Searched for: in-biosketch:yes
person:lechpm01
Can confocal laser endomicroscopy replace frozen section in diagnosis of brain tumors? A definite maybe [Comment]
Lechpammer, Mirna
PMID: 38486372
ISSN: 1523-5866
CID: 5657162
Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors
Lechpammer, Mirna; Todd, Austin; Tang, Vivian; Morningstar, Taryn; Borowsky, Alexander; Shahlaie, Kiarash; Kintner, John A; McPherson, John D; Bishop, John W; Fereidouni, Farzad; Harmany, Zachary T; Coley, Nicholas; Zagzag, David; Wong, Jason W H; Tao, Jiang; Hesson, Luke B; Burnett, Leslie; Levenson, Richard
Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.
PMCID:10813539
PMID: 38275528
ISSN: 2076-3425
CID: 5625372
Neuropathological Applications of Microscopy with Ultraviolet Surface Excitation (MUSE): A Concordance Study of Human Primary and Metastatic Brain Tumors
Lechpammer, Mirna; Todd, Austin; Tang, Vivian; Morningstar, Taryn; Borowsky, Alexander; Shahlaie, Kiarash; Kintner, John A.; McPherson, John D.; Bishop, John W.; Fereidouni, Farzad; Harmany, Zachary T.; Coley, Nicholas; Zagzag, David; Wong, Jason W.H.; Tao, Jiang; Hesson, Luke B.; Burnett, Leslie; Levenson, Richard
Whereas traditional histology and light microscopy require multiple steps of formalin fixation, paraffin embedding, and sectioning to generate images for pathologic diagnosis, Microscopy using Ultraviolet Surface Excitation (MUSE) operates through UV excitation on the cut surface of tissue, generating images of high resolution without the need to fix or section tissue and allowing for potential use for downstream molecular tests. Here, we present the first study of the use and suitability of MUSE microscopy for neuropathological samples. MUSE images were generated from surgical biopsy samples of primary and metastatic brain tumor biopsy samples (n = 27), and blinded assessments of diagnoses, tumor grades, and cellular features were compared to corresponding hematoxylin and eosin (H&E) images. A set of MUSE-treated samples subsequently underwent exome and targeted sequencing, and quality metrics were compared to those from fresh frozen specimens. Diagnostic accuracy was relatively high, and DNA and RNA integrity appeared to be preserved for this cohort. This suggests that MUSE may be a reliable method of generating high-quality diagnostic-grade histologic images for neuropathology on a rapid and sample-sparing basis and for subsequent molecular analysis of DNA and RNA.
SCOPUS:85183133975
ISSN: 2076-3425
CID: 5629222
Lessons learned from evolving frameworks in adult glioblastoma
Lechpammer, Mirna; Mahammedi, Abdelkader; Pomeranz Krummel, Daniel A; Sengupta, Soma
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.
PMID: 36796938
ISSN: 0072-9752
CID: 5427312
Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers
Lechpammer, Mirna; Rao, Rohan; Shah, Sanjit; Mirheydari, Mona; Bhattacharya, Debanjan; Koehler, Abigail; Toukam, Donatien Kamdem; Haworth, Kevin J; Pomeranz Krummel, Daniel; Sengupta, Soma
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.
PMCID:8997081
PMID: 35406398
ISSN: 2072-6694
CID: 5218962
Clinicopathological and genomic characterization of BCORL1-driven high-grade endometrial stromal sarcomas
Lin, Douglas I; Huang, Richard S P; Mata, Douglas A; Decker, Brennan; Danziger, Natalie; Lechpammer, Mirna; Hiemenz, Matthew; Ramkissoon, Shakti H; Ross, Jeffrey S; Elvin, Julia A
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.
PMID: 34302054
ISSN: 1530-0285
CID: 4948852
Clinicopathologic and Genomic Landscape of Breast Carcinoma Brain Metastases
Huang, Richard S P; Haberberger, James; McGregor, Kimberly; Mata, Douglas A; Decker, Brennan; Hiemenz, Matthew C; Lechpammer, Mirna; Danziger, Natalie; Schiavone, Kelsie; Creeden, James; Graf, Ryon P; Strowd, Roy; Lesser, Glenn J; Razis, Evangelia D; Bartsch, Rupert; Giannoudis, Athina; Bhogal, Talvinder; Lin, Nancy U; Pusztai, Lajos; Ross, Jeffrey S; Palmieri, Carlo; Ramkissoon, Shakti H
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 < 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 < 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.
PMID: 34105210
ISSN: 1549-490x
CID: 4899892
Extracellular GAPDH Promotes Alzheimer Disease Progression by Enhancing Amyloid-β Aggregation and Cytotoxicity
Lazarev, Vladimir F; Tsolaki, Magda; Mikhaylova, Elena R; Benken, Konstantin A; Shevtsov, Maxim A; Nikotina, Alina D; Lechpammer, Mirna; Mitkevich, Vladimir A; Makarov, Alexander A; Moskalev, Alexey A; Kozin, Sergey A; Margulis, Boris A; Guzhova, Irina V; Nudler, Evgeny
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-β (Aβ). 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 Aβ that is mediated by transglutaminase (tTG). The Q15A substitution weakens the interaction between Aβ and GAPDH and reduces Aβ-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 Aβ-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 Aβ aggregates and reversed memory deficit in AD transgenic mice. These findings argue that extracellular GAPDH compromises Aβ clearance and accelerates neurodegeneration, and, thus, is a promising pharmacological target for AD.
PMCID:8279520
PMID: 34341704
ISSN: 2152-5250
CID: 4972542
Neonatal encephalopathy: Focus on epidemiology and underexplored aspects of etiology
McIntyre, S; Nelson, K B; Mulkey, S B; Lechpammer, M; Molloy, E; Badawi, N
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.
PMID: 34305025
ISSN: 1878-0946
CID: 5005792
Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance
Shatalin, Konstantin; Nuthanakanti, Ashok; Kaushik, Abhishek; Shishov, Dmitry; Peselis, Alla; Shamovsky, Ilya; Pani, Bibhusita; Lechpammer, Mirna; Vasilyev, Nikita; Shatalina, Elena; Rebatchouk, Dmitri; Mironov, Alexander; Fedichev, Peter; Serganov, Alexander; Nudler, Evgeny
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 γ-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.
PMID: 34112687
ISSN: 1095-9203
CID: 4900242