Background
Disseminated diffuse midline glioma (DMG) is a devastating diagnosis. Molecular subtyping has increased our understanding of this tumor.
Case
Here, we report the case of an 8-year-old girl ...who presented with symptoms of brainstem dysfunction and was found to have disseminated DMG with lesions in the pons, thalamus and bilateral temporal lobes. Molecular subtyping of the temporal lobe tumor tissue was consistent with H3 K27me3 loss and EZHIP overexpression, falling under the newly designated “H3 K27-altered” AQ5WHO subtype of DMG. Pathology from biopsy of the orbital lesion showed poorly differentiated rhabdoid-like disseminated tumor cells. The patient went on to develop lesions in the peritoneum, infratemporal fossa, and along the lumbosacral nerve roots.
Conclusion
This unique case illustrates the aggressive behavior of H3 K27-altered tumors and their potential to metastasize.
Purpose To present a new complication of persistent corneal edema after collagen cross-linking (CXL) in keratoconus patients. Design Retrospective case series of postoperative corneal edema after ...CXL. Methods study population: All patients who underwent CXL treatment with subsequent corneal edema. Patients with stromal haze were excluded. intervention: The CXL treatments used the Dresden protocol with corneal thickness of more than 400 μm after epithelium was removed. main outcome measure: The resolution of corneal edema after surgery. Results Postoperative corneal edema was identified in 10 (2.9%) of 350 patients who were followed up for a mean of 14 ± 4 months. The edema started on postoperative day 1 (10/10) and increased for 3 weeks. Additional findings included: deep vascularization (2 eyes; 20%), iris atrophy (6 eyes; 60%), pigment dispersion (5 eyes; 50%), persistent epithelial defect (3 eyes; 30%), and infectious keratitis (1 eye; 10%). Specular microscopy was unsuccessful, but the fellow untreated eyes had normal endothelial counts. Intraocular pressure and lenticular evaluations were normal. Corneal edema improved in 4 patients and resolved in 1 patient. In these 5 patients, the logarithm of the minimal angle of resolution best-corrected visual acuity was 0.5 ± 0.18. Penetrating keratoplasty was offered to 5 patients when improvement plateaued at 3 months, but only 2 patients underwent penetrating keratoplasty. Conclusions CXL is a safe and effective procedure with few known side effects. This case series reports the possibility of corneal endothelial damage with visually significant corneal edema after CXL treatment. Based on the extent of endothelial damage, patients may require penetrating keratoplasty.
INTRODUCTION:
Myxedema is a severe form of hypothyroidism with various signs and symptoms. We present a rare case of myxedema ascites complicated with ischemic colitis (IC).
CASE DESCRIPTION/METHODS:
...A 71-year-old female with a history of coronary artery disease and congestive heart failure (Ejective fraction 40%) presented with abdominal distention. Pertinent vitals included blood pressure of 100/54 mmHg and heart rate 38 beats/min. Pertinent labs included hematocrit of 28.2 %, albumin 3.1 g/dL, transaminases mildly elevated, alkaline phosphatase (ALP) 382 IU/L, thyroid stimulating hormone (TSH) 141 IU/mL, free triiodothyronine (T3) 1.26 pg/ml, total T3 45.30 ng/dL. Rest of the electrolytes, blood counts, including coagulation parameters, were normal. Electrocardiogram showed sinus bradycardia. She was started on levothyroxine for severe hypothyroidism. Abdominal ultrasound showed a large volume of ascites and normal liver contour. Paracentesis showed total nucleated cells of 2242, total protein 3.6 g/dL, lactate dehydrogenase 229, albumin 1.8 g/dL, serum ascites albumin gradient (SAAG) < 1.1, and glucose 86 mg/dL. Ascitic fluid cultures were negative. Hence, the patient was diagnosed with neutrocytic ascites and treated with empiric antibiotics. Ascitic fluid was negative for malignancy and tuberculosis. She was managed with diuretics (furosemide and spironolactone) and therapeutic paracentesis. She later developed bloody diarrhea, and flexible sigmoidoscopy showed mild to moderate IC of the rectosigmoid colon. She was treated conservatively. Her transaminases normalized, but ALP remained elevated. She was discharged after a two-week hospital stay and six weeks follow up showed significant improvement in ascites and TSH of 10 IU/mL.
