Lessons learned from evolving frameworks in adult glioblastoma
Glioblastoma (GBM) is the most common and aggressive malignant adult brain tumor. Significant effort has been directed to achieve a molecular subtyping of GBM to impact treatment. The discovery of new unique molecular alterations has resulted in a more effective classification of tumors and has opened the door to subtype-specific therapeutic targets. Morphologically identical GBM may have different genetic, epigenetic, and transcriptomic alterations and therefore different progression trajectories and response to treatments. With a transition to molecularly guided diagnosis, there is now a potential to personalize and successfully manage this tumor type to improve outcomes. The steps to achieve subtype-specific molecular signatures can be extrapolated to other neuroproliferative as well as neurodegenerative disorders.
Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers
Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12-15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood-brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.
Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas
BCORL1 is a transcriptional corepressor homologous to BCOR. We describe 12 BCORL1-altered uterine sarcomas with striking resemblance to BCOR-altered endometrial stromal sarcoma (BCOR-ESS), including 5 with BCORL1 rearrangements (JAZF1-BCORL1, EP300-BCORL1, or internal BCORL1 rearrangement), 5 with inactivating BCORL1 mutations (T513fs*22, P600fs*1, R945*, R1196*, or R1265fs*4) and 2 with homozygous BCORL1 deletion. The median patient age was 57.5 years (range 33-79). An association with aggressive clinical behavior was identified. Diagnoses assigned prior to genomic testing varied: 7 tumors were previously diagnosed as ESS, 2 as high-grade uterine sarcomas, 2 as myxoid uterine leiomyosarcomas, and 1 as a uterine spindle cell neoplasm consistent with leiomyosarcoma. Tumors harbored frequent gelatinous, mucomyxoid-like appearance by gross examination and unique histology with morphological overlap with BCOR-ESS. Key microscopic features included (1) a spindle cell appearance, most often with at least focal myxoid stroma, (2) variable amounts of hypocellular fibromyxoid spindle areas with lower grade atypia and/or (3) variable amounts of epithelioid areas with higher grade atypia. Specifically, spindle and epithelioid components were present in 100 and 75% of sarcomas, respectively; myxoid stroma was identified in 83%, collagen plaques or fibrosis in 50%, and high-grade nuclear atypia was present in 42%. Like BCOR-ESS, 50% of BCORL1-altered sarcomas exhibited CDK4 amplification or CDKN2A loss. In contrast, 33% harbored NF1 alterations, while 25% had other alterations in the NF2-mTOR pathway, expanding potential therapeutic targets. In conclusion, inactivating BCORL1 genomic alterations may define a distinct subset of high-grade endometrial stromal sarcomas with biological overlap with BCOR-ESS, both of which may mimic myxoid leiomyosarcomas.
Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases
BACKGROUND:Among breast carcinoma patients with metastatic disease, 15-30% will eventually develop brain metastases. We examined the genomic landscape of a large cohort of breast carcinoma brain metastases (BCBMs) and compared them to a cohort of primary breast carcinomas (BCs). MATERIAL AND METHODS/METHODS:We retrospectively analyzed 733 BCBMs tested with comprehensive genomic profiling (CGP) and compared them to 10,772 primary breast carcinomas (not-paired) specimens. For a subset of 16 triple-negative breast carcinoma (TNBC)-brain metastasis (BM) samples, PD-L1 immunohistochemistry was performed concurrently. RESULTS:A total of 733 consecutive BCBMs were analyzed. Compared to primary BCs, BCBMs were enriched for genomic alterations in TP53 (72.0%, 528/733), ERBB2 (25.6%. 188/733), RAD21 (14.1%, 103/733), NF1 (9.0%, 66/733), BRCA1 (7.8%, 57/733), and ESR1 (6.3%,46/733) (p <â€‰0.05 for all comparisons). Immune checkpoint inhibitor (ICPI) biomarkers such as tumor mutational burden (TMB)-High (16.2%, 119/733), microsatellite instability (MSI)-High (1.9%, 14/733), CD274 amplification (3.6%, 27/733), and APOBEC mutational signature (5.9%, 43/733) were significantly higher in the BCBM cohort compared to the primary BC cohort (p <â€‰0.05 for all comparisons). When using both CGP and PD-L1 IHC, 37.5% (6/16) of the TNBC brain metastasis patients were eligible for atezolizumab based on PD-L1 IHC, and 18.8% (3/16) were eligible for pembrolizumab based on TMB-High status. CONCLUSION/CONCLUSIONS:We found a high prevalence of clinically relevant genomic alterations in BCBM patients, suggesting that tissue acquisition (surgery) and or cerebrospinal fluid (CSF) for CGP in addition to CGP of the primary tumor may be clinically warranted. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:We found a high prevalence of clinically relevant genomic alterations in BCBM patients, suggesting that tissue acquisition (surgery) and or cerebrospinal fluid (CSF) for CGP in addition to CGP of the primary tumor may be clinically warranted. In addition, we identified higher positive rates for FDA-approved immunotherapy biomarkers detected by CGP in BCBM patients, opening the possibility for new on-label treatments. Last, we noted limited correlation between TMB and PD-L1 IHC which exemplifies the importance to test with both PD-L1 IHC and CGP for ICPI eligibility of TNBC patients with brain metastases.
Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-Î² Aggregation and Cytotoxicity
Neuronal cell death at late stages of Alzheimer's disease (AD) causes the release of cytosolic proteins. One of the most abundant such proteins, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), forms stable aggregates with extracellular amyloid-Î² (AÎ²). We detect these aggregates in cerebrospinal fluid (CSF) from AD patients at levels directly proportional to the progressive stages of AD. We found that GAPDH forms a covalent bond with Q15 of AÎ² that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between AÎ² and GAPDH and reduces AÎ²-GAPDH cytotoxicity. Lentivirus-driven GAPDH overexpression in two AD animal models increased the level of apoptosis of hippocampal cells, neural degeneration, and cognitive dysfunction. In contrast, in vivo knockdown of GAPDH reversed these pathogenic abnormalities suggesting a pivotal role of GAPDH in AÎ²-stimulated neurodegeneration. CSF from animals with enhanced GAPDH expression demonstrates increased cytotoxicity in vitro. Furthermore, RX-624, a specific GAPDH small molecular ligand reduced accumulation of AÎ² aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises AÎ² clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.
Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology
Neonatal Encephalopathy (NE) is a neurologic syndrome in term and near-term infants who have depressed consciousness, difficulty initiating and maintaining respiration, and often abnormal tone, reflexes and neonatal seizures in varying combinations. Moderate/severe NE affects 0.5-3/1000 live births in high-income countries, more in low- and middle-income countries, and carries high risk of mortality or disability, including cerebral palsy. Reduced blood flow and/or oxygenation around the time of birth, as with ruptured uterus, placental abruption or umbilical cord prolapse can cause NE. This subset of NE, with accompanying low Apgar scores and acidemia, is termed Hypoxic-Ischemic Encephalopathy. Other causes of NE that can present similarly, include infections, inflammation, toxins, metabolic disease, stroke, placental disease, and genetic disorders. Aberrant fetal growth and congenital anomalies are strongly associated with NE, suggesting a major role for maldevelopment. As new tools for differential diagnosis emerge, their application for prevention, individualized treatment and prognostication will require further systematic studies of etiology of NE.
Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance
Emergent resistance to all clinical antibiotics calls for the next generation of therapeutics. Here we report an effective antimicrobial strategy targeting the bacterial hydrogen sulfide (H2S)-mediated defense system. We identified cystathionine Î³-lyase (CSE) as the primary generator of H2S in two major human pathogens, Staphylococcus aureus and Pseudomonas aeruginosa, and discovered small molecules that inhibit bacterial CSE. These inhibitors potentiate bactericidal antibiotics against both pathogens in vitro and in mouse models of infection. CSE inhibitors also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. Our results establish bacterial H2S as a multifunctional defense factor and CSE as a drug target for versatile antibiotic enhancers.
