Jan 8, 2018 | Instruments & Equipment, Laboratory Instruments & Laboratory Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Pathology, Laboratory Testing
Microbiome is once again leading scientists toward a new understanding of how human gut bacteria can impact the efficacy and side-effects of certain cancer therapies
Anatomic pathology researchers already know that a person’s genetics can affect the results of cancer treatments. Now it is becoming clear that a patient’s microbiome—which includes gut bacteria—may also impact the efficacy of particular cancer treatments. A recent study showed that gut bacteria can be used to determine whether a cancer drug will work for a certain individual and also if the patient might suffer side effects from certain cancer treatments.
Working with this knowledge, diagnostic test companies may possibly develop new clinical laboratory tests designed to help physicians better diagnose and treat cancer patients. This, in turn, advances personalized medicine and treatments for chronic diseases tailored to patients’ specific physiologies and conditions. This is a healthcare trend where medical laboratories can expect to play a critical role.
Gut Bacteria as Important as Genetics in Cancer Treatments
A recent article published in the journal Nature: npj Biofilms and Microbiomes, outlined a correlation between gut bacteria and side effects of irinotecan (sold as Camptosar), a drug used to treat metastatic colorectal cancer.
Libusha Kelly, PhD, Assistant Professor in the Departments of Systems and Computational Biology, and Microbiology and Immunology, led researchers from the Albert Einstein College of Medicine located in Bronx, N.Y., in conducting the study.
“We’ve known for some time that people’s genetic makeup can affect how they respond to a medication,” noted Kelly in an Einstein news release. “Now, it’s becoming clear that variations in one’s gut microbiome—the population of bacteria and other microbes that live in the digestive tract—can also influence the effects of treatment.”
Irinotecan is administered intravenously to colorectal cancer patients in an inactive form and is metabolized to an active form by liver enzymes. The drug is later converted back to an inactive form by other liver enzymes and the addition of a Glucuronidase chemical group. The irinotecan then enters the intestine for expulsion by the body.
Taken from the Einstein College of Medicine published study, the graph above illustrates “Two distinct metabolizer phenotypes or ‘metabotypes’ based on % SN-38 formation during a time course incubation of SN-38G with fecal samples from 20 individuals quantified by LC-MS/MS. Participants were sub-grouped into low (n = 16) and high (n = 4) metabolizer phenotypes. All samples were run in triplicate and values are the mean ± sem.” (Graphic copyright: Nature/Albert Einstein College of Medicine.)
However, bacteria residing in the digestive tract of some individuals prevent the medication from metabolizing properly and reactivates the medication, which transforms the irinotecan into a toxic substance that can cause side effects.
To perform the research, Kelly and her team collected fecal samples from 20 healthy individuals and treated those samples with inactive irinotecan. The samples were then examined and categorized by whether or not they were able to metabolize or reactivate the drug.
Identifying Potential for Side Effects in Patients a Powerful Tool for Medical Laboratories
Irinotecan can cause severe diarrhea and dehydration in up to 40% of patients who take the medication. By focusing on the presence of beta-glucuronidase (enzymes that are used to catalyze the breakdown of complex carbohydrates) the researchers found that gut bacteria can also be used to distinguish which patients will encounter side effects from the drug.
“As you can imagine, such patients are already quite ill, so giving them a treatment that causes intestinal problems can be very dangerous,” said Kelly in the news release. “At the same time, irinotecan is an important weapon against this type of cancer.”
Four of the 20 subjects in the study were determined to be high metabolizers. Due to differences in the composition of their microbiomes, the team concluded that the high metabolizers were more likely to experience side effects from irinotecan.
The research also demonstrated that beta-glucuronidase enzymes in the gut may adversely interact with some commonplace drugs, such as ibuprofen and other nonsteroidal anti-inflammatory medications (NSAIDs), morphine, and Tamoxifen, a drug that is prescribed mainly to breast cancer patients.
“In these cases, the issue for patients may not be diarrhea,” states Kelly in the news release. “Instead, if gut bacteria reactivate those drugs, then patients might be exposed to higher-than-intended doses. Our study provides a broad framework for understanding such drug-microbiome interactions.”
Microbiome Takes Center Stage in Pathology Research
As Dark Daily previously reported, from extending life to developing more powerful treatments for chronic diseases, the human microbiome is quickly becoming an important subject of research studies. The findings from such studies will trigger advances in precision medicine. And, the clinical laboratory assays developed from this research will give physicians the knowledge needed to select the most appropriate drug therapies and treatments for individual patients.
