Publications by authors named "Gerald Berry"

154 Publications

Higher levels of allograft injury in black patients early after heart transplantation.

J Heart Lung Transplant 2021 Dec 23. Epub 2021 Dec 23.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, Maryland; Laborarory of Applied Precision Omics (APO), Division of Intramural Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Department of Medicine, Stanford University School of Medicine, Palo Alto, California. Electronic address:

Black patients suffer higher rates of antibody-mediated rejection and have worse long-term graft survival after heart transplantation. Donor-derived cell free DNA (ddcfDNA) is released into the blood following allograft injury. This study analyzed %ddcfDNA in 63 heart transplant recipients categorized by Black and non-Black race, during the first 200 days after transplant. Immediately after transplant, %ddcfDNA was higher for Black patients (mean [SE]: 8.3% [1.3%] vs 3.2% [1.2%], p = 0.001). In the first week post-transplant, the rate of decay in %ddcfDNA was similar (0.7% [0.68] vs 0.7% [0.11], p = 0.78), and values declined in both groups to a comparable plateau at 7 days post-transplant (0.46% [0.03] vs 0.45% [0.04], p = 0.78). The proportion of Black patients experiencing AMR was higher than non-Black patients (21% vs 9% [hazard ratio of 2.61 [95% confidence interval: 0.651-10.43], p = 0.18). Black patients were more likely to receive a race mismatched organ than non-Black patients (69% vs 35%, p = 0.01), which may explain the higher levels of early allograft injury.
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http://dx.doi.org/10.1016/j.healun.2021.12.006DOI Listing
December 2021

Correlation Between Microvascular Inflammation in Endomyocardial Biopsies and Rejection Transcripts, Donor-specific Antibodies, and Graft Dysfunction in Antibody-mediated Rejection.

Transplantation 2021 Dec 21. Epub 2021 Dec 21.

Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié Salpêtriére Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP). Sorbonne University Medical School, Paris, France. Paris Translational Research Centre for Organ Transplantation, INSERM, UMR-S970, Paris, France. Pathology Department, Hôpital Necker, Assistance Publique - Hôpitaux de Paris, Paris, France. INSERM U1245, Centre Henri Becquerel, Rouen, France. Pathology Department, La Pitié Salpétrière, Assistance Publique - Hôpitaux de Paris, Paris, France. Pathology Department, Rouen University Hospital, France. Pathology Department, Strasbourg University Hospital, France. Pathology Department, Nantes University Hospital, France. Department of Pathology, Stanford University School of Medicine, Stanford, CA. Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padua, Padua, Italy. Université de Paris, Paris, France.

Background: The pathology-based diagnosis of cardiac antibody-mediated rejection (AMR) relies on the 2013 International Society for Heart and Lung Transplantation Working Formulation, in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMBs).

Methods: We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale in which MVI scores of 0, 1, 2, and 3 represented 0%, 1%-10%, 11%-50%, and >50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by microarrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pathologic AMR [pAMR]), anti-HLA donor-specific antibodies, and graft dysfunction.

Results: Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%), and 44 (15.1%) EMB were given MVI scores of 0, 1, 2, and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogeneous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independent of the C4d or CD68 status (P < 0.001). Both the frequency and mean fluorescence intensity of donor-specific antibodies gradually increased with the MVI score (P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 (P < 0.001).

Conclusions: The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance.
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http://dx.doi.org/10.1097/TP.0000000000004008DOI Listing
December 2021

Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.

Circ Genom Precis Med 2021 12 22;14(6):e003419. Epub 2021 Nov 22.

Division of Cardiovascular Medicine, Department of Medicine (M.E.L., D.J.-M., H.Z., K.S., D.A., C.Z., A.R., R.M., S.A., S.S., C.C., J.P., E.A.A., M.T.W.), Stanford University School of Medicine, CA.

Background: ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel mutations to reveal insights into the physiological function of ACTN2.

Methods: Patients harboring ACTN2 protein-truncating variants were identified using a custom mutation pipeline. In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry. Structural changes were analyzed through electron microscopy. For mechanistic studies, we used co-immunoprecipitation for ACTN2, followed by mass-spectrometry to investigate protein-protein interaction, and protein tagging followed by confocal microscopy to investigate introduction of truncated ACTN2 into the sarcomeres.

Results: Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure. In homozygous stop-gain cells, affinity-purification mass-spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 (alpha-actinin 1) and GJA1 (gap junction protein alpha 1), 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing.

Conclusions: Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of truncation as causative of disease.
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http://dx.doi.org/10.1161/CIRCGEN.121.003419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692448PMC
December 2021

Response by Shah et al to Letter Regarding Article, "Cell-Free DNA to Detect Heart Allograft Acute Rejection".

