Jeffrey A. Steinberg

The proteasome inhibitor CEP‐18770 enhances the anti‐myeloma activity of bortezomib and melphalan

The anti‐multiple myeloma (MM) efficacy of bortezomib has led to the development of other proteasome inhibitors (PI), including CEP‐18770 which has shown anti‐MM effects in preclinical studies. However, the efficacy of orally (PO) or intravenously (IV) administered CEP‐18770 in multiple MM models and in combination with conventional anti‐MM therapies has not been evaluated. Herein, we show that CEP‐18770 combined with melphalan or bortezomib induces synergistic inhibition of MM cell viability in vitro. In MM xenograft models, the addition of CEP‐18770 IV to melphalan completely prevented the growth of both melphalan‐sensitive and melphalan‐resistant tumours. The combination of CEP‐18770 IV and bortezomib induced complete regression of bortezomib‐sensitive tumours and markedly delayed progression of bortezomib‐resistant tumours compared to treatment with either agent alone. Single agent CEP‐18770 PO also showed marked anti‐MM effects in these xenograft models. These studies provide strong preclinical rationale for further development of this novel PI in the treatment of MM as a monotherapy as well as combined with either melphalan or bortezomib.

Pleiotrophin produced by multiple myeloma induces transdifferentiation of monocytes into vascular endothelial cells: a novel mechanism of tumor-induced vasculogenesis

Enhanced angiogenesis is a hallmark of cancer. Pleiotrophin (PTN) is an angiogenic factor that is produced by many different human cancers and stimulates tumor blood vessel formation when it is expressed in malignant cancer cells. Recent studies show that monocytes may give rise to vascular endothelium. In these studies, we show that PTN combined with macrophage colony-stimulating factor (M-CSF) induces expression of vascular endothelial cell (VEC) genes and proteins in human monocyte cell lines and monocytes from human peripheral blood (PB). Monocytes induce VEC gene expression and develop tube-like structures when they are exposed to serum or cultured with bone marrow (BM) from patients with multiple myeloma (MM) that express PTN, effects specifically blocked with antiPTN antibodies. When coinjected with human MM cells into severe combined immunodeficient (SCID) mice, green fluorescent protein (GFP)-marked human monocytes were found incorporated into tumor blood vessels and expressed human VEC protein markers and genes that were blocked by anti-PTN antibody. Our results suggest that vasculogenesis in human MM may develop from tumoral production of PTN, which orchestrates the transdifferentiation of monocytes into VECs.

Vorinostat enhances the antimyeloma effects of melphalan and bortezomib

Objectives:  Examine the antitumor activity of the histone deacetylase inhibitor vorinostat’s antitumor activity against multiple myeloma (MM) using cell lines and a murine xenograft model.

Extracellular vesicles as a platform for ‘liquid biopsy’ in glioblastoma patients

Extracellular vesicles (EVs) are cell-secreted vesicles that range from 30–2000 nm in size. These vesicles are secreted by both normal and neoplastic cells. Physiologically, EVs serve multiple critical biologic functions, including cellular remodeling, intracellular communication, modulation of the tumor microenvironment and regulation of immune function. Because EVs contain genetic and proteomic contents that reflect the cell of origin, it is possible to detect tumor-specific material in EVs secreted by cancer cells. Importantly, EVs secreted by cancer cells transgress anatomic compartments and can be detected in the blood, cerebrospinal fluid, and other biofluids of cancer patients. In this context, there is a growing interest in analyzing EVs from the biofluid of cancer patients as a means of disease diagnosis and therapeutic monitoring. In this article, we review the development of EVs as a diagnostic platform for the most common form of brain cancer, glioblastoma, discuss potential clinical translational opportunities and identify the central challenges associated with future clinical applications.

Antimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid

Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by nuclear factor kappa‐B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient (SCID)‐hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft IgG lambda light chain (LAGλ‐1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM LAGλ‐1 tumours were treated with single‐agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to control mice, whereas animals treated with ATO‐containing combinations showed markedly suppressed tumour growth and significantly reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or refractory MM.

The histone deacetylase inhibitor LBH589 enhances the anti-myeloma effects of chemotherapy in vitro and in vivo

Panobinostat (LBH589) is a potent histone deacetylase inhibitor (HDACi) that has shown anti-tumor activity in preclinical studies in both solid and hematological malignancies. We evaluated the anti-multiple myeloma (MM) effects of LBH589 alone and with melphalan or doxorubicin using MM cell lines and our human MM xenograft model LAGλ-1. LBH589 treatment resulted in increased acetylation of histones, induction of caspase cleavage, inhibition of cell proliferation and synergistic anti-MM effects with melphalan or doxorubicin in vitro. LBH589 with melphalan or doxorubicin also showed significantly enhanced anti-myeloma activity in vivo. These findings provide the basis for clinical development of these combination therapies.

TLR3 agonist and Sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression

Hepatocellular carcinoma (HCC) is associated with high mortality and the current therapy for advanced HCC, Sorafenib, offers limited survival benefits. Here we assessed whether combining the TLR3 agonist: lysine-stabilized polyinosinic-polycytidylic-acid (poly-ICLC) with Sorafenib could enhance tumor control in HCC. Combinatorial therapy with poly-ICLC and Sorafenib increased apoptosis and reduced proliferation of HCC cell lines in vitro, in association with impaired phosphorylation of AKT, MEK and ERK. In vivo, the combinatorial treatment enhanced control of tumor growth in two mouse models: one transplanted with Hepa 1-6 cells, and the other with liver tumors induced using the Sleeping beauty transposon. Tumor cell apoptosis and host immune responses in the tumor microenvironment were enhanced. Particularly, the activation of local NK cells, T cells, macrophages and dendritic cells was enhanced. Decreased expression of the inhibitory signaling molecules PD-1 and PD-L1 was observed in tumor-infiltrating CD8+ T cells and tumor cells, respectively. Tumor infiltration by monocytic-myeloid derived suppressor cells (Mo-MDSC) was also reduced indicating the reversion of the immunosuppressive tumor microenvironment. Our data demonstrated that the combinatorial therapy with poly-ICLC and Sorafenib enhances tumor control and local immune response hence providing a rationale for future clinical studies.