—JP Schlingman
Related Information:
Gut Bacteria Can Stop Cancer Drugs from Working
Gut Microbiome May Make Chemo Drug Toxic to Patients
Human Microbiome Signatures of Differential Colorectal Cancer Drug Metabolism
Researchers in Two Separate Studies Discover Gut Microbiome Can Affect Efficacy of Certain Cancer Drugs; Will Findings Lead to a New Clinical Laboratory Test?
Attention Microbiologists and Medical Laboratory Scientists: New Research Suggests an Organism’s Microbiome Might Be a Factor in Longer, More Active Lives
Mayo Clinic and Whole Biome Announce Collaboration to Research the Role of the Human Microbiome in Women’s Diseases Using Unique Medical Laboratory Tests
Jan 5, 2018 | Digital Pathology, Laboratory Management and Operations, Laboratory News, Laboratory Pathology, Laboratory Testing, Management & Operations
In the same way that BRCA1 and BRCA2 mutations helped pathologists identify women with increased breast cancer risks in the late 1990s, this new study isolates an additional 72 mutations medical laboratories may soon use to diagnose breast cancer and assess risk factors
For 20 years genetic scientists, anatomic pathologists, and medical laboratories have employed the BRCA1/BRCA2 genes to identify women at higher risk for breast cancer. And, because pathologists receive a high number of breast biopsies to diagnose, physicians and clinical laboratories already have collaborative experience working with genetic mutations supported by ample published evidence outlining their relationship with cancer.
Now, a global research study is adding 72 more mutations to the list of mutations already known to be associated with breast cancer.
In coming years, physicians and anatomic pathologists can expect to use the knowledge of these 72 genetic mutations when diagnosing breast cancer and possibly other types of cancers in which these mutations may be involved.
New Precision Medicine Tools to Improve Breast Cancer Survival
Combining the efforts of more than 550 researchers across 300 institutions and six continents, the OncoArray Consortium analyzed the DNA of nearly 300,000 blood samples. The analysis included samples of both estrogen receptor (ER-positive and ER-negative) cases.
Taken from a study published in the British Journal of Cancer, the graph above illustrates “proportions of familial risk of breast cancer explained by hereditary variants.” It is expected that anatomic pathologists will eventually incorporate these genetic variants into diagnostic test for breast and other cancers. (Graphic copyright: British Journal of Cancer.)
The results of their research were published in two separate studies: one in the scientific journal Nature and the other in Nature Genetics. The studies outlined 72 newly isolated genetic mutations that might help quantify the risk of a woman developing breast cancer in her lifetime.
Among the 72 mutations, seven genes were specifically associated with ER-negative cases. ER-negative breast cancer often fails to respond to hormone therapy. Thus, this discovery could be crucial to developing and administering precision medicine therapies tailored to specific patients’ physiologies and conditions. Treatments that improve patient outcomes and overall survival rates in ER-negative and ER-positive breast cancers.
Genetics Could Help Clinical Laboratories Wage War on All Cancers
According to data published by the Centers for Disease Control and Prevention (CDC), breast cancer is the most common form of cancer among women of all races. It’s the second-leading cause of all cancer deaths among most races and first among Hispanic women.
In the past, it was estimated that 5-10% of breast cancers were inherited through the passing of abnormal genes. However, Lisa Schlager, Vice President of community affairs and public policy for FORCE (Facing Our Risk of Cancer Empowered), told CNN, “This new information may mean that that estimate is low.” FORCE is a national nonprofit organization dedicated to fighting hereditary breast, ovarian, and related cancers.
Schlager calls upon health systems to “embrace the ability to use genetic information to tailor healthcare by providing affordable access to the needed screening and preventive interventions.” As precision therapy and genetic analysis continue to shape the way patients are treated, medical laboratories will play a significant role in providing the information powering these innovative approaches.
Furthermore, medical laboratories might leverage the same methods used by researchers to assess risk factors and identify genetic mutations and markers associated with other cancers. Douglas Easton, PhD, Director of the Centre for Cancer Genetic Epidemiology within the Department of Public Health and Primary Care at the University of Cambridge, and leader of the OncoArray Consortium investigation, explained to CNN that Illumina’s Infinium OncoArray is not limited to breast cancer, but is designed to work with other cancers, including:
· colorectal;
· ovarian; and,
· prostate cancers.
Identifying Women at Increased Risk for Breast Cancer
Peter Kraft, PhD, Professor of Epidemiology at Harvard’s T.H. Chan School of Public Health, and a study author, told CNN, “Taken together, these risk variants may identify a small proportion of women who are at three-times increased risk of breast cancer.”
