Laboratory of Pathology Training and Fellowship Programs
Updates from the Laboratory of Pathology
Check back for occasional news from NCI's Laboratory of Pathology.
LP's Dr. David Kleiner and Dr. Stefania Pittaluga participate in NIH COVID-19 Lecture Series
August 25, 2020
COVID-19 Autopsy Findings: A joint effort between NYU Winthrop Hospital and NCI - What have we learned so far?
Since the outbreak of COVID-19 disease, caused by SARS-CoV-2 infection, many studies focusing on clinical course, outcome, clinical parameters, prognostic markers, treatment strategies have been published. Although most patients experience mild symptoms, some have serious complications—including diffuse alveolar damage, hemodynamic shock, acute kidney failure, cardiac injury, and arrhythmia—that contribute to the high mortality rate. Autopsies can offer a better understanding of the underlying pathophysiology. Unfortunately few autopsies were performed early in the pandemic because of the potential risks. Untreated patients who died of SARS-CoV-2 were rarely autopsied. Most of the published autopsy studies have focused on lung disease with a few describing findings in other organs. We will discuss our experience with the first set of patient autopsies performed at NYU Winthrop Hospital as well as some of our own experience here at the NIH. We will review some of the key findings in major organ systems accompanied by immunohistochemical and in situ hybridization studies that examined some of the cytokines/chemokines that have been implicated in the pathogenesis of this viral infection.
Videocast can be viewed here: https://videocast.nih.gov/watch=38104
David Kleiner, M.D., Ph.D., Senior Research Physician, Laboratory of Pathology, CCR, NCI, NIH
Stefania Pittaluga, M.D., Ph.D., Senior Research Physician, Laboratory of Pathology, CCR, NCI, NIH
LP Designated as Laboratory for NCI-MATCH
August 20, 2020
The Laboratory of Pathology participates with the NCI-MATCH Designated Laboratory. The NCI-MATCH (EAY131) phase 2 precision medicine clinical trial (NCT02465060) is evaluating the effectiveness of treatment that is directed by genomic profiling in patients with solid tumors, lymphomas or myelomas that have progressed following standard treatments expected to prolong survival, or for rare cancer types for which there is no standard treatment. Hopefully this will provide you and your patients more options or opportunities beyond your clinical studies at the CCR.
The Laboratory of Pathology, ECOG-ACRIN and the NCI-MATCH study team are collaborating to identify eligible patients for NCI-MATCH, based on genomic profiling results from the Laboratory of Pathology. Effective immediately, our TSO500 is replaced Oncomine Comprehensive Assay for screening for MATCH variants. If a variant(s) is found to be a qualifying tumor gene variant, the variant will be sent to the MATCH study team for further review and you as an NIH clinician will received a referral letter from the Laboratory of Pathology.
To learn more about NCI-MATCH, including clinical trial sites across the country, visit www.ecog-acrin.org/nci-match-eay131 and https://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match. Please contact Dr. Mark Raffeld, or Ms. Kayla O’Donnell (NCI-MATCH coordinator) if there are any questions.
This is an update to an original article posted October 30, 2019.
Dr. David Kleiner's "At NCI, on the trail of drug-induced liver injury" featured in CAP Today
February 28, 2020
When looking at a liver biopsy, always suspect there might be drug-induced liver injury. “But then try hard to prove there isn’t. It’s always a diagnosis of exclusion and pattern evaluation,” says David E. Kleiner, MD, PhD, reference pathologist for the Drug-Induced Liver Injury Network. In that role, he pieces together clues that point to a drug having injured a liver—or not.
Drug-induced liver injury is rare, and few pathologists see it. “The incidence is between one in 100,000 and one in a million, depending on what survey you read,” Dr. Kleiner says. His advice: “Think of all the other things it could possibly be and rule those out before you say, yes, this is drug-induced liver injury. If it sounds like a big job, well, yes, it is. It’s probably the most challenging area in liver pathology.”
The Drug-Induced Liver Injury Network, or DILIN, was created in 2003 by the National Institute of Diabetes and Digestive and Kidney Diseases. It was in part “the result of a head-turning 2002 article [Lasser K, et al. JAMA. 287(17):2215–2220] that cited liver toxicity as the most common cause of a drug being withdrawn from the market or black boxed,” says Dr. Kleiner, who is a senior research physician in the Laboratory of Pathology at the National Cancer Institute, where he is also chief of the postmortem pathology section. “After that paper, there was a lot of attention by the FDA and Liver Diseases Research Branch of the NIDDK to see if they could explore this issue more.”
