COVID survivors frequently experience lingering neurological symptoms that resemble cancer therapy-related cognitive impairment, a syndrome for which white-matter microglial reactivity and consequent ...neural dysregulation is central. Here, we explored the neurobiological effects of respiratory SARS-CoV-2 infection and found white-matter-selective microglial reactivity in mice and humans. Following mild respiratory COVID in mice, persistently impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss were evident together with elevated CSF cytokines/chemokines including CCL11. Systemic CCL11 administration specifically caused hippocampal microglial reactivity and impaired neurogenesis. Concordantly, humans with lasting cognitive symptoms post-COVID exhibit elevated CCL11 levels. Compared to SARS-CoV-2, mild respiratory influenza in mice caused similar patterns of white matter-selective microglial reactivity, oligodendrocyte loss, impaired neurogenesis and elevated CCL11 at early timepoints, but after influenza only elevated CCL11 and hippocampal pathology persisted. These findings illustrate similar neuropathophysiology after cancer therapy and respiratory SARS-CoV-2 infection which may contribute to cognitive impairment following even mild COVID.
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Chondromyxoid fibroma (CMF) is a rare benign bone neoplasm that manifests histologically as a lobular proliferation of stellate to spindle-shaped cells in a myxoid background, exhibiting morphologic ...overlap with other cartilaginous and myxoid tumors of bone. CMF is characterized by recurrent genetic rearrangements that place the glutamate receptor gene GRM1 under the regulatory control of a constitutively active promoter, leading to increased gene expression. Here, we explore the diagnostic utility of GRM1 immunohistochemistry as a surrogate marker for GRM1 rearrangement using a commercially available monoclonal antibody in a study of 230 tumors, including 30 CMF cases represented by 35 specimens. GRM1 was positive by immunohistochemistry in 97% of CMF specimens (34/35), exhibiting moderate to strong staining in more than 50% of neoplastic cells; staining was diffuse (>95% of cells) in 25 specimens (71%). Among the 9 CMF specimens with documented exposure to acid decalcification, 4 (44%) exhibited diffuse immunoreactivity (>95%) for GRM1, whereas all 15 CMF specimens (100%) with lack of exposure to decalcification reagents were diffusely immunoreactive ( P =0.003). High GRM1 expression at the RNA level was previously observed by quantitative reverse transcription polymerase chain reaction in 9 CMF cases that were also positive by immunohistochemistry; low GRM1 expression was observed by quantitative reverse transcription polymerase chain reaction in the single case of CMF that was negative by immunohistochemistry. GRM1 immunohistochemistry was negative (<5%) in histologic mimics of CMF, including conventional chondrosarcoma, enchondroma, chondroblastoma, clear cell chondrosarcoma, giant cell tumor of the bone, fibrous dysplasia, chondroblastic osteosarcoma, myoepithelial tumor, primary aneurysmal bone cyst, brown tumor, phosphaturic mesenchymal tumor, CMF-like osteosarcoma, and extraskeletal myxoid chondrosarcoma. These results indicate that GRM1 immunohistochemistry may have utility in distinguishing CMF from its histologic mimics.
The human brain undergoes rapid development at mid-gestation from a pool of neural stem and progenitor cells (NSPCs) that give rise to the neurons, oligodendrocytes, and astrocytes of the mature ...brain. Functional study of these cell types has been hampered by a lack of precise purification methods. We describe a method for prospectively isolating ten distinct NSPC types from the developing human brain using cell-surface markers. CD24−THY1−/lo cells were enriched for radial glia, which robustly engrafted and differentiated into all three neural lineages in the mouse brain. THY1hi cells marked unipotent oligodendrocyte precursors committed to an oligodendroglial fate, and CD24+THY1−/lo cells marked committed excitatory and inhibitory neuronal lineages. Notably, we identify and functionally characterize a transcriptomically distinct THY1hiEGFRhiPDGFRA− bipotent glial progenitor cell (GPC), which is lineage-restricted to astrocytes and oligodendrocytes, but not to neurons. Our study provides a framework for the functional study of distinct cell types in human neurodevelopment.