Kraft notes that samples were sourced from women of primarily European ancestry. Further study of other ethnic populations could lead to yet more mutations and indicators for cancers more common outside of the European region.
Research authors also highlight the importance of continued standard screening, such as mammograms. However, they suggest that genetic mutations, such as those found in the OncoArray study, might be used to highlight high-risk individuals and screen sooner, or conduct more in-depth genetic analyses, to catch potential cancer cases earlier and improve outcomes.
“Many women are offered mammogram screening when they are middle-aged,” Georgia Chenevix-Trench, PhD, co-author of the Nature Genetics study and researcher at the QIMR Berghofer Medical Research Institute in Australia, told LabRoots. “But if we know a woman has genetic markers that place her at higher risk of breast cancer, we can recommend more intensive screening at a younger age.”
Anatomic pathologists and clinical laboratories can use these new insights to offer increased options for oncologists and physicians on the front lines of the battle against cancer. While the list of genetic mutations related to cancer is far from complete, each added mutation holds the potential to power a new treatment, improve early detection rates, and improve survival rates of this global killer.
—Jon Stone
Related Information:
Major Study of Genetics of Breast Cancer Provides Clues to Mechanisms Behind the Disease
Breast Cancer Genetics Revealed: 72 New Mutations Discovered in Global Study
Identification of Ten Variants Associated with Risk of Estrogen-Receptor-Negative Breast Cancer
Association Analysis Identifies 65 New Breast Cancer Risk Loci
An Unprecedented Study Has Revealed 72 New Breast Cancer Gene Variants
Study Finds 72 New Genetic Mutations Linked to Breast Cancer
Major Study Identifies 72 New Genetic Risk Factors for Breast Cancer
Breast Cancer: 72 New Gene Mutations Uncovered
Jan 3, 2018 | Laboratory Instruments & Laboratory Equipment, Laboratory News, Laboratory Operations, Laboratory Pathology, Laboratory Testing
University of Turin study in Italy shows under-vacuum sealing systems reduce exposure to formaldehyde by 75% among nurses handling tissue biopsy specimens during surgery
Histology technicians and anatomic pathology (AP) laboratories regularly handle dangerous chemicals such as formaldehyde. They understand the risks exposure brings and take precautions to minimize those risks. However, in operating suites worldwide, nurses assisting surgeons also are being exposed to this nasty chemical.
Nurses must place biopsies and other tissues into buckets of formaldehyde to preserve the tissue between the operating room (OR) and histology laboratory. Formaldehyde, along with toluene, and xylene, is used to process and preserve biopsy tissue, displace water, and to create glass slides. It is an important substance that has long been used to maintain the viability of tissue specimens. Thus, exposure to formaldehyde among nurses is well-documented.
According to a National Academy of Sciences report, formalin, a tissue preservative that is a form of formaldehyde, has been linked to:
· Myeloid leukemia;
· Nasopharyngeal cancer; and,
· Sinonasal cancer.
However, as Dark Daily previously reported, “One alternative to storing specimens in buckets with formalin is to vacuum-seal specimens … [so] that both the quality management of the patient specimen and worker safety for handling the specimens are greatly improved.” (See Dark Daily, “Anatomic Pathology Labs Adopt New Ways to Package, Transport, and Store Specimens to Reduce Formalin and Improve Staff Safety in Operating Theaters and Histology Laboratories,” October 13, 2014.)
Now, motivated by increasing formaldehyde regulations in Europe, as well as the need to increase awareness of exposure risks, the University of Turin (Unito), and other hospitals in Italy’s Piedmont region, conducted a cross-sectional study of 94 female nurses who were being potentially exposed to formaldehyde.
Researchers Aim for “Formalin-Free” Hospitals
The Unito study showed that nurses using an under-vacuum sealing (UVS) system in ORs are exposed to levels of formaldehyde 75% lower than those who did not use the system. This study differs from other similar tests because the level of exposure is not just potential, due to environmental contamination, but confirmed with analytic data from specific urine analyses.
The researchers divided the nurses into two groups:
· One group immersed samples in containers of formaldehyde following standard procedures;
· The other group worked in operating rooms equipped with a UVS system.
The researchers described a UVS system that called for the tissue removed during surgery to be sealed in a medical grade vacuum bag and refrigerated at four degrees centigrade before being transferred to the lab for fixation.
One example of a UVS system is TissueSAFE plus, developed by Milestone Medical, located in Bergamo, Italy, and Kalamazoo, Mich. According to the company’s website, the system, “Eliminates formalin in the operating theatre and allows a controlled formalin-free transfer of biospecimens to the laboratory.”