DISCUSSION:
Myxedema ascites is seen in only 4% of the patients with uncontrolled hypothyroidism. There are no case reports on IC in the setting of myxedema ascites thus far. It is a rare complication of myxedema megacolon; however, our patient had no signs of megacolon on repeated imaging. Therefore, our case is unique as it highlights a rare (ascites) and uncommon (IC) complication of severe hypothyroidism. Ascites with SAAG < 1.1 should prompt physicians to consider hypothyroidism in the differential diagnosis for ascites especially when total ascitic fluid protein is > 2.5 g/dL and other causes such as portal hypertension, malignancy, and infections are ruled out. It is easy to treat, can lead to complete resolution of ascites and decrease morbidity.
Abstract
PURPOSE
The goal of our project was to define the molecular features of recurrent glioblastoma (rGBM) and their prognostic significance.
METHODS
We retrospectively reviewed 121 consecutive ...glioblastoma patients who underwent re-resection at a single institution from 2016-2021. Primary treatment in all patients included maximal safe resection followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Capture-based targeted DNA sequencing for point mutations and copy number analysis was performed on all re-resection samples. Overall (OS) and progression-free survival (PFS) from re-resection were analyzed with the Kaplan-Meier method and Cox regression analyses.
RESULTS
Median age at first recurrence was 57 years (range, 27-78) and follow up from re-resection was 11 months. Salvage therapy comprised re-irradiation (n = 52, 43%), temozolomide (TMZ) (n = 39, 32%), lomustine (n = 47, 39%), and/or bevacizumab (n = 22, 18%). Median OS and PFS were 12.1 and 4.4 months, respectively. Median tumor mutation burden (TMB) was 4 mut/Mb (range, 1-650), average unstable microsatellite sites (MSI) were 1.16% (range, 0-20), and MGMT was methylated in 71 (59%) patients. Longer OS was found after postoperative TMZ (19.1 vs. 9.1), KPS > 70 (13.6 vs. 11.1), and/or re-irradiation (12.6 vs. 8.4) (p< .05). On multivariate analysis, TMZ (HR 0.2, 0.079-0.48), re-irradiation (HR 0.27, 0.12-0.58), and mutations in PDGFRA (HR 0.24, 0.067-0.83) or PTEN (HR 2.3, 1.1-4.8) genes were associated with longer OS after re-resection (p< .05). Multivariate predictors of re-irradiation response included MSI >1.16 (HR 0.25, 0.084-0.75), and mutations in PDGFRA (HR 0.04, 0.005-0.33), TERT (HR 0.16, 0.033-0.78), or PIK3R1 (HR 0.18, 0.041-0.8) genes. In the 46 matched primary/recurrent tumors, 40 (87%%) had a change in a mutation and 9 (20%) demonstrated hypermutation, of which 4 (44%) had mismatch repair deficiencies.
CONCLUSIONS
Our study outlines the molecular factors associated with survival and response to re-irradiation in rGBM as well as, the molecular differences between primary/recurrent samples.
Abstract
BACKGROUND
Glioblastomas harbor recurrent mutations in NF1 that activate Ras/Raf/MEK signaling, motivating pharmacologic approaches targeting downstream (MEK) or upstream (SHP2) of Ras ...signaling. However, the mechanisms underlying therapeutic response remain unclear. Here, we integrate genome wide CRISPRi screens and single cell sequencing in cell lines and mouse xenografts to identify functional genomic mechanisms underlying responses to the MEK inhibitor selumetinib or the SHP2 inhibitor RMC-4550.
METHODS
Human NF1 mutant GBM43 cells expressing CRISPRi machinery were used for CRISPRi screens with selumetinib or RMC-4550. Intracranial xenografts were established with GBM43 cells and treated with selumetinib or RMC-4550. Tumor growth kinetics were measured with bioluminescent imaging.
