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Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas

Lin, Lawrence Hsu; Allison, Douglas H R; Feng, Yang; Jour, George; Park, Kyung; Zhou, Fang; Moreira, Andre L; Shen, Guomiao; Feng, Xiaojun; Sabari, Joshua; Velcheti, Vamsidhar; Snuderl, Matija; Cotzia, Paolo
Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (p < 0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.
PMID: 34362997
ISSN: 1530-0285
CID: 4979862

Histomorphologic and Immunophenotypic Spectrum of Cutaneous Myoepitheliomas: A Series of 35 Cases

Plaza, Jose A; Brenn, Thomas; Chung, Catherine; Salim, Sadia; Konstantinos, Linos D; Jour, George; Duran Rincon, Juanita; Wick, Mark; Sangueza, Martin; Gru, Alejandro A
Myoepithelial tumors comprise a group of mesenchymal lesions that show heterogeneous histomorphological features, including dual epithelial, neural and myoid differentiation. Cutaneous myoepithelioma is a rare neoplasm that is composed primarily of myoepithelial cells and represents one end of a histopathologic spectrum of cutaneous myoepithelial neoplasms including chondroid syringoma and myoepithelial carcinoma. These tumors display a wide histopathological spectrum and immunophenotypical profile often showing epithelial and myoepithelial differentiation. In this series, we studied thirty-five cases, of cutaneous myoepitheliomas. Our cases highlighted the broad histologic range where most cases showed a non-infiltrative and non-encapsulated tumor exclusively located in the dermis and with no subcutaneous involvement. The majority of our cases had a solid growth pattern (syncytial pattern) and remainder of cases had a multinodular growth pattern. The tumor cells were epithelioid in 23 cases, spindled in eight cases and had a mixture of epithelioid and spindled cells in four cases. Mitotic figures ranged from 0 to 5 per 10 HPF. By immunohistochemistry EMA was expressed in 59% cases, S100 was positive in 88% of cases, CAM 5.2 was positive in 16% of cases, AE1/AE3 was positive in 44% of cases, p63 was positive in 17% of cases, SMA was positive in 38% of cases, desmin was positive in 6% of cases, calponin was positive in 22% of cases, and GFAP was positive in 36% of cases. In addition, there were five cases without EMA, keratin or p63 expression that only showed S100p expression. We describe a large series of cutaneous myoepitheliomas delineating their histomorphological spectrum and immunophenotypic profile. Awareness of some of the unusual histologic features and the heterogeneous immunohistochemical may pose difficulties for the diagnosis. This article is protected by copyright. All rights reserved.
PMID: 33340147
ISSN: 1600-0560
CID: 4725962

Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database

Dimitrova, Maya; Kim, Min Jae; Osman, Iman; Jour, George
BACKGROUND:In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES). AIM/OBJECTIVE:We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM. METHODS AND RESULTS/RESULTS:We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762). CONCLUSION/CONCLUSIONS:Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
PMID: 34109763
ISSN: 2573-8348
CID: 4900152

Evaluation of the lower airway microbiota in patients with severe sars-cov2 [Meeting Abstract]