The image above is from a research paper by Richard J. Zarbo, MD, Pathology and Laboratory Medicine, Henry Ford Health System. It describes “five validation trials of new vacuum sealing technologies that change the approach to the preanalytic ‘front end’ of specimen transport, handling, and processing, and illustrate their adaptation and integration into existing Lean laboratory operations with reduction in formalin use and personnel exposure to this toxic and potentially carcinogenic fixative.” (Image copyright: Henry Ford Health System/Springer International Publishing.)
Increased Scrutiny Leads to New Pathology Guidelines
In a paper published in Toxicology Research, a journal of The Royal Society of Chemistry, the researchers noted a marked difference related to the adoption of the under-vacuum sealing procedure, as an alternative to formaldehyde for preserving tissues. “Nurses, operating in surgical theatres, are traditionally exposed to formaldehyde because of the common and traditional practice of immersing surgical samples, of a size ranging between two and 30 centimeters, in this preservative liquid (three to five liters at a time) to be later transferred to a [histopathology] lab,” the authors wrote. “We evaluated the conditions favoring the risk of exposure to this toxic reagent and the effect of measures to prevent it.”
Throughout Europe, increased scrutiny has forced medical pathology associations to write new guidelines that accept alternative methods to formaldehyde-based tissue preservation methods.
“In Europe, and in Italy in particular, the level of attention to formaldehyde exposure in the public health hospital system has become very high, forcing pathology associations to rewrite guidelines,” Marco Bellini, General Manager of the Medical Division at Milestone Medical, told Dark Daily. “What makes this study unique from many other similar tests is that the level of exposure has been confirmed with data from specific urine analyses,” he added.
The Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPEC), a division of the International Academy of Pathology, wrote general guidelines for AP labs that have been accepted and officially published by the Italian Ministry of Health.
The main topic of these guidelines is the preanalytical aspects of specimen collection, transportation, and preservation, where the vacuum method has been indicated as a valid alternative to improve the standardization of these crucial steps in pathology. By moving the starting point for specimen fixation from the OR to the histology labs, parameters can be controlled and documented, with the main advantage of reducing formaldehyde exposure by operators at the collection point.
These guidelines will be presented at the European Society of Pathology (ESP) with the intent to extending them throughout Europe.
Toluene’s and Xylene’s Effects Studied
Formaldehyde is not the only potentially harmful substance in the clinical laboratory. As previously noted, common solvents toluene and xylene also are potentially hazardous.
In fact, a study of pathologists, lab technicians, and scientists who work with toluene and xylene published in the Journal of Rheumatology found that the chance of acquiring Raynaud Syndrome (a vascular condition) doubled for those workers. (See Dark Daily, “Health of Pathology Laboratory Technicians at Risk from Common Solvents like Xylene and Toluene,” July 5, 2011.)
Medical laboratory leaders are reminded to initiate processes that ensure safe specimen handling, transport, and processing, as well as workflow changes that eliminate chemical odors in the lab. Studies, such as those cited above, may provide information necessary to affect change.
—Donna Marie Pocius
Related Information:
Formaldehyde Fact Sheet
Towards a Formalin-Free Hospital: Levels of 15-F2t-isoprostane and malondialdehyde to Monitor Exposure to Formaldehyde in Nurses from Operating Theatres
Histologic Validation of Vacuum Sealed, Formalin-Free Tissue Preservation, and Transport System
Notes Regarding the Use of Formalin, Reclassified as “Carcinogenic”
Formaldehyde Substitute Fixatives: Analysis of Macroscopy, Morpholologic Analysis, and Immunohistochemical Analysis
Anatomic Pathology Labs Adopt New Ways to Package, Transport, and Store Specimens to Reduce Formalin and Improve Staff Safety in Operating Theaters and Histology Laboratories
Health of Pathology and Laboratory Technicians at Risk from Common Solvents Like Xylene and Toluene
National Academy of Sciences Confirms that Formaldehyde Can Cause Cancer in a Finding that has Implications for Anatomic Pathology and Histology Laboratories
Dec 29, 2017 | Instruments & Equipment, Laboratory Instruments & Laboratory Equipment, Laboratory News, Laboratory Pathology, Laboratory Testing
If the link between certain types of gut bacteria and improved effectiveness of certain cancer treatments can be leveraged, then medical laboratories could soon have another diagnostic tool to use in supporting physicians with cancer care
From improving treatments for chronic diseases to extending lives, gut microbiome (bacteria that is part of human microbiota) has been at the forefront of developing clinical laboratory testing and anatomic pathology diagnostic technologies in recent years. Now, two studies recently published in the online journal Science confirm research that the “composition” of gut bacteria may have a significant influence on the effectiveness of certain cancer drugs.