Circulation 2021 09 7;144(10):e198-e199. Epub 2021 Sep 7.

Genomic Research Alliance for Transplantation (GRAfT), Bethesda, MD (P.S., S.A-E., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.Marboe, G.J.B., H.A.V.).

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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055697DOI Listing
September 2021

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

J Heart Lung Transplant 2021 11 29;40(11):1251-1266. Epub 2021 Jul 29.

Veracyte Inc, San Francisco, California.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.
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http://dx.doi.org/10.1016/j.healun.2021.07.014DOI Listing
November 2021

Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study.

J Heart Lung Transplant 2021 08 24;40(8):822-830. Epub 2021 Apr 24.

Genomic Research Alliance for Transplantation (GRAfT), 10 Center Drive, 7S261, Bethesda, Maryland; Division of Intramural Research, National Heart, Lung and Blood Institute, 10 Center Drive, 7S261, Bethesda, Maryland; Division of Pulmonary and Critical Care Medicine, The Johns Hopkins School of Medicine, 1830 East Monument Street, Baltimore, Maryland. Electronic address:

Background: Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection.

Methods: This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection.

Results: ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology.

Conclusions: This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury.
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http://dx.doi.org/10.1016/j.healun.2021.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319066PMC
August 2021

Mammary Lobular Carcinoma-Like Salivary Gland Carcinoma: Report of a Rare Case.

Head Neck Pathol 2021 Jun 11. Epub 2021 Jun 11.

Department of Pathology, Stanford University Medical Center, Palo Alto, USA.

Salivary and mammary glands are both exocrine organs sharing multiple tumorigenic processes. To the best of our knowledge, salivary gland tumors mimicking invasive lobular carcinoma of the breast have not yet been described. Herein, we report a case of a 62-year-old male who presented with progressive facial paralysis. Pathologic examination revealed an ill-defined epithelial neoplasm exhibiting discohesive growth set within an extensively fibrotic stroma. Both perineural and intraneural invasion were present. E-cadherin and p120 immunostaining showed aberrant cytoplasmic expression. Targeted next-generation sequencing detected a frameshift mutation of the CTNNA1 gene as the only known pathogenic variant. The patient was treated with surgical resection, immunotherapy, and chemotherapy. Currently, he is alive with disease twenty months after disease onset.
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http://dx.doi.org/10.1007/s12105-021-01344-2DOI Listing
June 2021

First lung and kidney multi-organ transplant following COVID-19 Infection.

J Heart Lung Transplant 2021 08 2;40(8):856-859. Epub 2021 May 2.

Department of Cardiothoracic Surgery, Stanford University, Stanford, CA. Electronic address:

As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.
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http://dx.doi.org/10.1016/j.healun.2021.02.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088330PMC
August 2021

Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis.

Front Immunol 2021 2;12:652771. Epub 2021 Apr 2.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.
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http://dx.doi.org/10.3389/fimmu.2021.652771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8050350PMC
September 2021

Innate and Adaptive Immunity in Giant Cell Arteritis.

Front Immunol 2020 25;11:621098. Epub 2021 Feb 25.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Autoimmune diseases can afflict every organ system, including blood vessels that are critically important for host survival. The most frequent autoimmune vasculitis is giant cell arteritis (GCA), which causes aggressive wall inflammation in medium and large arteries and results in vaso-occlusive wall remodeling. GCA shares with other autoimmune diseases that it occurs in genetically predisposed individuals, that females are at higher risk, and that environmental triggers are suspected to beget the loss of immunological tolerance. GCA has features that distinguish it from other autoimmune diseases and predict the need for tailored diagnostic and therapeutic approaches. At the core of GCA pathology are CD4 T cells that gain access to the protected tissue niche of the vessel wall, differentiate into cytokine producers, attain tissue residency, and enforce macrophages differentiation into tissue-destructive effector cells. Several signaling pathways have been implicated in initiating and sustaining pathogenic CD4 T cell function, including the NOTCH1-Jagged1 pathway, the CD28 co-stimulatory pathway, the PD-1/PD-L1 co-inhibitory pathway, and the JAK/STAT signaling pathway. Inadequacy of mechanisms that normally dampen immune responses, such as defective expression of the PD-L1 ligand and malfunction of immunosuppressive CD8 T regulatory cells are a common theme in GCA immunopathology. Recent studies are providing a string of novel mechanisms that will permit more precise pathogenic modeling and therapeutic targeting in GCA and will fundamentally inform how abnormal immune responses in blood vessels lead to disease.
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http://dx.doi.org/10.3389/fimmu.2020.621098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947610PMC
July 2021

Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

Immunity 2021 03;54(3):586-602.e8

Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
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http://dx.doi.org/10.1016/j.immuni.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960510PMC
March 2021

Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation.