Barnett, C R; Sulaiman, I; Tsay, J; Wu, B; Krolikowski, K; Li, Y; Postelnicu, R; Carpenito, J; Rafeq, S; Clemente, J C; Angel, L F; Mukherjee, V; Pradhan, D; Brosnahan, S; Lubinsky, A S; Yeung, S; Jour, G; Shen, G; Chung, M; Khanna, K; Ghedin, E; Segal, L N
RATIONALE:Secondary infections with bacterial pathogens are thought to be responsible for poor outcomes in the 1918 Spanish and H1N1 pandemics. We postulate that poor prognosis in patients with SARS-CoV2 may be associated with uncontrollable viral replication, co-infection with a secondary pathogen, and over exuberant host immune response. We seek to evaluate whether there is an association between distinct features of the lower airway microbiota and poor clinical outcome in patients with SARS-CoV2.
METHOD(S):We collected lower airway samples in 148 patients from NYU admitted between 3/10/2020 and 5/10/2020 with severe respiratory failure requiring mechanical ventilation and that underwent bronchoscopy for airway clearance and/or tracheostomy. Clinical outcome was defined as dead vs alive. DNA was isolated in parallel using zymoBIOMICSTM DNA/RNA Miniprep Kit (Cat: R2002) as per manufacturer's instructions. The V4 region of the 16S rRNA gene marker was sequenced using Illumina MiSeq. Sequences were analyzed using the Quantitative Insights into Microbial Ecology (QIIME version 1.9.1) pipeline. Total bacterial load was evaluated in lower airway samples using digital droplet PCR targeting the 16S rRNA gene.
RESULT(S):Of the 148 patients included, 114 survived (77%) and 34 (23%) died. Among those with poor clinical outcome, there was a non-statistically significant trend towards higher age and BMI. Patients who died more commonly had chronic kidney disease and prior cerebrovascular accidents, and more often required dialysis. There was no statistically significant difference in the rate of positive bacterial respiratory or blood cultures among those that survived vs. those that died (75 vs. 73% and 43 vs 38%, respectively). Topographical analysis of the 16S RNA microbiome shows compositional differences between the upper and lower airways based on beta diversity comparisons. When comparing across clinical outcomes, the alpha diversity was lower in the dead group but there was no statistically significant difference in overall community composition (beta diversity). Taxonomic differential enrichment analysis using DESeq analysis showed that oral commensals were enriched in the group that survived. Patients that died had a higher bacterial load in their lower airways than those who survived.
CONCLUSION(S):Using samples obtained via bronchoscopy we identified lower airway microbiota signatures associated with mortality among critical patients infected with SARS-CoV2. Taxonomic signals identified as associated with poor prognosis did not reveal bacterial taxa commonly classified as respiratory pathogens. This data is not supportive of the hypothesis that secondary untreated bacterial co-infections are responsible for increased mortality in patients with severe SARS-CoV-2
ISSN: 1535-4970
CID: 4915522

Prepatellar Glomus Tumor of the Knee without an Identifiable Mass on MRI: A Case Report

Berlinberg, Elyse J; Markus, Danielle H; Jour, George; Strauss, Eric J
CASE:A 71-year-old man presented with extreme anterior knee pain. His history, physical examination, and imaging were consistent with prepatellar bursitis, but his pain seemed out of proportion for these findings. The patient eventually underwent marginal excision of the inflamed prepatellar bursa which histopathology identified as a glomangioma. Postoperatively, he has complete resolution of his pain and has returned to his daily activities. CONCLUSION:Glomus tumors are a rare cause of severe knee pain that completely resolves after excision. In the patient with extreme, localized knee sensitivity, it is important to consider this pathology even if no mass is identified on imaging.
PMID: 33979812
ISSN: 2160-3251
CID: 4867532

Microbial signatures in the lower airways of mechanically ventilated COVID19 patients associated with poor clinical outcome

Sulaiman, Imran; Chung, Matthew; Angel, Luis; Koralov, Sergei; Wu, Benjamin; Yeung, Stephen; Krolikowski, Kelsey; Li, Yonghua; Duerr, Ralf; Schluger, Rosemary; Thannickal, Sara; Koide, Akiko; Rafeq, Samaan; Barnett, Clea; Postelnicu, Radu; Wang, Chang; Banakis, Stephanie; Perez-Perez, Lizzette; Jour, George; Shen, Guomiao; Meyn, Peter; Carpenito, Joseph; Liu, Xiuxiu; Ji, Kun; Collazo, Destiny; Labarbiera, Anthony; Amoroso, Nancy; Brosnahan, Shari; Mukherjee, Vikramjit; Kaufman, David; Bakker, Jan; Lubinsky, Anthony; Pradhan, Deepak; Sterman, Daniel; Heguy, Adriana; Uyeki, Timothy; Clemente, Jose; de Wit, Emmie; Schmidt, Ann Marie; Shopsin, Bo; Desvignes, Ludovic; Wang, Chan; Li, Huilin; Zhang, Bin; Forst, Christian; Koide, Shohei; Stapleford, Kenneth; Khanna, Kamal; Ghedin, Elodie; Weiden, Michael; Segal, Leopoldo
Mortality among patients with COVID-19 and respiratory failure is high and there are no known lower airway biomarkers that predict clinical outcome. We investigated whether bacterial respiratory infections and viral load were associated with poor clinical outcome and host immune tone. We obtained bacterial and fungal culture data from 589 critically ill subjects with COVID-19 requiring mechanical ventilation. On a subset of the subjects that underwent bronchoscopy, we also quantified SARS-CoV-2 viral load, analyzed the microbiome of the lower airways by metagenome and metatranscriptome analyses and profiled the host immune response. We found that isolation of a hospital-acquired respiratory pathogen was not associated with fatal outcome. However, poor clinical outcome was associated with enrichment of the lower airway microbiota with an oral commensal ( Mycoplasma salivarium ), while high SARS-CoV-2 viral burden, poor anti-SARS-CoV-2 antibody response, together with a unique host transcriptome profile of the lower airways were most predictive of mortality. Collectively, these data support the hypothesis that 1) the extent of viral infectivity drives mortality in severe COVID-19, and therefore 2) clinical management strategies targeting viral replication and host responses to SARS-CoV-2 should be prioritized.
PMID: 33791687
ISSN: n/a
CID: 4830952

