133 in circulating tumor cells (CTCs) from patients with mCRPC and to test the hypothesis that patients with mCRPC had CD133-positive CTCs associated with increased cell proliferation, changes in the androgen receptor (AR) protein expression, or AR nuclear co-localization. We utilized ImageStreamX technology, which combines flow cytometry and fluorescence microscopy, to capture and analyze CD45-negative/EpCAM-positive CTCs for CD133, Ki-67, and AR. All patient samples (20/20) contained CD133-positive populations of CTCs, and on average 50.9 ± 28.2% (range of 18.2% to 100%) of CTCs were CD133-positive. CD133-positive CTCs have increased Ki-67 protein expression compared to CD133-negative CTCs, implying that CD133-positive CTCs may have greater proliferative potential when compared to their CD133-negative counterparts. CD133-positive and CD133-negative CTCs have similar levels of AR protein expression and cellular co-localization with nuclear markers, implying that CD133 expression is independent of AR pathway activity and an AR-independent marker of mCRPC proliferation. These studies demonstrate the presence of CD133-positive populations in CTCs from mCRPC with increased proliferative potential.

Pectin metabolism and assembly in the cell wall of the charophyte green alga Penium margaritaceum.

The pectin polymer homogalacturonan (HG) is a major component of land plant cell walls and is especially abundant in the middle lamella. Current models suggest that HG is deposited into the wall as a highly methylesterified polymer, demethylesterified by pectin methylesterase enzymes and cross-linked by calcium ions to form a gel. However, this idea is based largely on indirect evidence and in vitro studies. We took advantage of the wall architecture of the unicellular alga Penium margaritaceum, which forms an elaborate calcium cross-linked HG-rich lattice on its cell surface, to test this model and other aspects of pectin dynamics. Studies of live cells and microscopic imaging of wall domains confirmed that the degree of methylesterification and sufficient levels of calcium are critical for lattice formation in vivo. Pectinase treatments of live cells and immunological studies suggested the presence of another class of pectin polymer, rhamnogalacturonan I, and indicated its colocalization and structural association with HG. Carbohydrate microarray analysis of the walls of P. margaritaceum, Physcomitrella patens, and Arabidopsis (Arabidopsis thaliana) further suggested the conservation of pectin organization and interpolymer associations in the walls of green plants. The individual constituent HG polymers also have a similar size and branched structure to those of embryophytes. The HG-rich lattice of P. margaritaceum, a member of the charophyte green algae, the immediate ancestors of land plants, was shown to be important for cell adhesion. Therefore, the calcium-HG gel at the cell surface may represent an early evolutionary innovation that paved the way for an adhesive middle lamella in multicellular land plants.

Disruption of the microtubule network alters cellulose deposition and causes major changes in pectin distribution in the cell wall of the green alga, Penium margaritaceum.

Application of the dintroaniline compound, oryzalin, which inhibits microtubule formation, to the unicellular green alga Penium margaritaceum caused major perturbations to its cell morphology, such as swelling at the wall expansion zone in the central isthmus region. Cell wall structure was also notably altered, including a thinning of the inner cellulosic wall layer and a major disruption of the homogalacturonan (HG)-rich outer wall layer lattice. Polysaccharide microarray analysis indicated that the oryzalin treatment resulted in an increase in HG abundance in treated cells but a decrease in other cell wall components, specifically the pectin rhamnogalacturonan I (RG-I) and arabinogalactan proteins (AGPs). The ring of microtubules that characterizes the cortical area of the cell isthmus zone was significantly disrupted by oryzalin, as was the extensive peripheral network of actin microfilaments. It is proposed that the disruption of the microtubule network altered cellulose production, the main load-bearing component of the cell wall, which in turn affected the incorporation of HG in the two outer wall layers, suggesting coordinated mechanisms of wall polymer deposition.