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Glioblastoma is the most common primary malignant brain tumor, and is refractory to surgical resection, radiation, and chemotherapy. Human mesenchymal stem cells (hMSC) may be harvested from bone marrow (BMSC) and adipose (AMSC) tissue. These cells are a promising avenue of investigation for the delivery of adjuvant therapies. Despite extensive research into putative mechanisms for the tumor tropism of MSCs, there remains no direct comparison of the efficacy and specificity of AMSC and BMSC tropism towards glioma. Under an IRB-approved protocol, intraoperative human Adipose MSCs (hAMSCs) were established and characterized for cell surface markers of mesenchymal stem cell origin in conjunction with the potential for tri-lineage differentiation (adipogenic, chondrogenic, and osteogenic). Validated experimental hAMSCs were compared to commercially derived hBMSCs (Lonza) and hAMSCs (Invitrogen) for growth responsiveness and glioma tropism in response to glioma conditioned media obtained from primary glioma neurosphere cultures. Commercial and primary culture AMSCs and commercial BMSCs demonstrated no statistically significant difference in their migration towards glioma conditioned media in vitro. There was statistically significant difference in the proliferation rate of both commercial AMSCs and BMSCs as compared to primary culture AMSCs, suggesting primary cultures have a slower growth rate than commercially available cell lines. Adipose- and bone marrow-derived mesenchymal stem cells have similar in vitro glioma tropism. Given the well-documented ability to harvest larger numbers of AMSCs under local anesthesia, adipose tissue may provide a more efficient source of MSCs for research and clinical applications, while minimizing patient morbidity during cell harvesting.

Background The decision to biopsy a peripheral nerve tumor is largely based on its presumed behavior and prognosis, determined by patient history, clinical exam, and radiologic characteristics. Percutaneous image-guided biopsy is not without risk in patients with malignant peripheral nerve sheath tumors (MPNSTs); in particular, there may be concern regarding worsening neurologic function, increasing neuropathic pain, and incorrect or absent diagnosis. Methods Following approval by our institutional review board, we reviewed records from 1990 to 2019 at our institution’s three main sites (“our institution”). Patients with pathology-proven MPNST were selected. Further inclusion criteria included image-guided percutaneous biopsy performed at our institution, pathology report available for review, and follow-up documentation to determine post-biopsy complications. Results Three hundred thirty-one patients with MPNST were reviewed. In total, 73 patients undergoing image-guided percutaneous biopsies were included. Twenty-two (30.1%) had biopsy-related complications. This included ten patients with misdiagnosis (13.7%) and six patients with non-diagnostic biopsies (8.2%). Six patients had new or worsened pain that resolved with time and neuropathic pain medication (8.2%), and one patient had subjectively worsened proximal weakness (1.3%) which resolved. Conclusion We found nearly a third of patients undergoing biopsy had a biopsy-related complication. The single largest complication was the inability to obtain an accurate diagnosis (21.9%) with the first biopsy. This may lead to the need for repeat percutaneous or open biopsies, or a non-oncologic initial surgery with implications for disease-free and overall survival. Neurologic complications including exacerbation of pain or a deficit were rare and transient. It remains important that clinicians balance the potential risks and benefits based on individual patient characteristics when determining the necessity of an image-guided percutaneous biopsy.

Tamoxifen is widely used for the treatment of hormonally responsive breast cancers. However, some resistant breast cancers develop a growth proliferative response to this drug, as evidenced by tumor regression upon its withdrawal. To elucidate the molecular mediators of this paradox, tissue samples from a patient with tamoxifen-stimulated breast cancer were analyzed. These studies revealed that loss of the cyclin-dependent kinase inhibitor p21 was associated with a tamoxifen growth-inducing phenotype. Immortalized human breast epithelial cells with somatic deletion of the p21 gene were then generated and displayed a growth proliferative response to tamoxifen, whereas p21 wild-type cells demonstrated growth inhibition upon tamoxifen exposure. Mutational and biochemical analyses revealed that loss of p21's cyclin-dependent kinase inhibitory property results in hyperphosphorylation of estrogen receptor-α, with subsequent increased gene expression of estrogen receptor-regulated genes. These data reveal a previously uncharacterized molecular mechanism of tamoxifen resistance and have potential clinical implications for the management of tamoxifen-resistant breast cancers.