PLoS One 2021 16;16(2):e0247060. Epub 2021 Feb 16.

Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.

Mortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010-2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40-83 years old in the ventilated cohort and 14-80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247060PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886150PMC
February 2021

Examination of factors associated with lymph node metastases in lung carcinoids: Results from a single institution retrospective cohort study.

Lung Cancer 2021 04 23;154:186-194. Epub 2021 Jan 23.

Stanford University School of Medicine, Stanford Cancer Institute, Department of Medicine, Division of Oncology, 875 Blake Wilbur, Stanford, CA, 94305, USA. Electronic address:

Background: Well-differentiated lung neuroendocrine tumors (NETs), also known as typical and atypical carcinoids, have a decreased incidence of lymph node (LN) and distant metastases compared to poorly differentiated lung NETs. We aimed to (i) examine the clinicopathologic features associated with LN involvement in lung carcinoids and (ii) describe the postoperative management of patients with LN metastases.

Methods: We identified 98 patients who underwent surgical resection and lymph node sampling at Stanford University. We assessed the following and used AJCC staging version 7: clinical features (age, sex, race, prior malignancy, smoking history), tumor features (functional syndrome, histology, size, location, laterality), pre-operative workup performed (imaging and suspicion of LN metastases), surgery (nodes and stations sampled, margin status, surgical approach, and type of surgery), and recurrence outcome. These features were examined between patients with and without LN metastases using the Wilcoxon test (continuous variables) and Fisher's exact test (categorical variables).

Results: 87 patients (89%) had typical carcinoid and 11 patients (11%) had atypical carcinoid. 17 patients were found to have at least one positive lymph node, with 11 having N1 disease and 6 having N2 disease. In the univariable analysis, patients with lymph node disease were more likely to have recurrence of lung carcinoid (29% vs. 6%, p=0.01). In the multivariable logistic regression, there was a trend towards performance of preoperative SSTR imaging and lymph node involvement (OR = 3.06, p=0.07). No patients received adjuvant therapy.

Conclusion: We found a trend for the performance of SSTR imaging and association of lymph node metastases in both univariable and multivariable analysis. A large proportion (41%) of patients with lymph node positive disease had < 2 cm tumors. This suggests the potential importance of incorporating SSTR imaging into routine practice and not restricting the use of this staging modality in patients with small tumors.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026717PMC
April 2021

Targeted Treatment of Multiple Primary Lung Cancers Harboring Distinct EGFR or RET Alterations: A Case Report.

Clin Lung Cancer 2021 09 19;22(5):e673-e677. Epub 2020 Dec 19.

Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2020.12.005DOI Listing
September 2021

Cell-Free DNA to Detect Heart Allograft Acute Rejection.

Circulation 2021 03 13;143(12):1184-1197. Epub 2021 Jan 13.

Genomic Research Alliance for Transplantation, Bethesda, MD (S.A.-E., P.S., I.T., S.H., E.F., K.S., M.E.R., S.S.N., H.K., U.F., A.B., A.M., K.B., Y.Y., M.K.J., C.M., G.J.B., H.A.V.).

Background: After heart transplantation, endomyocardial biopsy (EMBx) is used to monitor for acute rejection (AR). Unfortunately, EMBx is invasive, and its conventional histological interpretation has limitations. This is a validation study to assess the performance of a sensitive blood biomarker-percent donor-derived cell-free DNA (%ddcfDNA)-for detection of AR in cardiac transplant recipients.

Methods: This multicenter, prospective cohort study recruited heart transplant subjects and collected plasma samples contemporaneously with EMBx for %ddcfDNA measurement by shotgun sequencing. Histopathology data were collected to define AR, its 2 phenotypes (acute cellular rejection [ACR] and antibody-mediated rejection [AMR]), and controls without rejection. The primary analysis was to compare %ddcfDNA levels (median and interquartile range [IQR]) for AR, AMR, and ACR with controls and to determine %ddcfDNA test characteristics using receiver-operator characteristics analysis.

