Novel Insights into Molecular Indicators of Response and Resistance to Modern Androgen-Axis Therapies in Prostate Cancer.

While androgen ablation remains a mainstay for advanced prostate cancer therapy, nearly all patients will inevitably develop disease escape with time. Upon the development of castration-resistant prostate cancer, other androgen-axis-targeted treatments may be added in an effort to starve the disease of its androgen signaling. Nevertheless, additional androgen-pathway resistance usually develops to these novel hormonal therapies. In this review, we will discuss the resistance mechanisms to modern androgen-axis modulators and how these alterations can influence a patient's response to novel hormonal therapy. We conceptualize these resistance pathways as three broad categories: (1) reactivation of androgen/AR-signaling, (2) AR bypass pathways, and (3) androgen/AR-independent mechanisms. We highlight examples of each, as well as potential therapeutic approaches to overcome these resistance mechanisms.

Ventral Intrameningeal Cyst Treatment and Management: Technical Note.

BACKGROUND: Intrameningeal cysts are rare lesions without definitive etiologies that can involve the dura or arachnoid mater. Spinal arachnoid cysts have been described, and several different etiologies have been hypothesized. This includes one-way valve mechanisms, traumatic herniation of arachnoid through the dura, and abnormal arachnoid membrane proliferation. To the authors' knowledge, no such descriptions exist regarding purely dural-based cystic lesions; however, the authors hypothesize similar mechanisms may be involved. Most notably, a traumatic injury to the dura leading to a one-way valve mechanism may allow for egress of cerebrospinal fluid between the dural layers, splitting them open. This progressive enlargement can lead to displacement of neural elements and subsequent neurological compromise. METHODS: We describe a 17-year-old girl who presented with progressive neck and back pain, left upper-extremity numbness, bilateral lower-extremity weakness, paresthesias, and numbness without obvious etiology despite an extensive neurologic investigation. She had undergone conservative management options including multiple medications, physical and chiropractic therapy, and epidural steroid injections. Computed tomography myelography revealed a cerebrospinal fluid leak into the lumbar epidural space for which surgical exploration was performed. Despite utilizing fluoroscopy and intrathecal fluorescein, no leak source was identified. Fluid collection was found contained within the dural layers rather than the epidural space. RESULTS: An intracystic blood patch was performed with near-complete resolution of the lesion by 6-week follow-up and near-complete return of neurologic function. CONCLUSIONS: Ventral panspinal cysts are an exceedingly rare cause of radiculopathy and myelopathy that can be resolved by an intracystic blood patch.

First U.S. Experience Using the Pipeline Flex Embolization Device with Shield Technology for Treatment of Intracranial Aneurysms.

BACKGROUND: The Pipeline Flex Embolization Device with Shield technology (PED-Shield [Medtronic, Dublin, Ireland]) is a third-generation flow diverter. Surface modification of the mesh with phosphorylcholine covalently bound to the metal struts aims to reduce thrombogenicity. In the present study, we report the results from the first U.S. series of patients with intracranial aneurysms treated with the PED-Shield and a comprehensive systematic literature review. METHODS: We retrospectively collected the patient demographics, aneurysm characteristics, procedural details, and periprocedural complications from our prospectively maintained endovascular database (April 2021 to July 2021). Our literature review encompassed 3 databases (PubMed, Embase, and MEDLINE). RESULTS: Ten patients with 11 anterior circulation unruptured wide-necked aneurysms (10 saccular, 1 fusiform) were included. The average patient age was 64.7 years (range, 45-86 years), and 9 were women. One device demonstrated insufficient distal opening. No other technical issues or intraprocedural complications had occurred. After the procedure, 1 patient had developed a groin hematoma and 1 had experienced a small intracranial hemorrhage, with no clinical repercussions. All patients were discharged with dual-antiplatelet therapy. In the review, we identified 15 studies. Most had been conducted in Europe and South America and 3 were U.S. case reports of compassionate use of the device. CONCLUSIONS: In our initial periprocedural experience with the PED-Shield for intracranial aneurysm treatment, the device demonstrated an excellent performance and no major complications. Further studies are required to evaluate the long-term follow-up results and the safety of different antiplatelet regimens.

Comparison of Freshly Isolated Adipose Tissue-derived Stromal Vascular Fraction and Bone Marrow Cells in a Posterolateral Lumbar Spinal Fusion Model.