BackgroundUsual management of peripheral nerve tumors is to avoid biopsy in those that are likely benign; the risk of biopsy outweighs the benefit of definitive tissue diagnosis. Biopsy of presumed malignant lesions is performed widely. There is a subset of peripheral nerve tumors that are not easily categorized as benign or malignant based on the clinical and/or radiological features alone. The role of biopsy in peripheral nerve tumors of uncertain character remains controversial and the risk of biopsy (and the potential risk/benefit ratio) for these lesions is not known.MethodsFollowing approval by our institutional review board, we reviewed all notes of a single peripheral nerve surgeon from 2000 to 2018 with respect to image-guided percutaneous biopsy of nerve tumors. We divided these patients into 3 groups based on clinicoradiologic features. We determined the risk of complications and the “hit rate” for patients with peripheral nerve tumors of uncertain behavior, defined as the percentage of patients sent for percutaneous biopsy who had a malignancy on their final pathology.ResultsOf 82 patients with tumors of uncertain behavior, 9 had complications, and 23 had malignant final pathology (a “hit rate” of 27.7%). Neurosurgical referral for biopsy of tumors of uncertain behavior was made in 60 patients. Twenty-two had malignant final pathology (“hit rate”= 36.7%). Non-neurosurgical referral for biopsy was made in 22 patients with tumors of uncertain behavior. Two had malignant final pathology (“hit rate”= 4.55%). There was a statistically significant difference between the “hit rate” for the two groups (p = 0.021).ConclusionsThe decision to biopsy a peripheral nerve tumor is largely based on the presumed behavior and prognosis, determined via clinicoradiologic characteristics. Patient care might be improved by delaying percutaneous biopsy of peripheral nerve lesions until after a neurosurgical evaluation.

The field of adoptive cellular therapy, using autologous T-cells modified ex vivo to specifically target tumor cells prior to being reintroduced to the patient, has become a new focus of research endeavors searching for a novel and efficacious treatment for oncologic disease, including glioblastoma. Chimeric Antigen Receptor (CAR)-T-cells consist of a single chain variable fragment of a monoclonal antibody coupled with extant T-cell intracellular signaling cascade systems using a viral vector ex vivo. This provides the advantage of targeting tumor specific surface markers, while minimizing off-target effects and potential toxicity. Additionally, the CAR T-cells bypass the need for MHC-restricted presentation, a system which is frequently down-regulated in tumor cells. Among the surface antigens described as targets for CAR T-cell therapy for GBMs, Epidermal growth factor variant III (EGFRvIII), HER2 (HER2/neu, ERBB2), interleukin-13 receptor α2 subunit (IL-13Rα2), and erythropoietin-producing hepatocellular carcinoma A2 (EphA2) are the leading options for tumor specific surface antigens to target with CAR-T cells. This article reviews history and advantages of CAR-T cell therapies, and discuss future directions.

INTRODUCTION In recent years, there has been a concerted effort to reduce gender disparities within the field of neurosurgery. These efforts have met with successes, but there remain inequities, particularly in the realm of academic neurosurgery, where a variety of factors play a role. METHODS Using Scopus, articles published in JNS and Neurosurgery from 1995–2019 were catalogued. These journals were chosen because of their high impact factor and their links to organized academic neurosurgery. Papers with a senior author based at a US institution, and with the majority of authors associated with a US institution were further analyzed. We excluded: editorials, letters, commentaries, book reviews, videos, journal clubs, obituaries, personal reflections, special articles, invited reviews, conference proceedings, and miscellaneous publications that were not classified as academic articles. Author names were inspected to determine author sex. In instances where the name was not recognized, an internet search was performed using the full name, institution, and/or degrees. If 30 search items failed to identify an author's sex, that author was excluded. We analyzed unique authors, with attention to female authors with MD/DO qualifications, and those who were neurosurgeons. Statistical significance of results was determined using Chi-Squared and linear regression models. RESULTS 8,013 articles were included, representing 15875 unique authors for whom author sex was identified. Overall, female MDs made up 7.00% of first authors and 4.69% of senior authors. Female neurosurgeons comprise 2.56% of first authors, and 1.32% of senior authors. To determine the change in female authorship over the 25-year period, we performed a sub-group analysis for 5-year periods. Female neurosurgeons as first author have increased over time: 2.11% (1995-1999) to 3.15% (2015-2019) (not statistically significant). The role of female neurosurgeons as senior authors has significantly increased over time: 0.41% (1995-1999) to 1.72% (2015-2019) (P = .003). CONCLUSION Although female authors, particularly female MDs and female neurosurgeons, remain a minority, there are improving trends over time. However, first and senior authorship lags behind the overall authorship trends.