Results: The study included 171 subjects with median posttransplant follow-up of 17.7 months (IQR, 12.1-23.6), with 1392 EMBx, and 1834 %ddcfDNA measures available for analysis. Median %ddcfDNA levels decayed after surgery to 0.13% (IQR, 0.03%-0.21%) by 28 days. Also, %ddcfDNA increased again with AR compared with control values (0.38% [IQR, 0.31-0.83%], versus 0.03% [IQR, 0.01-0.14%]; <0.001). The rise was detected 0.5 and 3.2 months before histopathologic diagnosis of ACR and AMR. The area under the receiver operator characteristic curve for AR was 0.92. A 0.25%ddcfDNA threshold had a negative predictive value for AR of 99% and would have safely eliminated 81% of EMBx. In addition, %ddcfDNA showed distinctive characteristics comparing AMR with ACR, including 5-fold higher levels (AMR ≥2, 1.68% [IQR, 0.49-2.79%] versus ACR grade ≥2R, 0.34% [IQR, 0.28-0.72%]), higher area under the receiver operator characteristic curve (0.95 versus 0.85), higher guanosine-cytosine content, and higher percentage of short ddcfDNA fragments.

Conclusions: We found that %ddcfDNA detected AR with a high area under the receiver operator characteristic curve and negative predictive value. Monitoring with ddcfDNA demonstrated excellent performance characteristics for both ACR and AMR and led to earlier detection than the EMBx-based monitoring. This study supports the use of %ddcfDNA to monitor for AR in patients with heart transplant and paves the way for a clinical utility study. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8221834PMC
March 2021

Deep learning model for the prediction of microsatellite instability in colorectal cancer: a diagnostic study.

Lancet Oncol 2021 01;22(1):132-141

Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Center for Artificial Intelligence in Medicine and Imaging, Stanford University, Stanford, CA, USA. Electronic address:

Background: Detecting microsatellite instability (MSI) in colorectal cancer is crucial for clinical decision making, as it identifies patients with differential treatment response and prognosis. Universal MSI testing is recommended, but many patients remain untested. A critical need exists for broadly accessible, cost-efficient tools to aid patient selection for testing. Here, we investigate the potential of a deep learning-based system for automated MSI prediction directly from haematoxylin and eosin (H&E)-stained whole-slide images (WSIs).

Methods: Our deep learning model (MSINet) was developed using 100 H&E-stained WSIs (50 with microsatellite stability [MSS] and 50 with MSI) scanned at 40× magnification, each from a patient randomly selected in a class-balanced manner from the pool of 343 patients who underwent primary colorectal cancer resection at Stanford University Medical Center (Stanford, CA, USA; internal dataset) between Jan 1, 2015, and Dec 31, 2017. We internally validated the model on a holdout test set (15 H&E-stained WSIs from 15 patients; seven cases with MSS and eight with MSI) and externally validated the model on 484 H&E-stained WSIs (402 cases with MSS and 77 with MSI; 479 patients) from The Cancer Genome Atlas, containing WSIs scanned at 40× and 20× magnification. Performance was primarily evaluated using the sensitivity, specificity, negative predictive value (NPV), and area under the receiver operating characteristic curve (AUROC). We compared the model's performance with that of five gastrointestinal pathologists on a class-balanced, randomly selected subset of 40× magnification WSIs from the external dataset (20 with MSS and 20 with MSI).

Findings: The MSINet model achieved an AUROC of 0·931 (95% CI 0·771-1·000) on the holdout test set from the internal dataset and 0·779 (0·720-0·838) on the external dataset. On the external dataset, using a sensitivity-weighted operating point, the model achieved an NPV of 93·7% (95% CI 90·3-96·2), sensitivity of 76·0% (64·8-85·1), and specificity of 66·6% (61·8-71·2). On the reader experiment (40 cases), the model achieved an AUROC of 0·865 (95% CI 0·735-0·995). The mean AUROC performance of the five pathologists was 0·605 (95% CI 0·453-0·757).

Interpretation: Our deep learning model exceeded the performance of experienced gastrointestinal pathologists at predicting MSI on H&E-stained WSIs. Within the current universal MSI testing paradigm, such a model might contribute value as an automated screening tool to triage patients for confirmatory testing, potentially reducing the number of tested patients, thereby resulting in substantial test-related labour and cost savings.

Funding: Stanford Cancer Institute and Stanford Departments of Pathology and Biomedical Data Science.
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http://dx.doi.org/10.1016/S1470-2045(20)30535-0DOI Listing
January 2021

A molecular cell atlas of the human lung from single-cell RNA sequencing.

Nature 2020 11 18;587(7835):619-625. Epub 2020 Nov 18.

Department of Biochemistry, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA.