The goal of both studies was to determine whether there was a link between gut bacteria and the efficacy of cancer drugs known as PD-1 inhibitors. These drugs are used for several types of cancer, including:
- Melanoma;
- Lung;
- Bladder; and,
- Stomach cancers.
They function by freeing up the immune system to attack cancer cells.
Greater Bacterial Diversity in Gut Brings Improved Response to PD-1 Inhibitors
One of the studies, “Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients,” found that a microbiome populated with “good” bacteria can elevate the potency of certain drug treatments. The researchers discovered that the gut bacteria in patients who responded well to PD-1 inhibitors differed from that found in patients who did not respond to the treatment.
For this study, researchers at the MD Anderson Cancer Center at the University of Texas collected oral, gut, and fecal microbiome samples and tumor biopsies from 112 patients with advanced melanoma. Clinical laboratorians took the samples before and after PD-1 treatments. They divided the patients into two groups—responders and non-responders—and profiled each microbiome using genetic sequencing.
“What we found was impressive: There were major differences both in the diversity and composition of the gut microbiome in responders versus non-responders,” Jennifer Wargo, MD, MMSc, leader of the study, told STAT. “Those who did well had greater bacterial diversity in their gut, whereas those whose tumors didn’t much shrink had fewer varieties of microbes present.”
Melanoma patients who experienced success with PD-1 therapy had a more diverse microbiome and higher concentrations of bacteria known as Ruminococcus and Faecalibacterium. Patients involved in the study who did not respond well to PD-1 therapy had the presence of another bacterium called Bacteroidales.
Jennifer Wargo, MD (above center) with her team at the MD Anderson laboratories. The researchers cautioned that clinical trials are needed before a definitive conclusion can be reached on whether altering gut bacteria can improve the effectiveness of PD-1 therapy. “If you’re changing the microbiome, depending on how you do it, it may not help you—and it might harm you,” Wargo emphasized in STAT. “Don’t try this at home.” (Photo copyright: MD Anderson.)
Antibiotics Can Reduce Effectiveness of PD-1Therapy
The other study, “Gut Microbiome Influences Efficacy of PD-1-based Immunotherapy Against Epithelial Tumors,” discovered that some drug therapies were less effective in patients who were also taking antibiotics to treat infections shortly before beginning treatment with PD-1 drugs.
Researchers for this study, led by Laurence Zitvogel, MD, PhD, of the Gustave Roussy Cancer Campus in Villejuif, France, examined 249 patients who were given a PD-1 inhibitor for lung, kidney, or urinary tract cancers. A little over one fourth of these patients had recently taken antibiotics, which can strip the gut of essential bacteria necessary to treat infections.
The team found that patients who had ingested an antibiotic relapsed faster and did not live as long as patients who had not taken an antibiotic before receiving PD-1 therapy. When they analyzed variances between patients who responded well to treatment versus patients who did not, they detected the presence of Akkermansia muciniphila, a mucin-degrading bacterium, in the responders.
Personalized Treatment Based on Each Patient’s Gut Microbiome
The culmination of this type of research raises questions about how cancer medications may interact with microbiomes.
“Should we be profiling the gut microbiome in cancer patients going into immunotherapy?” asked Wargo in the STAT article. “And, should we also be limiting, or closely monitoring, the antibiotic use in these patients?
“This is all very context-specific, and multiple different factors need to be considered on how best to change the microbiome,” she continued. “When it comes to optimizing cancer therapy, treatments will have to be heavily personalized, based on what a patient’s gut microbiome looks like already.”
Diagnostic tests that could determine whether a certain drug will be beneficial for a patient would perform a critical role in healthcare decision-making. Since cancer drug treatments can cost tens of thousands of dollars or more, it would be advantageous to know which therapies would be optimal for individual patients. The hope is that in the future, clinicians, working with anatomic pathologists and clinical laboratories, will have the tools needed to ascertain if patient’s microbiomes will best work with a particular drug and if they would likely encounter any side effects.