INTRODUCTION Both benign and malignant peripheral nerve sheath tumors (PNST) may arise spontaneously, in conjunction with tumor-forming syndromes, or in previously radiated patients. Distinguishing benign from malignant PNST may be challenging. METHODS We reviewed the electronic records for patients with benign peripheral nerve sheath tumors (BPNST) and those with MPNST. Data regarding the involved nerve(s), presence and magnitude of weakness were collected. Tumors involving cranial nerves or with spinal cord compression were excluded. The MRC scale was used to grade weakness (averages were calculated and rounded to the nearest valid MRC score). RESULTS There were 718 benign PNST of motor nerves (603 schwannoma, 115 neurofibroma) and 126 MPNST of motor nerves. For schwannomas, 38/603 had clinical weakness at presentation (6.3%). The average MRC score was 4.5 (range 2-4+, stdev 0.55). Only one patient had an MRC < 3, and this patient had a schwannoma within Guyon's canal causing compression of the nerve. For neurofibromas, 19/115 had clinical weakness at presentation (16.5%). The average MRC score was 4 (range 1-4+, stdev 0.88). Only plexiform neurofibromas had an MRC < 3. Eleven plexiform neuromas had clinical weakness; this included five neurofibroma chains along a single nerve, and six solitary plexiform neurofibromas. The average length of the solitary plexiform tumors was 7.74 cm (range: 3.2-12 cm). When plexiform tumors were excluded, the average MRC score was 4 (range 4−-4+, stdev 0.177). For MPNSTs, 54/126 had clinical weakness at presentation (42.9%). The average MRC score was 2 (range 0–4, stdev 1.51). There was a significant difference between the average MRC in patients with schwannomas versus MPNST (p < 0.0001), as well as between patients with neurofibromas versus MPNST (p < 0.0001). CONCLUSION MPNST had significantly lower MRC scores than benign PNST. An MRC < 3 was see almost exclusively in MPNSTs. Conveniently, an MRC 3 has an easily reproducible clinical definition. In the absence of a plexiform tumor, or a tumor compressing a nerve (i.e., within a canal or tunnel) a clinical exam demonstrating less than antigravity strength should prompt serious consideration of a MPNST.

Abstract BACKGROUND Clinicoradiologic differentiation between benign and malignant peripheral nerve sheath tumors (PNSTs) has important management implications. OBJECTIVE To develop and evaluate machine-learning approaches to differentiate benign from malignant PNSTs. METHODS We identified PNSTs treated at 3 institutions and extracted high-dimensional radiomics features from gadolinium-enhanced, T1-weighted magnetic resonance imaging (MRI) sequences. Training and test sets were selected randomly in a 70:30 ratio. A total of 900 image features were automatically extracted using the PyRadiomics package from Quantitative Imaging Feature Pipeline. Clinical data including age, sex, neurogenetic syndrome presence, spontaneous pain, and motor deficit were also incorporated. Features were selected using sparse regression analysis and retained features were further refined by gradient boost modeling to optimize the area under the curve (AUC) for diagnosis. We evaluated the performance of radiomics-based classifiers with and without clinical features and compared performance against human readers. RESULTS A total of 95 malignant and 171 benign PNSTs were included. The final classifier model included 21 imaging and clinical features. Sensitivity, specificity, and AUC of 0.676, 0.882, and 0.845, respectively, were achieved on the test set. Using imaging and clinical features, human experts collectively achieved sensitivity, specificity, and AUC of 0.786, 0.431, and 0.624, respectively. The AUC of the classifier was statistically better than expert humans (P = .002). Expert humans were not statistically better than the no-information rate, whereas the classifier was (P = .001). CONCLUSION Radiomics-based machine learning using routine MRI sequences and clinical features can aid in evaluation of PNSTs. Further improvement may be achieved by incorporating additional imaging sequences and clinical variables into future models.