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•Purification, functional validation of 10 NSPC types in human neurodevelopment•Index-sorting maps transcriptome onto immunophenotype to derive a gating strategy•Identification of transcriptomically, functionally defined glial progenitor cell (GPC)•GPCs likely arise from oRG, giving rise to oligodendrocytes/astrocytes but not neurons
A framework for the prospective isolation of neural stem and progenitor cells from the developing human brain is provided to facilitate the functional study of distinct cell types in human neurodevelopment.
Demand for anal cancer screening is expected to rise following the recent publication of the Anal Cancer–HSIL Outcomes Research trial, which showed that treatment of high-grade squamous ...intraepithelial lesions significantly reduces the rate of progression to anal cancer. While screening for human papillomavirus–associated squamous lesions in the cervix is well established and effective, this is less true for other sites in the lower anogenital tract. Current anal cancer screening and prevention rely on high-resolution anoscopy with biopsies. This procedure has a steep learning curve for providers and may cause patient discomfort. Scattering-based light-sheet microscopy (sLSM) is a novel imaging modality with the potential to mitigate these challenges through real-time, microscopic visualization of disease-susceptible tissue. Here, we report a proof-of-principle study that establishes feasibility of dysplasia detection using an sLSM device. We imaged 110 anal biopsy specimens collected prospectively at our institution’s dysplasia clinic (including 30 nondysplastic, 40 low-grade squamous intraepithelial lesion, and 40 high-grade squamous intraepithelial lesion specimens) and found that these optical images are highly interpretable and accurately recapitulate histopathologic features traditionally used for the diagnosis of human papillomavirus–associated squamous dysplasia. A reader study to assess diagnostic accuracy suggests that sLSM images are noninferior to hematoxylin and eosin images for the detection of anal dysplasia (sLSM accuracy = 0.87; hematoxylin and eosin accuracy = 0.80; P = .066). Given these results, we believe that sLSM technology holds great potential to enhance the efficacy of anal cancer screening by allowing accurate sampling of diagnostic tissue at the time of anoscopy. While the current imaging study was performed on ex vivo biopsy specimens, we are currently developing a handheld device for in vivo imaging that will provide immediate microscopic guidance to high-resolution anoscopy providers.
Myxopapillary ependymoma (MPE) is an uncommon variant of ependymoma, almost exclusively seen in conus medullaris or filum terminale. MPE can be diagnostically challenging, especially when arising ...extra‐axially. Here we report 5 cases of superficial soft tissue/cutaneous MPE, identified across three tertiary institutions. All patients were female and three of them (3/5, 60%) were children (median age 11 years, range 6–58 years). The tumors presented as slow‐growing masses of the sacrococcygeal subcutaneous soft tissues, occasionally identified after minor trauma and clinically favored to be pilonidal sinuses. Imaging showed no neuraxis connection. Macroscopically, tumors were well‐circumscribed, lobulated, and solid and microscopically they exhibited typical histopathology of MPE, at least focally. Two of the tumors (2/5, 40%) showed predominantly solid or trabecular architecture with greater cellular pleomorphism, scattered giant cells, and increased mitotic activity. All tumors (5/5, 100%) showed strong diffuse immunohistochemical expression of GFAP. One tumor clustered at the category “ependymoma, myxopapillary” by methylome analysis. Two patients (2/5, 40%) had local recurrence at 8 and 30 months after the initial surgery. No patients developed metastases during the follow‐up period (median 60 months, range 6–116 months). Since a subset of extra‐axial MPEs behaves more aggressively, timely and accurate diagnosis is of paramount importance.
We describe 3 patients in California, USA, with trichodysplasia spinulosa polyomavirus (TSPyV) infection of endothelium after steroid administration. We detected TSPyV RNA in tissue specimens by in ...situ hybridization, which revealed localization to endothelial cells. These cases suggest that diseases associated with endothelial inflammation could be associated with TSPyV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Meningiomas are the most the common primary brain tumors in adults, representing approximately a third of all intracranial neoplasms. They classically are found to be more common in females, with the ...exception of higher grades that have a predilection for males, and patients of older age. Meningiomas can also be seen as a spectrum of inherited syndromes such as neurofibromatosis 2 as well as ionizing radiation. In general, the 5-year survival for a WHO grade I meningioma exceeds 80%; however, survival is greatly reduced in anaplastic meningiomas. The standard of care for meningiomas in a surgically-accessible location is gross total resection. Radiation therapy is generally saved for atypical, anaplastic, recurrent, and surgically inaccessible benign meningiomas with a total dose of ~60 Gy. However, the method of radiation, regimen and timing is still evolving and is an area of active research with ongoing clinical trials. While there are currently no good adjuvant chemotherapeutic agents available, recent advances in the genomic and epigenomic landscape of meningiomas are being explored for potential targeted therapy.