Although single-cell RNA sequencing studies have begun to provide compendia of cell expression profiles, it has been difficult to systematically identify and localize all molecular cell types in individual organs to create a full molecular cell atlas. Here, using droplet- and plate-based single-cell RNA sequencing of approximately 75,000 human cells across all lung tissue compartments and circulating blood, combined with a multi-pronged cell annotation approach, we create an extensive cell atlas of the human lung. We define the gene expression profiles and anatomical locations of 58 cell populations in the human lung, including 41 out of 45 previously known cell types and 14 previously unknown ones. This comprehensive molecular atlas identifies the biochemical functions of lung cells and the transcription factors and markers for making and monitoring them; defines the cell targets of circulating hormones and predicts local signalling interactions and immune cell homing; and identifies cell types that are directly affected by lung disease genes and respiratory viruses. By comparing human and mouse data, we identified 17 molecular cell types that have been gained or lost during lung evolution and others with substantially altered expression profiles, revealing extensive plasticity of cell types and cell-type-specific gene expression during organ evolution including expression switches between cell types. This atlas provides the molecular foundation for investigating how lung cell identities, functions and interactions are achieved in development and tissue engineering and altered in disease and evolution.
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http://dx.doi.org/10.1038/s41586-020-2922-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704697PMC
November 2020

Two Cases of Pulmonary Tumor Thrombotic Microangiopathy Associated with ROS1-Rearranged Non-Small-Cell Lung Cancer.

Clin Lung Cancer 2021 03 15;22(2):e153-e156. Epub 2020 Oct 15.

Division of Oncology, Stanford University, Stanford, CA. Electronic address:

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http://dx.doi.org/10.1016/j.cllc.2020.09.020DOI Listing
March 2021

Cellular Signaling Pathways in Medium and Large Vessel Vasculitis.

Front Immunol 2020 25;11:587089. Epub 2020 Sep 25.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Autoimmune and autoinflammatory diseases of the medium and large arteries, including the aorta, cause life-threatening complications due to vessel wall destruction but also by wall remodeling, such as the formation of wall-penetrating microvessels and lumen-stenosing neointima. The two most frequent large vessel vasculitides, giant cell arteritis (GCA) and Takayasu arteritis (TAK), are HLA-associated diseases, strongly suggestive for a critical role of T cells and antigen recognition in disease pathogenesis. Recent studies have revealed a growing spectrum of effector functions through which T cells participate in the immunopathology of GCA and TAK; causing the disease-specific patterning of pathology and clinical outcome. Core pathogenic features of disease-relevant T cells rely on the interaction with endothelial cells, dendritic cells and macrophages and lead to vessel wall invasion, formation of tissue-damaging granulomatous infiltrates and induction of the name-giving multinucleated giant cells. Besides antigen, pathogenic T cells encounter danger signals in their immediate microenvironment that they translate into disease-relevant effector functions. Decisive signaling pathways, such as the AKT pathway, the NOTCH pathway, and the JAK/STAT pathway modify antigen-induced T cell activation and emerge as promising therapeutic targets to halt disease progression and, eventually, reset the immune system to reestablish the immune privilege of the arterial wall.
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http://dx.doi.org/10.3389/fimmu.2020.587089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544845PMC
June 2021

NOTCH-induced rerouting of endosomal trafficking disables regulatory T cells in vasculitis.

J Clin Invest 2021 01;131(1)

Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.

The aorta and the large conductive arteries are immunoprivileged tissues and are protected against inflammatory attack. A breakdown of immunoprivilege leads to autoimmune vasculitis, such as giant cell arteritis, in which CD8+ Treg cells fail to contain CD4+ T cells and macrophages, resulting in the formation of tissue-destructive granulomatous lesions. Here, we report that the molecular defect of malfunctioning CD8+ Treg cells lies in aberrant NOTCH4 signaling that deviates endosomal trafficking and minimizes exosome production. By transcriptionally controlling the profile of RAB GTPases, NOTCH4 signaling restricted vesicular secretion of the enzyme NADPH oxidase 2 (NOX2). Specifically, NOTCH4hiCD8+ Treg cells increased RAB5A and RAB11A expression and suppressed RAB7A, culminating in the accumulation of early and recycling endosomes and sequestering of NOX2 in an intracellular compartment. RAB7AloCD8+ Treg cells failed in the surface translocation and exosomal release of NOX2. NOTCH4hiRAB5AhiRAB7AloRAB11AhiCD8+ Treg cells left adaptive immunity unopposed, enabling a breakdown in tissue tolerance and aggressive vessel wall inflammation. Inhibiting NOTCH4 signaling corrected the defect and protected arteries from inflammatory insult. This study implicates NOTCH4-dependent transcriptional control of RAB proteins and intracellular vesicle trafficking in autoimmune disease and in vascular inflammation.
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http://dx.doi.org/10.1172/JCI136042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773364PMC
January 2021

Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee.

Transpl Infect Dis 2021 Feb 22;23(1):e13458. Epub 2020 Sep 22.

Department of Pediatrics, Division of Pediatric Infectious Diseases, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.

Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.
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http://dx.doi.org/10.1111/tid.13458DOI Listing
February 2021

Pathogenesis of Giant Cell Arteritis and Takayasu Arteritis-Similarities and Differences.

Curr Rheumatol Rep 2020 08 26;22(10):68. Epub 2020 Aug 26.

Department of Medicine, Stanford University School of Medicine, CCSR Building Room 2225, 269 Campus Drive West, Stanford, CA, 94305-5166, USA.

Purpose Of Review: Giant cell arteritis (GCA) and Takayasu arteritis (TAK) are auto-inflammatory and autoimmune diseases with a highly selective tissue tropism for medium and large arteries. In both diseases, CD4 T cells and macrophages form granulomatous lesions within the arterial wall, a tissue site normally protected by immune privilege. Vascular lesions can be accompanied by an extravascular component, typically an intense hepatic acute phase response that produces well-known laboratory abnormalities, e.g., elevated ESR and CRP. It is unclear whether GCA and TAK lie on a spectrum of disease or whether they represent fundamentally different disease processes.

Recent Findings: GCA and TAK share many clinical features, but there are substantial differences in genetics, epidemiology, disease mechanisms, response to treatment, and treatment complications that give rise to different disease trajectories. A significant difference lies in the composition of the wall-infiltrating immune cell compartment, which in TAK includes a significant population of CD8 T cells as well as natural killer cells, specifying disparate disease effector pathways mediating tissue damage and vessel wall remodeling. Despite the similarities in tissue tropism and histomorphology, GCA and TAK are two distinct vasculitides that rely on separate disease mechanisms and require disease-specific approaches in diagnosis and management.
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http://dx.doi.org/10.1007/s11926-020-00948-xDOI Listing
August 2020

Dysphagia and Dysphonia, a Pairing of Symptoms Caused by an Unusual Pair of Diseases: Castleman's Disease and Myasthenia Gravis.

Ann Otol Rhinol Laryngol 2021 Mar 19;130(3):319-324. Epub 2020 Aug 19.

Division of Laryngology, Otolaryngology - Head and Neck Surgery, Stanford University, Palo Alto, CA, USA.

Objectives: To describe a case of coincident Castleman's disease and myasthenia gravis that initially presented as rapidly progressive dysphagia and dysphonia and to review the unique pathophysiology of these two uncommon diagnoses.

Methods: Case report and literature review.

Results: Castleman's disease, angiofollicular or giant lymph node hyperplasia, is a rare benign lymphoid proliferation. Traditionally, the disease is classified based on histologic and clinical characteristics. Fewer than 10 cases with concurrent myasthenia gravis have been reported. Myasthenia gravis and thymic epithelial tumors are both associated with acetylcholine receptor antibody. While patients with isolated Castleman's disease are usually asymptomatic, those who have concurrent myasthenia gravis and undergo surgical treatment are at increased risk of postoperative myasthenic crisis. Both pre- and postoperative plasmapheresis are suggested to improve muscle strength and prevent severe postoperative complications.

Conclusions: In the setting of multiple cranial neuropathies including velopalatal insufficiency and bilateral ptosis it is important to consider myasthenia gravis. Castleman's disease occurs rarely in conjunction with myasthenia gravis but may increase the risk of myasthenic crisis.
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http://dx.doi.org/10.1177/0003489420949581DOI Listing
March 2021

Radiology-pathology Correlation in Recovered COVID-19, Demonstrating Organizing Pneumonia.

Am J Respir Crit Care Med 2020 Jul 1. Epub 2020 Jul 1.

Stanford University School of Medicine, Radiology, Stanford, California, United States;

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http://dx.doi.org/10.1164/rccm.202004-1278IMDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427386PMC
July 2020

The XVth Banff Conference on Allograft Pathology the Banff Workshop Heart Report: Improving the diagnostic yield from endomyocardial biopsies and Quilty effect revisited.

Am J Transplant 2020 12 28;20(12):3308-3318. Epub 2020 Jun 28.

Department of Pathology, Stanford University, Stanford, California, USA.

