BACKGROUND:Silent corticotroph adenomas (SCAs) are only identified after surgical removal and pathological analysis. Defective processing of pro-opiomelanocortin (POMC) may underlie these tumors' failure to secrete biologically active ACTH. While prior studies found elevated plasma POMC in patients with Cushing disease (CD) due to macroadenomas and ectopic ACTH-secreting tumors, plasma POMC has not been measured in a clinically non-functioning pituitary adenoma (CNFPA) cohort. We hypothesized that elevated plasma POMC could serve as a marker of the SCA sub-type of CNFPAs. METHODS:We measured plasma POMC levels in 264 CNFPAs in a prospective, observational study (157 treated surgically and 107 observed without surgery), 10 known SCAs, and 3 patients with CD using a POMC 2-site ELISA that detects POMC and pro-ACTH but not ACTH. Surgically removed tumors underwent immunohistochemistry to classify them into SCA and Not SCA subtypes. Normal POMC levels were < 39 fmol/mL. RESULTS:POMC levels were higher in SCA (n = 7) than Not SCA (n = 138) groups (median 73 vs. 14 fmol/mL, p < 0.001) and elevated (≥ 39 fmol/mL) in 85.7% of SCAs. Elevated POMC predicted SCA presence amongst CNFPAs with a sensitivity of 85.7% and specificity of 97.9%. POMC was elevated in all known SCAs with visible residual tumor, ranging from 49.6 to 3796 fmol/mL. CONCLUSION:We found plasma POMC level to be a promising predictor of SCA presence in a CNFPA cohort. POMC measurement could become part of the initial CNFPA evaluation and used for monitoring for residual and recurrent tumor after surgery. These preliminary findings warrant further investigation.

IDH-mutant gliomas are the most common malignant brain tumor in patients under 50 years old and have no cure. A major challenge in treatment is intratumoral heterogeneity, where drug-resistant subpopulations drive recurrence. Ferroptosis, a form of iron-dependent cell death, and IDH inhibition both target metabolic vulnerabilities in glioma. Prior evidence in glioblastoma demonstrates that ferroptosis can selectively target vulnerable tumor subpopulations and may exploit metabolic shifts associated with IDH inhibition, a therapy now in clinical use. We have established methods to generate acute slices from human glioma surgical specimens, treat with drugs ex vivo, and assess drug responses by single-cell sequencing. This preserves tumor heterogeneity to enable identification of drug sensitivities in specific subpopulations, which is crucial for identifying effective molecular targets and therapeutic combinations. Using this platform, we tested drugs that induce ferroptosis via GPX4 inhibition and an IDH inhibitor in human IDH-mutant glioma samples. Our preliminary data suggests differential sensitivity to ferroptosis inducers and IDH inhibitors across tumor subpopulations, where responses correlate to metabolic state. These studies are especially timely and relevant for the growing subset of IDH-mutant glioma patients currently undergoing treatment with IDH inhibitors.

In the mammalian isocortex, CD44, a cell surface receptor for extracellular matrix molecules, is present in pial-based and fibrous astrocytes of white matter but not in protoplasmic astrocytes. In the hominid isocortex, CD44+ astrocytes comprise the subpial "interlaminar" astrocytes, sending long processes into the cortex. The hippocampus also contains similar astrocytes. We have examined all levels of the human central nervous system and found CD44+ astrocytes in every region. Astrocytes in white matter and astrocytes that interact with large blood vessels but not with capillaries in gray matter are CD44+, the latter extending long processes into the parenchyma. Motor neurons in the brainstem and spinal cord, such as oculomotor, facial, hypoglossal, and in the anterior horn of the spinal cord, are surrounded by CD44+ processes, contrasting with neurons in the cortex, basal ganglia, and thalamus. We found CD44+ processes that intercalate between ependymal cells to reach the ventricle. We also found CD44+ astrocytes in the molecular layer of the cerebellar cortex. Protoplasmic astrocytes, which do not normally contain CD44, acquire it in pathologies like hypoxia and seizures. The pervasive and inducible expression of CD44 in astrocytes is a novel finding that lays the foundations for functional studies into the significance of CD44 in health and disease.

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional ‘tissue-states’ defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment.

A 31-year-old woman with transthyretin (TTR) amyloidosis secondary to a Thr60Ala mutation developed recurrent stroke-like episodes with fluctuating mental status. Evaluation for stroke and seizures was unrevealing. She was found to have leptomeningeal contrast enhancement on magnetic resonance imaging, which was confirmed to be CNS TTR amyloidosis on histopathology following brain and dura biopsy. While leptomeningeal disease has rarely been known to be associated with TTR amyloidosis, this is the first documented case of leptomeningeal disease secondary to a Thr60Ala mutation in the TTR gene. A literature review of TTR amyloidosis is presented with special focus on the treatment of leptomeningeal TTR amyloidosis.

