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Federated ML (FL) provides an alternative to train accurate and generalizable ML models, by only sharing numerical model updates. Here, the authors present the largest FL study to-date to generate an automatic tumor boundary detector for glioblastoma.

Radiographic contact of glioblastoma (GBM) tumors with the lateral ventricle and adjacent stem cell niche correlates with poor patient prognosis, but the cellular basis of this difference is unclear. Here, we reveal and functionally characterize distinct immune microenvironments that predominate in subtypes of GBM distinguished by proximity to the lateral ventricle. Mass cytometry analysis of isocitrate dehydrogenase wild-type human tumors identified elevated T cell checkpoint receptor expression and greater abundance of a specific CD32+CD44+HLA-DRhi macrophage population in ventricle-contacting GBM. Multiple computational analysis approaches, phospho-specific cytometry, and focal resection of GBMs validated and extended these findings. Phospho-flow quantified cytokine-induced immune cell signaling in ventricle-contacting GBM, revealing differential signaling between GBM subtypes. Subregion analysis within a given tumor supported initial findings and revealed intratumor compartmentalization of T cell memory and exhaustion phenotypes within GBM subtypes. Collectively, these results characterize immunotherapeutically targetable features of macrophages and suppressed lymphocytes in GBMs defined by MRI-detectable lateral ventricle contact.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Tumor-induced osteomalacia (TIO) is a rare disease in which patients suffer from fractures and progressive disabling bone pain and muscle weakness. TIO is caused by the hypersecretion of Fibroblast Growth Factor 23 (FGF23) from rare neoplasms of mesenchymal origin. This case report describes a 29-year-old male with 2 years of low back/hip pain, gait changes, proximal muscle weakness, and multiple stress fractures. Bone densitometry was remarkable for severe osteoporosis, hypophosphatemia was seen on routine labs, and advanced labs demonstrated an “inappropriately normal” FGF23 level. A 68Ga-DOTATATE scan and MRI showed a 1.3 × 1.1 × 1.0 cm intracranial mass. The patient underwent tumor resection by Neurosurgery. Shortly after, laboratory levels normalized, and the patient's symptoms improved drastically. This case exemplifies the notion that TIO can be caused by FGF23 levels within normal limits, the role of 68-Ga DOTATATE imaging for establishing a diagnosis, and that these tumors can arise anywhere—even intracranially. We also review current surgical and nonsurgical treatment options, as well as emerging novel therapeutics. Keywords: TIO, Paraneoplastic syndrome, Tumor-induced osteomalacia, Fibroblast growth factor 23, 68Ga-DOTATATE, MRI, DXA, Burosumab

Glioblastoma multiforme (GBM) is a highly heterogeneous disease, which is initiated and sustained by various molecular alterations in an array of signal transduction pathways. Heat-shock protein 90 (Hsp90) is a molecular chaperone and is critically implicated in folding and activation of a diverse group of client proteins, many of which are key regulators for glioblastoma biology. We here assessed the anti-neoplastic efficacy of a novel brain-penetrating Hsp90 inhibitor NXD30001 as a monotherapy and combined with radiation in vitro and in vivo. Our results demonstrated that NXD30001 potently inhibited neurosphere formation, growth, and survival of CD133+ GBM cells with the half maximal inhibitory concentration at low nanomolar range, but CD133− GBM cells were less sensitive to NXD30001. NXD30001 also increased radio-sensitivity in glioblastoma stem cells (GSCs) at suboptimal concentrations. Moreover, NXD30001 dose-dependently decreased phosphorylation levels of multiple Hsp90 client proteins which play key roles in GBM, such as EGFR, Akt, c-Myc, and Notch1. In addition, NXD30001 could impair DNA damage response and endoplasmic reticulum stress response after radiotherapy by alteration of the related proteins expression. In a murine orthotopic model of human glioblastoma, NXD30001 marvelously induced tumor regression and extended median survival of tumor-bearing mice by approximately 20% when compared with the vehicle group (37 d vs 31 d, P

Objective: Review the clinical presentation and management of meningeal hemangiopericytomas of the lateral skull base and cerebellopontine angle (CPA), and describe a case of anaplastic hemangiopericytoma of the CPA presenting as a middle ear mass. Study design: Case report and literature review. Case description: A 51-year-old male presented with a one year history of hearing loss, pulsatile tinnitus, and disequilibrium. Physical examination demonstrated a mass in the left middle ear. Magnetic resonance imaging revealed a 4 cm, T1-/T2-isointense, contrast-enhancing mass in the middle cranial fossa. The erosive mass extended into the middle ear and surrounding temporal lobe. A trans-zygomatic approach with a pterional craniotomy exposed a well-encapsulated, highly vascular mass. Manipulation of the tumor resulted in significant hemorrhage. Following removal from the temporal lobe and middle ear, an anterior petrosectomy was performed to remove tumor from the internal auditory canal (IAC) and carotid artery. The facial nerve near the IAC was encased in tumor, and all but a small amount of tumor adherent to the nerve was successfully removed. The final pathologic diagnosis was anaplastic hemangiopericytoma (WHO Grade III). Metastatic workup revealed no extracranial disease, and the patient underwent adjuvant radiation therapy. He continues to do well with only mild disequilibrium at one year follow-up. Conclusions: Hemangiopericytomas are rare, malignant neoplasms that are aggressive and highly vascular. Current management recommendations include excision followed by radiotherapy. Close surveillance is required for patients with anaplastic hemangiopericytoma due to the aggressive nature of this tumor and its propensity for recurrence or metastasis. Keywords: Hemangiopericytoma, Transzygomatic, Skull base, Middle ear mass, Middle cranial fossa, Tumor