—JP Schlingman
Related Information:
Patients’ Gut Bugs May Play Role in Cancer Care
Gut Microbiome Modulates Response to Anti–PD-1 Immunotherapy in Melanoma Patients
Gut Microbiome Influences Efficacy Of PD-1–Based Immunotherapy Against Epithelial Tumors
Your Gut Bacteria Could Determine How You Respond to Cutting-edge Cancer Drugs
The Bacteria in Your Gut Could Help Determine if a Cancer Therapy Will Work
Attention Microbiologists and Medical Laboratory Scientists: New Research Suggests an Organism’s Microbiome Might Be a Factor in Longer, More Active Lives
Get the Poop on Organisms Living in Your Gut with a New Consumer Laboratory Test Offered by American Gut and uBiome
Mayo Clinic and Whole Biome Announce Collaboration to Research the Role of the Human Microbiome in Women’s Diseases Using Unique Medical Laboratory Tests
Dec 27, 2017 | Compliance, Legal, and Malpractice, Laboratory News, Laboratory Pathology, Laboratory Testing
Radboud University researchers fear oncology, molecular biology, pharmacology, and other cell-centric medical research efforts are at risk due to verification that at least 30,000 studies published in 33,000 scientific journals included data derived from misidentified or contaminated cell lines
Many research findings that underpin the science behind various diagnostic technologies used regularly by clinical laboratories and anatomic pathology groups may not be valid. This is because a large number of published studies may have used misidentified or contaminated cell lines.
Biomedical scientists have known for a long time that many research papers exist containing reports on the wrong cells due to cell line misidentification. And yet, few studies have measured the true scope of the problem. Until now. Researchers at Radboud University in the Netherlands have determined that this problem may have influenced the findings of thousands of published research studies and upon which many other research studies were conducted.
Because clinical laboratories and anatomic pathology groups use assays and diagnostic tests that are developed as a result of these research studies, identifying how many published papers have inaccurate findings that cannot be duplicated would affect how and when it is appropriate for physicians to order certain medical laboratory tests and rely on the results.
Additionally, cancer research is based on cell line studies as well. Thus, it may prove necessary to restudy existing published findings and revise them as appropriate. In turn, these new findings might change how and when some cancer tests are ordered and the results interpreted.
Identifying Corrupted Published Data
Radboud researchers Serge P. J. M. Horbach, a doctoral student, and Willem Halffman, PhD, Associate Professor, Philosophy and Science Studies, used the Web of Science database to track down any scientific articles based on “known misidentified cell lines as listed by the International Cell Line Authentication Committee’s (ICLAC) Register of Misidentified Cell Lines,” according to an article in ScienceAlert.
“We considered a reference to this original article as a good proxy for the usage of a cell line,” the researchers noted in their study published in the journal PLOS ONE. “Since typically the original papers are focused on reporting the establishment of the cell line only.”
They focused on misidentified cell lines that were caused by HeLa cells, also known as “immortalized cells.” HeLa cells have been used in scientific research for decades. They were the first mass-producible cells that could be used in vitro, making them highly desirable for biomedical research.
However, the process of creating immortalized cells involves mutation, during which contamination can be introduced by other cells. Immortalized cells can be identified as one type of cell when in fact they are actually another type of cell.
Research scientists have been aware of this problem for about as long as immortalized cells have been in use. They attempt to take it into account when completing their analyses, though not always successfully.
The Radboud researchers found 32,655 records of primary literature based on contaminated cell lines. They then cross-referenced the ICLAC Register of Misidentified Cell Lines with a range of databases to determine if articles were available for each of the 451 cell lines listed on Table One of the ICLAC Register.
The databases they used included the:
With this information, they further researched published articles in the Web of Science database using cell line identifiers. They noted both primary literature and any citation report entries for each cell line.
The researchers noted in their published study, “As we only searched for cell lines known to be misidentified, this constitutes a conservative estimate of the scale of contamination in the primary literature. Moreover, to avoid false positives, we excluded several cell lines, such as the ones with non-unique identifiers or the cell lines for which verified stock is still in circulation.”
Their estimate for secondary contaminated literature based off primary articles is larger still. “In total, we can conservatively estimate the citations to the primary contaminated primary literature at over 500,000, excluding self-citations,” the authors noted in their PLOS ONE article. “Thereby leaving traces in a substantial share of the biomedical literature.” They concluded, “… the amount of research potentially building on false grounds remains worrisome.”
Impact of Contaminated Cell Lines on Research, Clinical Laboratory Communities
Many of the assays and diagnostic tests performed by clinical laboratories and pathology groups were developed using cell line research. Should further scrutiny into the ability to duplicate and verify study findings fail to produce positive outcomes, it might call into question the validity and appropriate use of these tests.
For the research community, these findings represent yet another call to promote accountability and define standards for verifying authenticity of cell lines to further strengthen research findings.