Exposure to DMSO during infancy alters neurochemistry, social interactions, and brain morphology in long-evans rats
INTRODUCTION/BACKGROUND:Dimethyl sulfoxide (DMSO) is a widely used solvent to dissolve hydrophobic substances for clinical uses and experimental in vivo purposes. While usually regarded safe, our prior studies suggest changes to behavior following DMSO exposure. We therefore evaluated the effects of a five-day, short-term exposure to DMSO on postnatal infant rats (P6-10). METHODS:DMSO was intraperitoneally injected for five days at 0.2, 2.0, and 4.0Â ml/kg body mass. One cohort of animals was sacrificed 24Â hr after DMSO exposure to analyze the neurometabolic changes in four brain regions (cortex, hippocampus, basal ganglia, and cerebellum) by hydrophilic interaction liquid chromatography. A second cohort of animals was used to analyze chronic alterations to behavior and pathological changes to glia and neuronal cells later in life (P21-P40). RESULTS:164 metabolites, including key regulatory molecules (retinoic acid, orotic acid, adrenic acid, and hypotaurine), were found significantly altered by DMSO exposure in at least one of the brain regions at P11 (pÂ <Â .05). Behavioral tests showed significant hypoactive behavior and decreased social habits to the 2.0 and 4.0Â ml DMSO/kg groups (pÂ <Â .01). Significant increases in number of microglia and astrocytes at P40 were observed in the 4.0Â ml DMSO/kg group (at pÂ <Â .015.) CONCLUSIONS: Despite short-term exposure at low, putatively nontoxic concentrations, DMSO led to changes in behavior and social preferences, chronic alterations in glial cells, and changes in essential regulatory brain metabolites. The chronic neurological effects of DMSO exposure reported here raise concerns about its neurotoxicity and consequent safety in human medical applications and clinical trials.
Pituitary stalk gangliogliomas: Case report and literature review
INTRODUCTION/BACKGROUND:Gangliogliomas rarely occur in the sella or suprasellar region and are almost never seen in the pituitary stalk. Seven cases of gangliogliomas occurring in this region have been reported; only one case involved a tumor within the pituitary stalk. Of the six tumors external to the pituitary stalk, two occurred in the neurohypophysis, one was in the adenohypophysis, the location of one was unspecified, and two extensively invaded the optic chiasm, hypothalamus and brainstem. This is only the second reported case of a pituitary stalk ganglioglioma, and it is unique in its use of an extended endoscopic endonasal approach for biopsy. CASE REPORT/METHODS:A 51-year old woman presented with an eleven-month history of polydipsia and polyuria leading to the diagnosis of diabetes insipidus. Magnetic Resonance Imaging of the brain revealed contrast-enhanced thickening and anterior bowing of the hypophyseal stalk. An extended endoscopic endonasal approach permitted midline removal of the tuberculum sella, opening of underlying dura, and exposure of the pituitary stalk. A firm, white, 4 mm diameter mass, integral to the right side of the enlarged pituitary stalk was seen and biopsied. Histopathological analysis was consistent with WHO grade 1 ganglioglioma. The patient tolerated the procedure well and required no endocrinologic treatment other than desmopressin. CONCLUSION/CONCLUSIONS:Pituitary stalk gangliogliomas are extremely rare. The diagnosis should be considered in patients with pituitary stalk enlargement. Endoscopic endonasal approach is a safe surgical approach to establish a tissue diagnosis which is essential for pathologic certainty given the wide differential diagnosis of stalk lesions.
Congenital presentation of synchronous Atypical Teratoid Rhabdoid Tumor and Malignant Rhabdoid Tumor of the urinary bladder in a term infant [Case Report]
Atypical teratoid/rhabdoid tumor (AT/RT) is a rare central nervous system (CNS) tumor diagnosed primarily in infants and usually portends a poor prognosis. Despite being the most common embryonal tumor in children less than 1 year old, diagnosis is difficult to make based on clinical findings or imaging alone. A complete diagnosis of AT/RT requires identification of loss of integrase interactor 1 (INI1) protein or the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1 (SMARCB1) gene, in its most common presentation. Moreover, their presentation with other primary rhabdoid tumors in the body raises significant suspicion for rhabdoid tumor predisposition syndrome (RTPS). We report a case of a one-month-old infant admitted for worsening emesis and failure to thrive, who was later found to have brain and bladder masses on radiologic imaging. Autopsy with subsequent immunoprofile and molecular testing were crucial in establishing the absence of INI1 nuclear expression and possible homozygous deletion of SMARCB1 in the urinary bladder tumor tissue. Sequencing of the peripheral blood demonstrated probable single copy loss at the SMARCB1 locus. The constellation of findings in tumor and peripheral blood sequencing suggested the possibility of germline single copy SMARCB1 loss, followed by somatic loss of the remaining SMARCB1 allele due to copy neutral loss-of-heterozygosity. Such a sequence of genetic events has been described in malignant rhabdoid tumors (MRT). Dedicated germline testing of this patient's family members could yield answers as to whether rhabdoid tumor predisposition syndrome will continue to have implications for the patient's family.