Treatment of Recurrent Intracranial Hemangiopericytoma with SRC-Related Tyrosine Kinase Targeted Therapy: A Case Report

Hemangiopericytoma (HPC) is a rare sarcomatous tumor arising from pericytes, a support cell found in blood vessels. These tumors can occur throughout the body, particularly in the lower extremities and retroperitoneum. In rare circumstances, HPCs can arise from the meninges. In these cases, they behave similar to meningiomas, in particular angiomatous meningiomas, but tend to be more aggressive and are likely to recur. Treatment usually focuses on surgical resection and radiotherapy with possible inclusion of chemotherapy for control of recurrent disease. We describe a case of recurrent right temporal HPC that first manifested as a paraneoplastic syndrome of oncogenic osteomalacia. Despite maximum therapy, this patient experienced multiple recurrences of the tumor, and immunohistochemical analysis revealed overexpression of platelet-derived growth factor receptor, a member of the SRC-related tyrosine kinases. After multiple recurrences, the patient's tumor has been stable with treatment with monotherapy utilizing molecularly targeted therapy to SRC-related tyrosine kinases. This is the first case report of the treatment of recurrent meningeal HPC with molecularly targeted therapy to SRC-related tyrosine kinases

Everolimus and Bevacizumab in the Management of Recurrent, Progressive Intracranial NF2 Mutated Meningioma

Meningiomas are primary CNS tumors that arise from the arachnoid layer of the meninges. Genomic sequencing has revealed that NF2 mutations are the most common genetic alteration seen in meningiomas. Meningiomas although usually low grade, can sometimes progress to high grade. A patient who had several recurrences of meningiomas since childhood presented with recurrent headaches. Imaging showed that he had another recurrence of a meningioma. He underwent surgery for resection of the meningioma and histopathology showed NF2 mutation. He was started on everolimus and bevacizumab with good effect. Studies have shown that NF-2 mutated meningiomas have a good response to everolimus and bevacizumab with increased progression-free survival time and progression-free survival time at 6 months

Matters of Ethics, Trust, and Potential Liability for Autonomous Systems

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG geförderten) Allianz- bzw. Nationallizenz frei zugänglich.This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.The objective of this panel was to discuss issues related to the development and use of autonomous systems, with specific focus on the overriding themes of ethical considerations and potential liability for Human Factors and Ergonomics (HF/E) professionals who are involved in their development. Chris Brill provided opening remarks to frame the discussion and introduce the panelists. James Bliss discussed legal implications related to our collective penchant for developing conservative, false-alarm prone automation. Peter Hancock advocated for human-centered constraints on autonomous systems, as they may, one day, pose an existential threat to humanity. Dietrich Manzey discussed ethical considerations for autonomous systems, including how design can encourage ethical user behavior. Joachim Meyer argued that HF/E professionals have an obligation to help designers understand the ethical implications of poor design, particularly in the context of autonomous systems. Lastly, Alison Vredenburgh provided thoughts on potential liability for HF/E professionals, particularly in light of the relative newness of autonomous systems. The panel then turned to facilitated discussion with panelists and audience members. Specific themes included the boundaries of our responsibilities as HF/E professionals for ill-conceived or morally-objectionable systems, potential implications of manipulating user trust through design, cross-cultural perspectives on public acceptance and legal peril, and how concerns might differ by domain (e.g., medical vs. combat vs. manufacturing). The session concluded with panelists summarizing how ethics influence design and recommendations for how HF/E professionals can potentially protect themselves from legal liability for mishaps involving autonomous systems they helped develop

Primary Meningeal Rhabdomyosarcoma

Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy

Nonmyeloablative regimen preserves "niches" allowing for peripheral expansion of donor T-cells