The Radboud researchers ranked the number of contaminated articles they discovered by research area. Top affected areas include:
- Oncology
- Molecular Biology
- Pharmacology
- Cell Biology
- Immunology
The distribution of contaminated primary literature over the research areas as defined by Web of Science. Only the 25 most affected research areas are included. (Graphic copyright: PLOS ONE.)
Addressing the Problem of Cell Line Contamination and Misidentification
Adapting the ever-growing body of published medical literature to reflect the known misidentifications, as well as the possibility of invalid results, will be a major undertaking. Ultimately, resolving this problem could require changes to practices and procedures currently used by research facilities and medical laboratories.
While the cost to authenticate cell lines adds to the bottom line of research projects, the money spent on research that becomes invalidated by misidentified cell lines is far greater.
In a 2015 Retraction Watch article, Leonard P. Freeman, PhD, President, Global Biological Standards Institute, notes, “An NIH RePORT search identified 9,000 active projects using cell lines, totaling $3.7 billion. Required use of authentication techniques would affect over $900 million in research dollars annually.”
Additionally, failure to adapt authentication as a part of standard operations brings other consequences. “A 2004 survey reported that just one-third of laboratories authenticate their cell lines,” Freeman noted. “10 years later, a Sigma-Aldrich survey found that only 37% of respondents ‘validate the purity and identity before first use’ of cell lines. Understanding the existing barriers that prevent implementation of universal cell authentication is central to changing this sad state of affairs.”
Mixed Recommendations for Fixing Inaccurate Published Studies
Of course, none of this will change the vast body of archived literature that might contain errors due to misidentification. Recommendations for addressing this aspect of the problem vary. The Radboud study authors suggest posting notes on any previously published articles stating that misidentified cell lines were used.
However, in a STAT article, Ivan Oransky, MD, and Adam Marcus, Managing Editor, Gastroenterology and Endoscopy News, co-founders of Retraction Watch, recommend more severe measures. “When we polled readers of Retraction Watch last December about the issue, 55% said journals should correct papers known to describe contaminated or misidentified cell lines, and more than 40% said retraction was the right choice.”
Thanks to the Radboud study, as cell lines continue to power the innovations of modern biomedical research, concerns will surely increase surrounding cell-line authentication and research findings. For pathology groups and medical laboratories, staying abreast of these developments will work to ensure data validity and reduce reputation and liability concerns.
—Jon Stone
Related Information:
Over 30,000 Published Studies Could Be Wrong Due to Contaminated Cells
The Ghosts of HeLa: How Cell Line Misidentification Contaminates the Scientific Literature
The Economics of Reproducibility in Preclinical Research
Crosscontamination of Cells in Culture
Cell Authentication Survey Shows Little Progress in a Decade
Apparent HeLa Cell Contamination of Human Heteroploid Cell Lines
Some 30,000 Biomedical Publications Report on Misidentified Cells
Cell Line Misidentification: The Beginning of the End
Fixing Problems with Cell Lines
Thousands of Studies Used the Wrong Cells, and Journals Are Doing Nothing
We’re Wasting a Lot of Research Funding Using the Wrong Cell Lines. Here’s One Thing We Can Do
Misidentified and Contaminated Cell Lines Lead to Faulty Cancer Science, Experts Say
STR Analysis for Cell Line Authentication Gaining Traction in Research Community
Dec 22, 2017 | Compliance, Legal, and Malpractice, Instruments & Equipment, Laboratory Management and Operations, Laboratory News, Laboratory Pathology, Laboratory Testing
New study published in the Annals of Family Medicine (AFM) indicates that despite efforts to improve EHR usability and efficiency, primary care physicians continue to spend more than 50% of their workdays on computerized physician order entry (CPOE) and other clerical tasks instead of engaging in direct patient care
Do electronic health record (EHR) systems improve or degrade the productivity of physicians? That question has been the subject of robust debate. Now comes a new study in a peer-reviewed journal with a surprising finding: physicians spend up to 50% or more of their workday on EHR-related tasks.
In theory, EHRs offer a wealth of benefits over traditional paper-based systems. In practice, however, between interoperability concerns and implementation costs, they have proven a daunting undertaking for even the largest healthcare systems.
While EHRs might offer easy access to patient data—including medical laboratory records and anatomic pathology reports—this information doesn’t enter itself into databases or make itself instantly accessible. That requires human interaction, which is time consuming and prone to errors.
Thus, research from the American Medical Association (AMA) and the University of Wisconsin revealing that the time it takes to enter data, address communications, and perform other clerical tasks adds up to more than 50% of a physician’s workday is of paramount importance. That’s because physician dissatisfaction and departures from medical practice have increased each year since the EHR revolution began, and reports are the situation is getting worse.