Abstract Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Summary: Accumulating evidence suggests that cancer cells with stem cell-like phenotypes drive disease progression and therapeutic resistance in glioblastoma (GBM). NOTCH regulates self-renewal and resistance to chemoradiotherapy in GBM stem cells. However, NOTCH-targeted γ-secretase inhibitors (GSIs) exhibited limited efficacy in GBM patients. We found that farnesyltransferase inhibitors (FTIs) significantly improved sensitivity to GSIs. This combination showed significant antineoplastic and radiosensitizing activities in GBM stem cells, whereas non-stem GBM cells were resistant. These combinatorial effects were mediated, at least partially, through inhibition of AKT and cell-cycle progression. Using subcutaneous and orthotopic GBM models, we showed that the combination of FTIs and GSIs, but not either agent alone, significantly reduced tumor growth. With concurrent radiation, this combination induced a durable response in a subset of orthotopic tumors. These findings collectively suggest that the combination of FTIs and GSIs is a promising therapeutic strategy for GBM through selectively targeting the cancer stem cell subpopulation. : NOTCH-targeted agents may selectively compromise glioblastoma stem cells. In this article, Wang and colleagues demonstrate that farnesyltransferase inhibitors significantly augmented the sensitivity of glioblastoma stem cells to γ-secretase inhibitors and improved tumor growth control in xenograft models. This combination therapy also promoted radiosensitivity and resulted in a durable response in orthotopic glioblastoma models with concurrent radiation. Keywords: Notch, glioblastoma stem cells, γ-secretase inhibitors, farnesyltransferase inhibitors

Conventional image-guided neurosurgery relies on preoperative images to provide surgical navigational information and visualization. However, these images are no longer accurate once the skull has been opened and brain shift occurs. To account for changes in the shape of the brain caused by mechanical (e.g., gravity-induced deformations) and physiological effects (e.g., hyperosmotic drug-induced shrinking, or edema-induced swelling), updated images of the brain must be provided to the neuronavigation system in a timely manner for practical use in the operating room. In this paper, a novel preoperative and intraoperative computational processing pipeline for near real-time brain shift correction in the operating room was developed to automate and simplify the processing steps. Preoperatively, a computer model of the patient's brain with a subsequent atlas of potential deformations due to surgery is generated from diagnostic image volumes. In the case of interim gross changes between diagnosis, and surgery when reimaging is necessary, our preoperative pipeline can be generated within one day of surgery. Intraoperatively, sparse data measuring the cortical brain surface is collected using an optically tracked portable laser range scanner. These data are then used to guide an inverse modeling framework whereby full volumetric brain deformations are reconstructed from precomputed atlas solutions to rapidly match intraoperative cortical surface shift measurements. Once complete, the volumetric displacement field is used to update, i.e., deform, preoperative brain images to their intraoperative shifted state. In this paper, five surgical cases were analyzed with respect to the computational pipeline and workflow timing. With respect to postcortical surface data acquisition, the approximate execution time was 4.5 min. The total update process which included positioning the scanner, data acquisition, inverse model processing, and image deforming was ~ 11-13 min. In addition, easily implemented hardware, software, and workflow processes were identified for improved performance in the near future.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

A goal of cancer research is to reveal cell subsets linked to continuous clinical outcomes to generate new therapeutic and biomarker hypotheses. We introduce a machine learning algorithm, Risk Assessment Population IDentification (RAPID), that is unsupervised and automated, identifies phenotypically distinct cell populations, and determines whether these populations stratify patient survival. With a pilot mass cytometry dataset of 2 million cells from 28 glioblastomas, RAPID identified tumor cells whose abundance independently and continuously stratified patient survival. Statistical validation within the workflow included repeated runs of stochastic steps and cell subsampling. Biological validation used an orthogonal platform, immunohistochemistry, and a larger cohort of 73 glioblastoma patients to confirm the findings from the pilot cohort. RAPID was also validated to find known risk stratifying cells and features using published data from blood cancer. Thus, RAPID provides an automated, unsupervised approach for finding statistically and biologically significant cells using cytometry data from patient samples.

Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.