Molecular Analysis of Encapsulated Papillary Carcinoma of the Breast with and without Invasion

Schwartz, Christopher J; Boroujeni, Amir Momeni; Khodadai-Jamayran, Alireza; Heguy, Adriana; Snuderl, Matija; Jour, George; Cotzia, Paolo; Darvishian, Farbod
Encapsulated papillary carcinomas (EPC) of the breast is a unique variant of papillary carcinoma confined to a cystic space with absent or attenuated myoepithelial cell layer. Although staged as an in-situ lesion, it can be associated with invasive ductal carcinoma (IDC). We sought to compare the genomic characteristics of pure EPC and EPC with associated invasive carcinoma (EPCi) at the genomic level. All cases of EPCi harbored recurrent hotspot mutations in PIK3CA. PIK3CA, KMT2A and CREBBP deleterious somatic events were found across both tumor groups, irrespective of invasion status. At the whole transcriptomic level, EPCi cases displayed remarkably similar mRNA profiles when compared to EPC. When EPCi cases were compared with their corresponding IDC, despite significant overlap, we identified differential gene expression in 39 genes with enrichment of multiple pathways including extracellular matrix regulation, cell adhesion and collagen fibril organization. Despite morphologic, genotypic and transcriptomic overlap between pure EPC and EPCi, the latter tumors are likely advanced lesions with PIK3CA activating mutations and enrichment of stromal-related genes implicated in the switch to IDC.
PMID: 33667422
ISSN: 1532-8392
CID: 4801982

Optimization of an automated tumor-infiltrating lymphocyte algorithm for improved prognostication in primary melanoma

Chou, Margaret; Illa-Bochaca, Irineu; Minxi, Ben; Darvishian, Farbod; Johannet, Paul; Moran, Una; Shapiro, Richard L; Berman, Russell S; Osman, Iman; Jour, George; Zhong, Hua
Tumor-infiltrating lymphocytes (TIL) have potential prognostic value in melanoma and have been considered for inclusion in the American Joint Committee on Cancer (AJCC) staging criteria. However, interobserver discordance continues to prevent the adoption of TIL into clinical practice. Computational image analysis offers a solution to this obstacle, representing a methodological approach for reproducibly counting TIL. We sought to evaluate the ability of a TIL-quantifying machine learning algorithm to predict survival in primary melanoma. Digitized hematoxylin and eosin (H&E) slides from prospectively enrolled patients in the NYU melanoma database were scored for % TIL using machine learning and manually graded by pathologists using Clark's model. We evaluated the association of % TIL with recurrence-free survival (RFS) and overall survival (OS) using Cox proportional hazards modeling and concordance indices. Discordance between algorithmic and manual TIL quantification was assessed with McNemar's test and visually by an attending dermatopathologist. In total, 453 primary melanoma patients were scored using machine learning. Automated % TIL scoring significantly differentiated survival using an estimated cutoff of 16.6% TIL (log-rank P < 0.001 for RFS; P = 0.002 for OS). % TIL was associated with significantly longer RFS (adjusted HR = 0.92 [0.84-1.00] per 10% increase in % TIL) and OS (adjusted HR = 0.90 [0.83-0.99] per 10% increase in % TIL). In comparison, a subset of the cohort (n = 240) was graded for TIL by melanoma pathologists. However, TIL did not associate with RFS between groups (P > 0.05) when categorized as brisk, nonbrisk, or absent. A standardized and automated % TIL scoring algorithm can improve the prognostic impact of TIL. Incorporation of quantitative TIL scoring into the AJCC staging criteria should be considered.
PMID: 33005020
ISSN: 1530-0285
CID: 4617292

The histopathologic characteristics of the gastrointestinal system in SARS-COV-2 infected patients who underwent biopsy or resection [Meeting Abstract]