DILIN consists of one data coordinating center, at Duke University, and hepatologists working at a half-dozen clinical sites. There are prospective and retrospective studies; Dr. Kleiner works on the prospective side. “Patients suspected of having drug-induced liver injury and meeting certain criteria can be enrolled in the network’s study. They’re followed for up to two years with periodic evaluations. Clinicians collect biosamples, blood, DNA. And then when there is a liver biopsy—and if they can get re-cuts of the biopsy—it is sent, under code, to me.”
All of the drugs the network concerns itself with are considered to cause injuries that are idiosyncratic in nature. “These drugs are generally thought to be one-offs,” Dr. Kleiner says. “Even if patients have susceptibility to these, they may not develop injury. The incidence varies between about one in a thousand to one in a million patients taking the drugs. Because it’s such a low number, usually these drugs are not caught as potential problems during clinical trials.” Read more...
Elaine S. Jaffe, M.D. named NIH Distinguished Investigator
October 29, 2019
Congratulations Dr. Jaffe!
TruSight Oncology ~500 Gene Panel (TSO500) is now available
Kenneth Aldape, MD
October 17, 2019
I am pleased to announce a major step forward in the NCI’s Comprehensive Oncologic Molecular Pathology and Sequencing Service (NCI-COMPASS) of the Laboratory of Pathology.
Effective immediately, a new clinical molecular test, TruSight Oncology ~500 Gene Panel (TSO500) is now available on the Molecular Pathology CRIS order menu, which is relevant for a large variety of solid tumors.
The TSO500 is our next-generation sequencing (NGS) assay that analyzes cancer-relevant genes from both DNA and RNA in one integrated workflow. During library preparation, enrichment chemistry is optimized to capture nucleic acid targets from formalin-fixed, paraffin-embedded (FFPE) tissues. With simultaneous analysis of both DNA and RNA, various types of biomarkers relevant to a given tumor type (single nucleotide variants (SNVs), indels, fusions, splice variants, tumor mutation burden (TMB), and microsatellite instability (MSI)) can be assessed from the same sample in a single assay. The RNA panel uses a probe design that enables capture of both known fusions and novel fusion partners. The TSO500 panel includes 523 genes for DNA mutation detection and 55 genes for fusion and splice variant detection.
The new molecular pathology report is also incorporated with reporting software for clinical actionability as Tier levels of FDA-approved drug and clinical trials, and pathogenicity based on AMP/ASCO/CAP/ACMG guidelines.
NIH staff may access the CRIS order instructions and full gene list of TSO500 on the NCI-COMPASS webpage. Although Oncomine Assay is still available in CRIS menu for a period, for most applications, the TSO500 can replace the Oncomine Assay for all tumor types, given that it has added features including TMB score, and MSI. In the near future, copy number variation (CNV) will be available. There will be no need to order the Oncomine assay in the future if the TSO500 panel is requested.
Please contact Dr. Liqiang Xi if there are any questions regarding this assay, or Ms. Kayla O’Donnell for question about ordering Molecular Assays.
NCI-Connections features LP's Dr. Kenneth Aldape
October 10, 2019
Why a Precise Diagnosis is Vital to Treat Brain and Spine Tumors
Most people first learn they have a tumor from their primary care doctor. They are then referred to neuro-oncologists or doctors who have expertise in their tumor type. Part of this specialized healthcare team is a neuropathologist, a doctor who examines brain and spine tumor tissue to make a precise diagnosis.
“We come up with the best definition of the tumor possible based on the specific changes we see in the tumor under the microscope,” says Kenneth Aldape, M.D., Ph.D., senior investigator and chief of the Laboratory of Pathology in the Center for Cancer Research at NCI.
Dr. Aldape studies the genomic and epigenomic alterations in brain and spine tumors – or the way genes behave and change in cancer. He characterizes the biology of specific genomic alterations and how they contribute to the development of the disease. He also studies how they impact treatment resistance of aggressive brain tumors.
The goal of understanding these alterations is to be able to identify and better classify tumor types. “We believe that classifying brain tumors based on their biology will lead to a greater understanding of why specific tumor subtypes may be more or less sensitive to therapies,” Dr. Aldape says.
He is also pushing for precision diagnosis for patients because of the rate of diagnostic discrepancy. “We want to reduce errors because without a proper diagnosis a lot of precision medicine may not go as well as planned,” Dr. Aldape says.
Making an Accurate Diagnosis
Dr. Aldape works on the NCI-CONNECT healthcare team to help accurately diagnose rare brain and spine tumors. “Some of these rare tumors can be challenging to diagnose because they are so rare,” Dr. Aldape says.
At NIH, all patients who visit the Neuro-Oncology Branch have their diagnosis reviewed by a neuropathologist. Dr. Aldape receives tumor tissue in the form of a tissue block or unstained slides from the hospital where a patient had his or her surgery. If a patient has not had surgery or a biopsy, he or she can consult with NIH’s neurosurgical oncology team. Dr. Aldape examines the tissue closely under a microscope looking at alterations in the tissue. Read more...