The XVth Banff Conference on Allograft Pathology meeting was held on September 23-27, 2019, in Pittsburgh, Pennsylvania, USA. During this meeting, two main topics in cardiac transplant pathology were addressed: (a) Improvement of endomyocardial biopsy (EMB) accuracy for the diagnosis of rejection and other significant injury patterns, and (b) the orphaned lesion known as Quilty effect or nodular endocardial infiltrates. Molecular technologies have evolved in recent years, deciphering pathophysiology of cardiac rejection. Diagnostically, it is time to integrate the histopathology of EMBs and molecular data. The goal is to incorporate molecular pathology, performed on the same paraffin block as a companion test for histopathology, to yield more accurate and objective EMB interpretation. Application of digital image analysis from hematoxylin and eosin (H&E) stain to multiplex labeling is another means of extracting additional information from EMBs. New concepts have emerged exploring the multifaceted significance of myocardial injury, minimal rejection patterns supported by molecular profiles, and lesions of arteriolitis/vasculitis in the setting of T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR). The orphaned lesion known as Quilty effect or nodular endocardial infiltrates. A state-of-the-art session with historical aspects and current dilemmas was reviewed, and possible pathogenesis proposed, based on advances in immunology to explain conflicting data. The Quilty effect will be the subject of a multicenter project to explore whether it functions as a tertiary lymphoid organ.
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http://dx.doi.org/10.1111/ajt.16083DOI Listing
December 2020

Using Bronchoscopic Lung Cryobiopsy and a Genomic Classifier in the Multidisciplinary Diagnosis of Diffuse Interstitial Lung Diseases.

Chest 2020 11 25;158(5):2015-2025. Epub 2020 May 25.

Division of Pulmonary and Critical Care, Department of Medicine, Tulane University School of Medicine, New Orleans, LA. Electronic address:

Background: Challenges remain for establishing a specific diagnosis in cases of interstitial lung disease (ILD). Bronchoscopic lung cryobiopsy (BLC) has impacted the diagnostic impression and confidence of multidisciplinary discussions (MDDs) in the evaluation of ILD. Reports indicate that a genomic classifier (GC) can distinguish usual interstitial pneumonia (UIP) from non-UIP.

Research Question: What is the impact of sequentially presented data from BLC and GC on the diagnostic confidence of MDDs in diagnosing ILD?

Study Design And Methods: Two MDD teams met to discuss 24 patients with ILD without a definitive UIP pattern. MDD1 sequentially reviewed clinical-radiologic findings, BLC, and GC. MDD2 sequentially reviewed GC before BLC. At each step in the process the MDD diagnosis and confidence level were recorded.

Results: MDD1 had a significant increase in diagnostic confidence, from 43% to 93% (P = .023), in patients with probable UIP after the addition of GC to BLC. MDD2 had an increase in diagnostic confidence, from 27% to 73% (P = .074), after the addition of BLC to GC. The concordance coefficients and percentage agreement of categorical idiopathic pulmonary fibrosis (IPF) and non-IPF diagnoses were as follows: GC vs MDD1: 0.92, 96%; GC vs MDD2: 0.83, 92%; BLC1 vs MDD1: 0.67, 83%; BLC2 vs MDD2: 0.66, 83%.

Interpretation: GC increased diagnostic confidence when added to BLC for patients with a probable UIP pattern, and in appropriate clinical settings can be used without BLC. In contrast, BLC had the greatest impact regarding a specific diagnosis when the likelihood of UIP was considered low following clinical-radiographic review.
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http://dx.doi.org/10.1016/j.chest.2020.05.532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039001PMC
November 2020

Classifying non-small cell lung cancer types and transcriptomic subtypes using convolutional neural networks.

J Am Med Inform Assoc 2020 05;27(5):757-769

Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.

Objective: Non-small cell lung cancer is a leading cause of cancer death worldwide, and histopathological evaluation plays the primary role in its diagnosis. However, the morphological patterns associated with the molecular subtypes have not been systematically studied. To bridge this gap, we developed a quantitative histopathology analytic framework to identify the types and gene expression subtypes of non-small cell lung cancer objectively.

Materials And Methods: We processed whole-slide histopathology images of lung adenocarcinoma (n = 427) and lung squamous cell carcinoma patients (n = 457) in the Cancer Genome Atlas. We built convolutional neural networks to classify histopathology images, evaluated their performance by the areas under the receiver-operating characteristic curves (AUCs), and validated the results in an independent cohort (n = 125).

Results: To establish neural networks for quantitative image analyses, we first built convolutional neural network models to identify tumor regions from adjacent dense benign tissues (AUCs > 0.935) and recapitulated expert pathologists' diagnosis (AUCs > 0.877), with the results validated in an independent cohort (AUCs = 0.726-0.864). We further demonstrated that quantitative histopathology morphology features identified the major transcriptomic subtypes of both adenocarcinoma and squamous cell carcinoma (P < .01).

Discussion: Our study is the first to classify the transcriptomic subtypes of non-small cell lung cancer using fully automated machine learning methods. Our approach does not rely on prior pathology knowledge and can discover novel clinically relevant histopathology patterns objectively. The developed procedure is generalizable to other tumor types or diseases.
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http://dx.doi.org/10.1093/jamia/ocz230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309263PMC
May 2020

Integrating genomic features for non-invasive early lung cancer detection.