RESULTS
Genome-wide CRISPRi screens with selumetinib or RMC-4550 in NF1 mutant human GBM43 cells identified 39 genes (14 sensitivity, 25 resistance) mediating selumetinib response and 327 genes (51 sensitivity, 276 resistance) mediating RMC-4550 response. While both selumetinib and RMC-4550 hits were enriched for components of Ras/Raf/MEK, hits sensitizing RMC-4550 response were uniquely enriched for PI3K signaling and focal adhesion components while hits mediating resistance were enriched for cell cycle genes. In NF1 mutant GBM43, RMC-4550 significantly reduced tumor volume (p=0.02) while selumetinib did not. Single cell RNA-sequencing (scRNA-seq) analysis of 90,782 tumor cells from NF1 mutant GBM43 xenografts treated with selumetinib or RMC-4550 identified 12 clusters across all samples. RMC-4550, but not selumetinib, resulted in significant depletion of cells expressing an epithelial-mesenchymal transition (EMT) signature marked by expression of focal adhesion genes mediating RMC-4550 sensitivity, suggesting this signature comprises a distinct mechanism of action in response to RMC-4550 but not selumetinib.
CONCLUSIONS
In NF1 mutant glioblastoma in vitro and in vivo models, cellular response to both upstream (SHP2) and downstream (MEK) inhibition are mediated by Ras/Raf/MEK signaling while RMC-4550 alone uniquely regulates a focal adhesion network associated with EMT and demonstrates improved efficacy in vivo.
Abstract
Clonally expanded CD8+ T cells outnumber their CD4+ counterparts in MS lesions yet their role in disease pathogenesis and the relevant target antigen(s) remain unknown. We posited that CNS ...CD8+ T cells are specific for neuronal antigen and may participate in axon or neuron injury in multiple sclerosis—thereby contributing to cumulative disability. Here we show using neuron-specific translational profiling that demyelination is sufficient to drive neuronal expression of MHC class I genes as well as antigen processing genes. We further demonstrate that neuron-targeted neoantigen (ovalbumin) is sampled by peripheral immune cells even in the absence of demyelination—as assessed by neuroantigen-specific (OTI) CD8+ T cell activation in cervical lymph nodes. However, OTI T cell retention in the healthy CNS was not observed. In contrast, cuprizone diet induced demyelination drives increased OTI T cell proliferation as well as accumulation of these cells to the CNS, leading to elimination of ovalbumin+ neurons. CNS recruited OT1 cells were found to be juxtaposed next to degenerating ovalbumin+ neurons and axons. These findings support a role for autoreactive CD8+ T cells in the axonal injury that underlies progression in multiple sclerosis. Future studies are aimed at identifying patients with pathogenic anti-axonal CD8+ T cells who may be responsive to targeted immunotherapy.
Abstract
Chromosomal instability due to mutations in genes guarding the stability of the genome is a well-known mechanism underlying tumorigenesis and malignant progression in numerous cancers. The ...effect of this process in gliomas is mostly unknown with relatively little research examining the effects of chromosomal instability on patient outcome and therapeutic efficacy, although studies have shown that overall/total copy number variation (CNV) is elevated in higher histologic grades and in cases with more rapid progression and shorter patient survival. Herein, we examine a 70-gene mRNA expression signature (CIN70), which has been previously shown to correlate tightly with chromosomal instability, in 2 independent cohorts of IDH-mutant astrocytomas (total n = 241), IDH-wildtype astrocytomas (n = 228), and oligodendrogliomas (n = 128). Our results show that CIN70 expression levels correlate with total CNV, as well as higher grade, progression-free survival, and overall survival in both IDH-mutant and IDH-wildtype astrocytomas. In oligodendrogliomas, these mRNA signatures correlate with total CNV but not consistently with clinical outcome. These data suggest that chromosomal instability is an underlying factor in aggressive behavior and progression of a subset of diffuse astrocytomas. In addition, chromosomal instability may in part explain the poor response of diffuse gliomas to treatment and may serve as a future therapeutic target.