Laboratory of Pathology's June 2019 Newsletter
Kenneth Aldape, MD
June 5, 2019
It is axiomatic that precision medicine in oncology will require advances in precision diagnostics, and advances in our understanding of tumor genomics provide a promising approach towards improvements in precision cancer diagnostics. Individuals bearing tumors with specific molecular alterations, such as gene mutations, amplifications and translocations, and microsatellite instability can be identified using molecular diagnostic tools available in pathology departments, and recent clinical trials for molecularly targeted agents and immunotherapies have been shown to produce unprecedented extended survival in patients with molecularly-defined tumors. While it remains to be determined whether establishing a comprehensive tumor molecular profile of the tumor improves outcome following therapy overall, the evidence to date indicates that this approach represents a promising and dynamic pathway to this goal for specific cancer subsets, and with new data and trials that emerge on an almost a weekly basis, the future remains bright in this area. Read more...
Flow Cytometry section of the Laboratory of Pathology, NCI receives an award from Wiley publishing.
June 3, 2019
Image: Marrow recovery and circulating transitional B-cells in a lymphoblastic leukemia patient post CAR-T cell therapy.
The NCI LP Flow Cytometry section achieved recognition for a Top 20 Article in Cytometry Part B: Clinical Cytometry for their original work entitled, “Early recovery of circulating immature B cells in B-lymphoblastic leukemia patients after CD19 targeted CAR T cell therapy: A pitfall for minimal residual disease detection”. This publication was recognized as one of the journal's top downloaded recent papers. Amongst articles published between January 2017 and December 2018, this work received some of the most downloads in the 12 months following its online publication. This original work highlighted an unusual B-cell marrow recovery response resulting in a notable population of circulating immature B-lymphocytes. These immature B-lymphocytes, if not carefully evaluated, might be mistaken for residual B-lymphoblastic leukemia, due to their immunophenotypic features. In fact, the presence of these cells, likely representing transitional B-cells, may reflect brisk regeneration of the B-cell compartment and bone marrow recovery following treatment with CAR T-cell therapy. Furthermore, the work details specific clinical flow cytometric strategies that can be used for evaluation and prevent a mis-diagnosis of B-lymphoblastic leukemia. According to Wiley publishing, the work generated immediate impact and visibility, contributing significantly to the advancement of the field of clinical flow cytometry.
Methylation Classifier Now in Use as a Clinical Diagnostic Tool
May 24, 2019
Sample image of a patient’s results produced by the tumor methylation diagnostic tool.
The NCI Laboratory of Pathology has recently begun to use a new clinically-reportable diagnostic tool that uses genome-wide DNA methylation profiling as a diagnostic for tumors of the central nervous system. The validated tool is based, in part, on data published in a recent Nature study that showed tumor methylation profiles can provide definitive evidence to complement and refine morphology-based diagnostics in tumors of the brain and spinal cord. In the study, methylation data resulted in a change in diagnosis for 129 cases (12%) of the cohort.
The NCI Laboratory of Pathology is poised to become a diagnostic reference center to implement this tool for diagnostically challenging neuropathology cases. Going forward, it is likely that new methylation-based classifiers will emerge for additional tumor types and we are poised to lead in this area. Areas of future growth include the implementation of clinical whole-exome sequencing, RNAseq gene expression diagnostics, and a dynamic liquid biopsy program.
For more information about access to the Laboratory of Pathology's methylation diagnostic tool, please email Kayla O’Donnell.
April 11, 2019
Elaine Jaffe, M.D., Senior Investigator in the Laboratory of Pathology, has received the 2019 United States and Canadian Academy of Pathology (USCAP) Board’s Distinguished Pathologist award. The award recognizes an individual for making major contributions to pathology over the years.
The Board’s Distinguished Pathologist award was established by the Board of Directors of USCAP for recognition of distinguished service in the development of the discipline of pathology. This award is presented to an individual who is recognized for making major contributions to pathology over the years. Read more...
LP Chief Ken Aldape Participates in NCI Facebook Live Event
"Genomics: How DNA Can Inform Cancer Diagnosis and Treatment"
February 14, 2019
The National Cancer Institute hosted a Facebook Live on February 14, at 3 p.m. ET. The event featured NCI subject matter experts Kenneth Aldape, M.D., of the Center for Cancer Research, Megan Frone, M.S., C.G.C., of the Division of Cancer Epidemiology and Genetics, and Lyndsay Harris, M.D., of the Cancer Diagnosis Program. They discussed the role of genetics in cancer diagnosis and treatment. At the end of the event, experts answered live questions from viewers.
Laboratory of Pathology Training and Fellowship Programs
Center for Cancer Research
National Cancer Institute
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Bethesda, MD 20892-1500