Vessel wall signal enhancement on 3-T MRI in acute stroke patients after stent retriever thrombectomy.

OBJECTIVE In vivo and in vitro studies have demonstrated histological evidence of iatrogenic endothelial injury after stent retriever thrombectomy. However, noncontrast vessel wall (VW)-MRI is insufficient to demonstrate vessel injury. Authors of this study prospectively evaluated iatrogenic endothelial damage after stent retriever thrombectomy in humans by utilizing high-resolution contrast-enhanced VW-MRI. Characterization of VW-MRI changes in vessels subject to mechanical injury from thrombectomy may allow better understanding of the biological effects of this intervention. METHODS The authors prospectively recruited 11 patients for this study. The treatment group included 6 postthrombectomy patients and the control group included 5 subjects undergoing MRI for nonvascular indications. All subjects were evaluated on a Signa HD× 3.0-T MRI scanner with an 8-channel head coil. Both pre- and postcontrast T1-weighted Cube VW images as well as MR angiograms were acquired. Sequences obtained for evaluation of the brain parenchyma included diffusion-weighted, gradient echo, and T2-FLAIR imaging. Two independent neuroradiologists, who were blinded to the treatment status of each patient, determined the presence of VW enhancement. Patient age, National Institutes of Health Stroke Scale score on presentation, location of occlusion, stroke etiology, type of device used, number of device deployments, Thrombolysis in Cerebral Infarction (TICI) reperfusion score, stroke volume, and 90-day modified Rankin Scale score were also noted. RESULTS Postcontrast T1-weighted VW enhancement was detected in the M2 segment in 100% of the thrombectomy patients, in the M1 segment in 83%, and in the internal carotid artery in 50%. One patient also demonstrated A1 segment enhancement, which was attributable to thrombectomy treatment of that vessel segment during the same procedure. None of the control patients demonstrated VW enhancement of their intracranial vasculature on T1-weighted images. CONCLUSIONS The study findings suggest that VW injury incurred during stent retriever thrombectomy can be reliably detected utilizing contrast-enhanced 3-T VW-MRI. The results further demonstrate that endothelial injury is associated with oversizing of stent retrievers relative to the treated vessel. Further studies are needed to evaluate the clinical significance of endothelial injury and to characterize the differential effects of various devices.

Simulator-Based Angiography and Endovascular Neurosurgery Curriculum: A Longitudinal Evaluation of Performance Following Simulator-Based Angiography Training

This study establishes performance metrics for angiography and neuroendovascular surgery procedures based on longitudinal improvement in individual trainees with differing levels of training and experience. Over the course of 30 days, five trainees performed 10 diagnostic angiograms, coiled 10 carotid terminus aneurysms in the setting of subarachnoid hemorrhage, and performed 10 left middle cerebral artery embolectomies on a Simbionix Angio Mentor™ simulator. All procedures were nonconsecutive. Total procedure time, fluoroscopy time, contrast dose, heart rate, blood pressures, medications administered, packing densities, the number of coils used, and the number of stent-retriever passes were recorded. Image quality was rated, and the absolute value of technically unsafe events was recorded. The trainees’ device selection, macrovascular access, microvascular access, clinical management, and the overall performance of the trainee was rated during each procedure based on a traditional Likert scale score of 1=fail, 2=poor, 3=satisfactory, 4=good, and 5=excellent. These ordinal values correspond with published assessment scales on surgical technique. After performing five diagnostic angiograms and five embolectomies, all participants demonstrated marked decreases in procedure time, fluoroscopy doses, contrast doses, and adverse technical events; marked improvements in image quality, device selection, access scores, and overall technical performance were additionally observed (p < 0.05). Similarly, trainees demonstrated marked improvement in technical performance and clinical management after five coiling procedures (p < 0.05). However, trainees with less prior experience deploying coils continued to experience intra-procedural ruptures up to the eighth embolization procedure; this observation likely corresponded with less tactile procedural experience to an exertion of greater force than appropriate for coil placement. Trainees across all levels of training and prior experience demonstrated a significant performance improvement after completion of our simulator curriculum consisting of five diagnostic angiograms, five embolectomy cases, and 10 aneurysm coil embolizations.

Endometriosis of the conus medullaris causing cyclic radiculopathy

Intramedullary spinal cord hematomas are a rare neurosurgical pathological entity typically arising from vascular and neoplastic lesions. Endometriosis is an extremely rare cause of intramedullary spinal cord hematoma, with only 5 previously reported cases in the literature. Endometriosis is characterized by ectopic endometrial tissue, typically located in the female pelvic cavity, that causes a cyclical pain syndrome, bleeding, and infertility. In the rare case of intramedullary endometriosis of the spinal cord, symptoms include cyclical lower-extremity radiculopathies and voiding difficulties, and can acutely cause cauda equina syndrome. The authors report a case of endometriosis of the conus medullaris, the first to include radiological, intraoperative, and histopathological imaging. A brief review of the literature is also presented, with discussion including etiological theories surrounding intramedullary endometriosis.