While neurotrophic tropomyosin receptor kinase (NTRK) fusions represent rare oncogenic drivers (<1% of solid cancers), the recent approval of NTRK inhibitors (larotrectinib and entrectinib) led to ...dramatic responses in patients with NTRK fusion+ tumors. Both drugs have phase I data, demonstrating efficacy in the central nervous system (CNS), including both primary brain tumors and brain metastases. We present a 29-year-old woman who was diagnosed with NTRK3-SPECC1L fusion+ undifferentiated uterine sarcoma and underwent resection, chemotherapy, and radiotherapy. Two years later, lung metastases were discovered. She was started on larotrectinib with complete response. She remained stable on larotrectinib until she presented with altered mental status and seizures. MRI demonstrated leptomeningeal enhancement, but because leptomeningeal progression from sarcoma is exceedingly rare and her symptoms improved dramatically with antiepileptics, these findings were initially attributed to seizures. After 2 unrevealing lumbar punctures and stable systemic imaging, a brain biopsy demonstrated metastatic sarcoma, still showing NTRK positivity. She underwent whole brain radiotherapy and was switched to entrectinib, but had clinical progression 1 month later and transitioned to hospice. This case demonstrates the efficacy of NTRK inhibitors in rare and aggressive cancer but highlights that these patients can develop isolated CNS progression even in the setting of CNS-penetrant drugs. CNS progression can occur if there is incomplete CNS drug penetration, discordance in molecular profiles between CNS and systemic disease, or acquired NTRK inhibitor resistance. In this case, CNS disease maintained the NTRK fusion status, but either inadequate CNS penetration or development of a resistance gene may explain the isolated CNS progression.
Background
Romanowsky staining is often the initial method used to stain hematologic and cytologic materials. While immunocytochemistry (ICC) is a well‐established method on air‐dried smears, there ...are rare veterinary reports of ICC involving Romanowsky‐stained slides.
Objectives
This study aimed to compare immunoreactivity of unstained vs Romanowsky‐stained specimens, evaluate reactions over time, and assess ICC associations with confirmatory tests of 50 lymphoma cases. Another goal aimed to optimize manual ICC protocols with cellular and tissue immunomarkers to detect CD3ε, CD20, Pax5, MHCII, lysozyme, MUM1, vimentin, cytokeratin, and Melan‐A antigens on Romanowsky‐stained specimens.
Materials and methods
Cytologic specimens from cases of lymphoid and nonlymphoid neoplasms were stained with a methanolic Romanowsky method. Additional unstained slides from these cases were used for comparison with the stained materials. Antigen retrieval involved a citrate buffer pH6 or Tris/EDTA pH9 at 95°C for 25 minutes in a decloaking chamber. Immunocytochemistry used known positive and secondary antibody‐only negative cytologic controls. Immunoreactivity of unstained and prestained lymphoma slides was graded by the intensity and percent of stained cells. Signal grading was monitored over time for diagnostic differences.
Results
Unstained and Romanowsky‐stained slides had similar membrane/cytoplasm graded reactions, but unstained slides produced stronger signals. Romanowsky‐stained blood films from B‐cell and T‐cell leukemias showed minimal loss of signal when monitored over 20 weeks. Signal differences did not change the diagnosis. There was a significant association between ICC and confirmatory tests. Optimization involved antibody dilution and antigen retrieval methodology for each antibody tested.
Conclusions
Immunocytochemistry of Romanowsky‐stained material can be successfully performed using antibodies against CD3ε, CD20, cytokeratin, lysozyme, Melan‐A, MHCII, MUM1, Pax5, and vimentin.
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