Nature 2020 04 25;580(7802):245-251. Epub 2020 Mar 25.

Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality; however, a small minority of eligible individuals undergo such screening in the United States. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq), a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.
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http://dx.doi.org/10.1038/s41586-020-2140-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230734PMC
April 2020

Impact of a deep learning assistant on the histopathologic classification of liver cancer.

NPJ Digit Med 2020 26;3:23. Epub 2020 Feb 26.

3Center for Artificial Intelligence in Medicine & Imaging, Stanford University, Stanford, CA USA.

Artificial intelligence (AI) algorithms continue to rival human performance on a variety of clinical tasks, while their actual impact on human diagnosticians, when incorporated into clinical workflows, remains relatively unexplored. In this study, we developed a deep learning-based assistant to help pathologists differentiate between two subtypes of primary liver cancer, hepatocellular carcinoma and cholangiocarcinoma, on hematoxylin and eosin-stained whole-slide images (WSI), and evaluated its effect on the diagnostic performance of 11 pathologists with varying levels of expertise. Our model achieved accuracies of 0.885 on a validation set of 26 WSI, and 0.842 on an independent test set of 80 WSI. Although use of the assistant did not change the mean accuracy of the 11 pathologists ( = 0.184, OR = 1.281), it significantly improved the accuracy ( = 0.045, OR = 1.499) of a subset of nine pathologists who fell within well-defined experience levels (GI subspecialists, non-GI subspecialists, and trainees). In the assisted state, model accuracy significantly impacted the diagnostic decisions of all 11 pathologists. As expected, when the model's prediction was correct, assistance significantly improved accuracy ( = 0.000, OR = 4.289), whereas when the model's prediction was incorrect, assistance significantly decreased accuracy ( = 0.000, OR = 0.253), with both effects holding across all pathologist experience levels and case difficulty levels. Our results highlight the challenges of translating AI models into the clinical setting, and emphasize the importance of taking into account potential unintended negative consequences of model assistance when designing and testing medical AI-assistance tools.
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http://dx.doi.org/10.1038/s41746-020-0232-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044422PMC
February 2020

Neutrophil Extracellular Traps Induce Tissue-Invasive Monocytes in Granulomatosis With Polyangiitis.

Front Immunol 2019 13;10:2617. Epub 2019 Nov 13.

Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States.

Granulomatosis with polyangiitis (GPA) is a multi-organ vasculitic syndrome typically associated with neutrophil extracellular trap (NET) formation and aggressive tissue inflammation. Manifestations in head and neck (H&N) GPA include septal perforations, saddle-nose deformities, bony erosions of the orbital and sinus walls, middle ear damage and epiglottitis, indicative of bone, cartilage, and connective tissue destruction. Whether H&N-centric lesions engage disease pathways distinctive from the ischemic tissue damage in the lungs, kidneys, skin, and peripheral nerves is unknown. We have compared inflammatory responses triggered by neutrophilic NETs in patients with H&N GPA and systemic GPA (sGPA). Neutrophils and monocytes were isolated from the peripheral blood of patients with H&N GPA, sGPA, and age/gender matched healthy individuals. Neutrophil NETosis was induced. NETs were isolated and cocultured with monocytes. Gene induction was quantified by RT-PCR, protein upregulation by flow cytometry. Tissue invasiveness of monocytes was measured in a 3D collagen matrix system. Expression of MMP-9 in tissue-residing macrophages was assessed by immunohistochemistry in tissue biopsies. Neutrophils from H&N GPA patients showed more intense NETosis with higher frequencies of netting neutrophils ( < 0.001) and release of higher amounts of NETs ( < 0.001). Isolated NETs from H&N GPA functioned as an inducer of danger-associated molecular patterns in monocytes; specifically, alarmin S100A9. NET-induced upregulation of monocyte S100A9 required recognition of DNA. S100A9 release resulted in the induction of metalloproteinases, including MMP-9, and enabled monocytes to invade into extracellular matrix. Anti-MMP-9 treatment attenuated the tissue invasiveness of monocytes primed with NETs from H&N GPA patients. MMP-9-producing macrophages dominated the tissue infiltrates in naso-sinal biopsies from H&N GPA patients. Distinct disease patterns in GPA are associated with differences in NET formation and NET content. H&N GPA patients with midline cartilaginous and bony lesions are highly efficient in generating NETs. H&N GPA neutrophils trigger the induction of the alarmin S100A9, followed by production of MMP-9, endowing monocytes with tissue-invasive capabilities.
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http://dx.doi.org/10.3389/fimmu.2019.02617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874157PMC
November 2020
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