The new WHO 2021 classification included CDKN2A/B loss and TERT mutation as new criteria for Grade 3 meningiomas, but excluded H3K27me3 loss. Malignant behavior may be influenced by DNA methyltransferases (DNMT3A). SUFU mutations may carry a predisposition for multiple meningiomas. In this retrospective study, 228 patients with Grade 2, Grade 3 or recurrent Grade 1 meningiomas with resections from 1990 to July 2021 at Columbia University Medical Center were assessed for recurrence, histologic features, and molecular alterations. Of 228 patients with meningiomas, 9 were recurrent Grade 1, 9 were Grade 1 transformed to Grade 2, 109 were non-recurrent Grade 2, 77 were recurrent Grade 2, 13 were transformed Grade 2 to Grade 3, and 5 were non-recurrent Grade 3 and 6 were recurrent Grade 3. Median follow-up was 42.0 months. Of the recurrent/transformed tumors, 89 were radiation-resistant. Average mitotic counts for non-recurrent Grade 2 vs. recurrent/transformed Grade 2 and non-recurrent Grade 3 vs. recurrent Grade 3 meningiomas were 4 vs. 5, 24 vs. 27 mitoses/10HPF, respectively. Of 36 meningiomas evaluated with NGS, the most common alterations was NF2 (20/36). CDKN2A/B was lost in 5 meningiomas, three with Grade 2 that transformed to Grade 3 and two with recurrent disease. TERT was mutant in 3/36, 2 of which were Grade 2 that transformed to Grade 3 meningiomas. H3K27M me3 was tested by IHC in 4 patients, 3 with retained staining, all of whom did not recur and 1 with loss of staining in a Grade 1 transformed to Grade 2. DNMT3A was found in 2 tumors, both radiation-induced. SUFU occurred in 3/16, one of each grade, all solitary. In our limited cohort, we observed concordance with the new WHO 2021 criteria for Grade 3 meningiomas

Autonomous driving is one of the most popular technologies in artificial intelligence. Collision detection is an important issue in automatic driving, which is related to the safety of automatic driving. Many collision detection methods have been proposed, but they all have certain limitations and cannot meet the requirements for automatic driving. Camera is one of the most popular methods to detect objects. The obstacle detection of the current camera is mostly completed by two or more cameras (binocular technology) or used in conjunction with other sensors (such as a depth camera) to achieve the purpose of distance detection. In this paper, we propose an algorithm to detect obstacle distances from photos or videos of a single camera.

We present the case of a 41-year-old man who developed worsening mid-thoracic back pain and imaging revealed a well-circumscribed intramedullary tumor in the thoracic spinal cord. Subtotal resection was performed, and histopathological analysis showed a cytologically bland, minimally proliferative glial neoplasm. Sequencing revealed H3 K27M and an activating PTPN11 mutation. Serial imaging revealed slow tumor regrowth over a three year period which prompted a second resection. The recurrent tumor displayed a similar low grade-appearing histology and harbored the same H3 K27M and PTPN11 mutations as the primary. While the prognostic importance of isolated H3 K27M in spinal gliomas is well-known, the combination of these two mutations in spinal low grade glioma has not been previously reported. Importantly, PTPN11 is a component of the MAPK signaling pathway. Thus, as building evidence shows that low grade-appearing gliomas harboring H3 K27M mutations along with BRAF or FGFR1 mutations have a relatively more favorable course compared to isolated H3 K27M-mutant midline gliomas, the present case provides new evidence for the prognostic importance of activating mutations in other components of the MAPK signaling pathway. This case further highlights the importance of clinico-radio-pathologic correlation when incorporating evolving genetic data into the integrated diagnosis of rare neuroepithelial tumors.

Anti-amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β-amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80). Brain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double-blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open-label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death. Clinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR-SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta-amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near-absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2). In this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β-amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β-amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.

HER2 amplification, which results in overexpression of the receptor tyrosine kinase HER2, has been described in a wide variety of malignancies. HER2-targeting agents have been incorporated into the treatment paradigms for HER2-overexpressing breast and gastric cancer. More recently, these agents have shown promise in other gastrointestinal malignancies, such as colon cancer and biliary tract tumors. This study discusses two patients with gallbladder carcinoma and a third with ampullary carcinoma who were able to achieve marked responses to HER2-directed therapy. These cases underscore the importance of molecular analysis for HER2 amplification/HER2 overexpression, irrespective of tumor histology, and highlight a need for further investigation of HER2-directed therapy beyond breast and gastroesophageal cancers. Key Points Current guidelines recommend molecular assessment for HER2 overexpression exclusively in breast and gastric adenocarcinoma. The focus of this report is on three cases (two biliary tract and one ampullary carcinoma) in which amplification of HER2 or overexpression of HER2 was detected and treatment with HER2-directed therapy resulted in robust responses. These cases exemplify responsiveness of non-breast/gastric histologies to HER2-directed therapies, highlighting several promising new settings for these agents. Testing for amplification of HER2 or overexpression of HER2 should be considered especially in rare diseases with limited treatment options.