Ahmed, S; Hoskoppal, D; Lin, L; Suarez, Y; Liu, W; Cho, M; Thomas, K; Guzzetta, M; Hajdu, C; Theise, N; Jour, G; Sarkar, S; Cao, W
Background: In addition to respiratory distress, GI symptoms have been reported in COVID-19 patients at various stages of the disease. Among the GI symptoms that have been reported, diarrhea, nausea, vomiting, abdominal pain and GI bleeding were often seen. Age and comorbid conditions such as obesity, HTN, DM and/or CAD have been considered as risk factors for COVID-19 patients for severe disease. GI manifestations in COVID-19 patients appeared to act as a sign for a serious condition. The virus has been identified in the stool and in rectal swabs of some infected patients, even after a negative nasopharyngeal test. There is a lack of reports on pathological alterations of the GI tract in COVID-19 infected patients.
Design(s): 16 PCR confirmed COVID-19 patients (11 males and 5 females) were included in the study. Biopsy or resection specimens were taken from the esophagus (4), stomach (6), small intestine (5), appendix (3), colon (5) and gallbladder (3). Clinical information including demographics, comorbidities, GI symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): The age of the patients ranged from 10 to 84 years old, with an average of 47 years. Eight (50%) patients had at least one comorbid condition, two patients (12.5%) had prior history of cancer, and six patients had no significant medical history. Abdominal pain and GI bleeding were the most common presenting symptoms. Histologically, acute and chronic inflammation was seen in 14 of 16, and 15 of 16 cases, respectively. Eight cases showed severe acute inflammation with ulceration. The mucosal changes included nonspecific reactive change, hypermucinous, atrophic/ischemic changes, and necrosis, were indiscriminately noticed in these cases. Four cases showed intraepithelial lymphocytosis. Viral like inclusions were found in four cases. Microthrombi were identified in 5 cases with an average patient age of 60 years. Notably, microthrombi were seen in about 5 out of 8 (62%) patients with comorbidities. The patients with microthrombi had a higher D dimer test value than those without thrombus. Three patients died shortly after operation, and two of them showed microthrombi in the tissue specimens.
Conclusion(s): Acute and chronic inflammation were indiscriminately seen in these cases. Microthrombi were dominantly found in aging patients with comorbidities, suggesting microthrombi in the GI tract may be a histologic indication for severe COVID-19 patients with GI symptoms
ISSN: 1530-0307
CID: 4857062

Rectal SWAB SARS-COV-2 testing and histologic findings in the small intestine of 18 autopsy patients [Meeting Abstract]

Lin, L; Ahmed, S; Thomas, K; Guzzetta, M; Hoskoppal, D; Cho, M; Suarez, Y; Liu, W; Hajdu, C; Theise, N; Jour, G; Sarkar, S; Cao, W
Background: Digestive symptoms are often seen in COVID-19 patients with poor outcomes. The Viral RNA is mostly positive in the stool of these patients, and has a longer delay before viral clearance. However, its diagnostic value and significance for guiding clinical treatment remain unknown. And the pathologic alterations in the GI tract in COVID-19 patients have not been well defined. We evaluated rectal swab SAS-CoV-2 test and histopathologic changes in the small intestine in autopsy patients.
Design(s): 18 autopsy cases with confirmed SAS-CoV2 infection were included. Nasal, bronchial, and rectal swab SARS-CoV-2 PCR were performed at the time of autopsy. Clinical information included demographics, comorbidities, presenting symptoms, related laboratory tests were collected. Histopathologic evaluation was performed and correlated with clinical properties.
Result(s): 83% (15/18) of patients were male. Median age is 50 years. 7/18 (38.9%) patients had diarrhea in addition to cough, fever and other symptoms. Except in one case, all patients had underlying comorbidities of diabetes, hypertension and /or obesity. In the small intestine, acute inflammation was not seen in any cases. 5/18 displayed mild and one showed moderate chronic inflammation. Hypermucinous change was found in six patients but not associated with diarrhea. 3 cases had microthrombi identified in the sections. Notably, obviously increased D dimer in lab tests were noticed in all patients. Postmortem 17/17 (100%) nasal, 18/18 (100%) bronchial and 7/16 (43.8%) rectal swabs showed SARS-CoV-2 PCR positivity. 3 of 7 (42.9%) patients with diarrhea are positive in rectal swab for SARS-CoV-2.
Conclusion(s): There are no specific COVID-19 changes in the small intestine. More investigations are needed, especially on tissues from different locations of the GI tract. Data from rectal swab testing suggests that it is not ideal for diagnosing COVID-19, guiding treatment, or predicting small intestinal pathology
ISSN: 1530-0307
CID: 4857032