STUDY DESIGN: Rat posterolateral lumbar fusion model. OBJECTIVE: The aim of this study was to compare the efficacy of freshly isolated adipose tissue-derived stromal vascular fraction (A-SVF) and bone marrow cells (BMCs) cells in achieving spinal fusion in a rat model. SUMMARY OF BACKGROUND DATA: Adipose tissue-derived stromal cells (ASCs) offer advantages as a clinical cell source compared to bone marrow-derived stromal cells (BMSCs), including larger available tissue volumes and reduced donor site morbidity. While pre-clinical studies have shown that ex vivo expanded ASCs can be successfully used in spinal fusion, the use of A-SVF cells better allows for clinical translation. METHODS: A-SVF cells were isolated from the inguinal fat pads, whereas BMCs were isolated from the long bones of syngeneic 6- to 8-week-old Lewis rats and combined with Vitoss (Stryker) bone graft substitute for subsequent transplantation. Posterolateral spinal fusion surgery at L4-L5 was performed on 36 female Lewis rats divided into three experimental groups: Vitoss bone graft substitute only (VO group); Vitoss + 2.5 × 106 A-SVF cells/side; and, Vitoss + 2.5 × 106 BMCs/side. Fusion was assessed 8 weeks post-surgery via manual palpation, micro-computed tomography (µCT) imaging, and histology. RESULTS: µCT imaging analyses revealed that fusion volumes and µCT fusion scores in the A-SVF group were significantly higher than in the VO group; however, they were not significantly different between the A-SVF group and the BMC group. The average manual palpation score was highest in the A-SVF group compared with the BMC and VO groups. Fusion masses arising from cell-seeded implants yielded better bone quality than nonseeded bone graft substitute. CONCLUSION: In a rat model, A-SVF cells yielded a comparable fusion mass volume and radiographic rate of fusion to BMCs when combined with a clinical-grade bone graft substitute. These results suggest the feasibility of using freshly isolated A-SVF cells in spinal fusion procedures.Level of Evidence: N/A.

Surgical Decompression for Cervical Spondylotic Myelopathy in Patients with Associated Hypertension: A Single-Center Retrospective Cohort and Systematic Review of the Literature.

OBJECTIVE: To explore the relationship between spinal cord compression and hypertension through analysis of blood pressure (BP) variations in a cervical spondylotic myelopathy (CSM) cohort after surgical decompression, along with a review of the literature. METHODS: A single-institution retrospective review of patients with CSM who underwent cervical decompression between 2016 and 2017 was conducted. Baseline clinical and imaging characteristics, preoperative and postoperative BP readings, heart rate, functional status, and pain scores were collected. In addition, a PRISMA guidelines-based systematic review was performed. RESULTS: We identified 264 patients with CSM treated surgically; 149 (56.4%) of these had hypertension. The degree of spinal canal compromise and spinal cord compression, preoperative neurologic examination, and the presence of T2-signal hyperintensity on magnetic resonance imaging were associated with hypertension. Overall mean arterial pressure (MAP) decreased significantly at 1 and 12 months after surgery. Patients without T2-signal hyperintensity on imaging showed a MAP reduction at 12 months postoperatively, whereas those with T2-signal hyperintensity showed a transient MAP reduction at 1 month postoperatively before returning to preoperative values. At 12 months after surgery, 24 of 97 patients (24.7%) with initially uncontrolled hypertension had controlled BP values with significant reduction of MAP, systolic BP, and diastolic BP. Including the present study, 5 articles were eligible for systematic review, with all reporting a BP decrease in patients with CSM after decompression. CONCLUSIONS: Analysis of our retrospective cohort and a systematic review suggest that cervical surgical decompression reduces BP in some patients with CSM. However, this improvement is less apparent in patients with preoperative spinal cord T2-signal hyperintensity.

The Effects of High-Dose Parathyroid Hormone Treatment on Fusion Outcomes in a Rabbit Model of Posterolateral Lumbar Spinal Fusion Alone and in Combination with Bone Morphogenetic Protein 2 Treatment.

BACKGROUND: Parathyroid hormone (PTH) (1-34) treatment reduces fracture risk in osteoporotic patients. Previously, we demonstrated in a rabbit model that low-dose PTH treatment resulted in increased fusion mass volume. As effects of PTH on bone are dose-dependent, we aimed to evaluate whether increasing dosage of PTH increases both volume and biomechanical stiffness of the resulting fusion masses and/or exhibits synergistic effects with low-dose bone morphogenetic protein 2 (BMP-2). METHODS: Posterolateral lumbar spinal fusion surgery was performed on 60 New Zealand White rabbits divided into 6 experimental groups: iliac crest autograft alone, autograft plus 20 µg/kg/day PTH, autograft plus 40 µg/kg/day PTH, BMP-2 alone, BMP-2 plus 20 µg/kg/day PTH, and BMP-2 plus 40 µg/kg PTH. Fusion was assessed at postoperative week 6 via manual palpation, volumetric computed tomography analysis, and 4-point bending biomechanical testing. RESULTS: All groups treated with BMP-2 fused. Increasing doses of PTH resulted in increased fusion mass volume compared with autograft alone. Autograft plus 40 µg/kg/day PTH yielded fusion mass volumes comparable to BMP-2. When the autograft groups were considered alone, increased mechanical stiffness was observed only in the 20 µg/kg/day group. No significant stiffness differences were observed between BMP-2 groups. CONCLUSIONS: Treatment with the highest dose of PTH resulted in fusion mass volumes similar to those obtained with BMP-2. When the autograft groups were considered alone, significant increases in mechanical stiffness were observed at a dosage of 20 µg/kg/day, suggesting there may be an optimal dose of PTH in the rabbit model. Effects of BMP-2 on fusion were dominant.

Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Androgen receptor splice variant 7 (AR-V7) has been implicated in resistance to abiraterone and enzalutamide treatment in men with metastatic castration-resistant prostate cancer (mCRPC). Tissue- or cell-based in situ detection of AR-V7, however, has been limited by lack of specificity. OBJECTIVE: To address current limitations in precision measurement of AR-V7 by developing a novel junction-specific AR-V7 RNA in situ hybridization (RISH) assay compatible with automated quantification. DESIGN, SETTING, AND PARTICIPANTS: We designed a RISH method to visualize single splice junctions in cells and tissue. Using the validated assay for junction-specific detection of the full-length AR (AR-FL) and AR-V7, we generated quantitative data, blinded to clinical data, for 63 prostate tumor biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated clinical correlates of AR-FL/AR-V7 measurements, including association with prostate-specific antigen progression-free survival (PSA-PFS) and clinical and radiographic progression-free survival (PFS), in a subset of patients starting treatment with abiraterone or enzalutamide following biopsy. RESULTS AND LIMITATIONS: Quantitative AR-FL/AR-V7 data were generated from 56 of the 63 (88.9%) biopsy specimens examined, of which 44 were mCRPC biopsies. Positive AR-V7 signals were detected in 34.1% (15/44) mCRPC specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 11.9% (range 2.7-30.3%). Positive detection of AR-V7 was correlated with indicators of high disease burden at baseline. Among the 25 CRPC biopsies collected before treatment with abiraterone or enzalutamide, positive AR-V7 detection, but not higher AR-FL, was significantly associated with shorter PSA-PFS (hazard ratio 2.789, 95% confidence interval 1.12-6.95; p=0.0081). CONCLUSIONS: We report for the first time a RISH method for highly specific and quantifiable detection of splice junctions, allowing further characterization of AR-V7 and its clinical significance. PATIENT SUMMARY: Higher AR-V7 levels detected and quantified using a novel method were associated with poorer response to abiraterone or enzalutamide in prostate cancer.

Clinical Significance of Androgen Receptor Splice Variant-7 mRNA Detection in Circulating Tumor Cells of Men With Metastatic Castration-Resistant Prostate Cancer Treated With First- and Second-Line Abiraterone and Enzalutamide.

Purpose We reported previously that the detection of androgen receptor splice variant-7 (AR-V7) mRNA in circulating tumor cells (CTCs) correlated with poor outcomes from the use of abiraterone and enzalutamide in patients with castration-resistant prostate cancer (CRPC). Here, we expanded our cohort size to better characterize the prognostic significance of AR-V7 in this setting. Methods We prospectively enrolled 202 patients with CRPC starting abiraterone or enzalutamide and investigated the prognostic value of CTC detection (+ v -) and AR-V7 detection (+ v -) using a CTC-based AR-V7 mRNA assay. We examined ≥ 50% prostate-specific antigen (PSA) responses, PSA progression-free survival, clinical and radiologic progression-free survival, and overall survival. We constructed multivariable models adjusting for PSA, Gleason sum, number of prior hormone therapies, prior abiraterone or enzalutamide use, prior taxane use, presence of visceral metastases, and Eastern Cooperative Oncology Group score. We also separately examined the first-line and second-line novel hormonal therapy (NHT) settings. Results Median follow-up times were 15.0, 21.7, and 14.6 months for CTC-, CTC+/AR-V7- and CTC+/AR-V7+ patients, respectively. CTC+/AR-V7+ patients were more likely to have Gleason scores ≥ 8 ( P = .05), metastatic disease at diagnosis ( P = .01), higher PSA ( P < .01), prior abiraterone or enzalutamide use ( P = .03), prior taxane use ( P = .02), and Eastern Cooperative Oncology Group ≥ 1 ( P = .01). Outcomes for the overall cohort (and separately for the first-line and second-line NHT cohorts) were best for CTC- patients, intermediate for CTC+/AR-V7- patients, and worse for CTC+/AR-V7+ patients. These correlations remained significant in multivariable models. Conclusion This expanded analysis further characterizes the importance of CTC-based AR-V7 mRNA detection in predicting outcomes in patients with CRPC receiving first- and second-line NHT and, to the best of our knowledge, is the first to suggest that this assay be interpreted using three separate prognostic categories: CTC-, CTC+/AR-V7-, and CTC+/AR-V7+.