AbstractT-cell recovery following myeloablative preparatory regimens and cord blood transplantation in adult patients gen erally occurs between 1 and 3 years following allogeneic bone marrow transplantation. T-cell reconstitution may involve thymic education of donor-derived precursors or peripheral expansion of mature T-cells transferred in the graft. We measured quantitative and qualitative immunologic reconstitution, T-cell receptor spectratyping, and T-cell receptor excision circle (TREC) levels in adult recipients of umbilical cord blood transplants following a novel nonmyeloablative regimen. These results were compared to previously published results of similar patients receiving a myeloablative regimen and cord blood stem cells. With small numbers of patients treated so far, T-cells (CD3+) reached normal levels in adults 6 to 12 months following nonmyeloablative transplantation compared with 24 months in adults receiving a myeloablative regimen. At 12 months after transplantation, the numbers of phenotypically naive (CD45RA) T-cells were higher in those receiving the nonmyeloablative regimen. The T-cell repertoire in cord blood recipients treated with a nonmyeloablative regimen was markedly more diverse and robust compared with the repertoire in those receiving the myeloablative regimen at similar time points. TRECs (which are generated within the thymus and identify new thymic emigrants and those that have not divided) were detected 12 months after transplantation in the nonmyeloablative recipients, whereas TRECs were not detected in adults until 18 to 24 months in those receiving myeloablative regimens. Thus, in adults receiving a nonmyeloablative preparatory regimen, the quantitative and qualitative recovery of T-cells occurs through rapid peripheral expansion. The ability of patients receiving a nonmyeloablative regimen to recover within a few months suggests that the peripheral niches in which T-cells can proliferate are preserved in these patients compared to those receiving ablative regimens. Moreover, the presence of TREC-positive cells within 1 year suggests that thymic recovery is likewise accelerated in non myeloablative compared to myeloablative regimens.Biol Blood Marrow Transplant 2002;8(5):249-56

Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study.

BackgroundVB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM).MethodsPatients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS).ResultsVB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease.ConclusionsPatients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study

Antibody Targeting of Cathepsin S Inhibits Angiogenesis and Synergistically Enhances Anti-VEGF

Angiogenesis is a key hallmark of tumourigenesis and its inhibition is a proven strategy for the development of novel anti-cancer therapeutics. An important aspect of early angiogenesis is the co-ordinated migration and invasion of endothelial cells through the hypoxic tumour tissue. Cathepsin S has been shown to play an important role in angiogenesis as has vascular endothelial growth factor (VEGF). We sought to assess the anti-angiogenic effect of Fsn0503, a novel cathepsin S inhibitory antibody, when combined with anti-VEGF on vascular development. where it significantly retarded the development of vasculature in human xenograft models. Furthermore, when Fsn0503 was combined with an anti-VEGF antibody, a synergistic inhibition of microvascular development was observed.Taken together, this data demonstrates that the antibody-mediated targeting of cathepsin S represents a novel method of inhibiting angiogenesis. Furthermore, when used in combination with anti-VEGF therapies, Fsn0503 has the potential to significantly enhance current treatments of tumour neovascularisation and may also be of use in the treatment of other conditions associated with inappropriate angiogenesis

PDGF-C Induces Maturation of Blood Vessels in a Model of Glioblastoma and Attenuates the Response to Anti-VEGF Treatment

Recent clinical trials of VEGF inhibitors have shown promise in the treatment of recurrent glioblastomas (GBM). However, the survival benefit is usually short-lived as tumors escape anti-VEGF therapies. Here we tested the hypothesis that Platelet Derived Growth Factor-C (PDGF-C), an isoform of the PDGF family, affects GBM progression independent of VEGF pathway and hinders anti-VEGF therapy.We first showed that PDGF-C is present in human GBMs. Then, we overexpressed or downregulated PDGF-C in a human GBM cell line, U87MG, and grew them in cranial windows in nude mice to assess vessel structure and function using intravital microscopy. PDGF-C overexpressing tumors had smaller vessel diameters and lower vascular permeability compared to the parental or siRNA-transfected tumors. Furthermore, vessels in PDGF-C overexpressing tumors had more extensive coverage with NG2 positive perivascular cells and a thicker collagen IV basement membrane than the controls. Treatment with DC101, an anti-VEGFR-2 antibody, induced decreases in vessel density in the parental tumors, but had no effect on the PDGF-C overexpressing tumors.These results suggest that PDGF-C plays an important role in glioma vessel maturation and stabilization, and that it can attenuate the response to anti-VEGF therapy, potentially contributing to escape from vascular normalization