In their retrospective cohort study involving 142 family medicine physicians, published in the Annals of Family Medicine (AFM), Brian G. Arndt, MD, from the School of Medicine and Public Health, Department of Family Medicine and Community Health, University of Wisconsin, et al, reported that clinicians spend 52% of their 11.4-hour workday interacting with an EHR system. On average, nearly 1.5 hours of this EHR interaction occurred outside clinic hours during physicians’ personal time. The researchers assessed interactions using event logs from the Epic EHR system spanning from July 1, 2013, to June 30, 2016.
Researchers validated their data through direct observation of 14 nonresident family medicine physicians from May through June of 2016. This observation showed similar findings. During clinical hours, 60% of physician time related to non-EHR tasks, with 40% of time devoted to EHR tasks.
Documentation Burden Leads to Physician Burnout, Dissatisfaction
“Our family medicine physicians spent 44% of their workday (157 minutes) in the EHR doing clerical and other administrative tasks,” study authors reported. “Computerized physician order entry accounted for 12.1% of their clinic hours (43 minutes) in the EHR. The burden related to order entry has been associated with clinician burnout, dissatisfaction, and intent to leave practice.”
Researchers tracked various tasks and assigned them to categories. Of the tasks tracked, only 32.1% fell under the heading of “medical care.” Reviewing chart notes, chart medications, and problem lists topped medical care tasks.
Review of clinical laboratory results in charts ranked near the bottom, with only 2.5% of the total time spent performing medical care tasks. These tasks, however, could offer opportunities for medical laboratories to help physicians identify opportunities to optimize reporting and test-ordering processes and improve productivity for clinicians who are responsible for most of the data entry burden associated with EHRs.
One potential solution to EHR burnout involves the use of medical scribes who work with physicians during and after a patient’s visit inputting encounter data. Alan Bank, MD, cardiologist at Allina Health, and medical scribe Jaeda Roth, are shown above during a patient visit. Bank told the StarTribune that he’s convinced scribes help doctors get more done and reduce billing errors. (Photo and caption copyright: Elizabeth Flores/StarTribune.)
Researchers also questioned the EHR’s role as a communication or telemedicine hub. “There is insufficient evidence that such asynchronous care improves health outcomes, cost, and overall healthcare use,” they noted.
However, even for intra-practice communications between healthcare professionals, EHRs may not be the most efficient approach. “Face-to-face communication is associated with increased efficiency,” the researchers noted. “Whereas more electronic communication among team members leads to greater clinician and staff dissatisfaction, as well as poorer clinical outcomes and increased healthcare use among patients with coronary artery disease.”
EHR Cost/Benefits Generate Debate
This latest study is not the first to suggest that EHRs are creating problems for clinicians. While there appear to be no trends between studies, multiple researchers have highlighted the workload created by EHR systems in recent years.
In a study published in the Annals of Internal Medicine (AIM), Christine A. Sinsky, MD, of the American Medical Association, et al, analyzed data from the observation of 57 US-based physicians in family medicine, internal medicine, cardiology, and orthopedics.
Comparing data across 430 hours of observation, researchers concluded, “For every hour physicians provide direct clinical face time to patients, nearly two additional hours are spent on EHR and desk work within the clinic day. Outside office hours, physicians spend another one to two hours of personal time each night doing additional computer and other clerical work.”
However, in a 2015 study published in the Annals of Family Medicine (AFM), Valerie Gilchrist, MD, Chair of the Department of Family Medicine and Family Health at the School of Medicine and Public Health, University of Wisconsin, et al, found lower numbers. Observing 27 community-based family physicians across a single practice day, the researchers found that 39% of the practice day on average was devoted to office-based time. Of that time, 61% was spent on medical care related tasks.
Building a Better EHR
While medical laboratories and diagnostic specialists—such as anatomic pathologists—can work with physicians to streamline ordering and reporting processes relating to EHRs, much of the burden comes from how EHR systems are designed and used.
In a 2016 New England Journal of Medicine Catalyst Panel on EHRs, Tait Shanafelt, MD, Director of the Mayo Clinic Department Program on Physician Wellness, noted that one of the most contested features of EHR systems in the US, according to the AMA and Mayo Clinic, is computerized physician order entry (CPOE).
Later in the discussion, Sinsky discussed a recent trip to the UK, where she observed general practitioners (GPs) at the National Health Service (NHS). She noted that most GPs loved their EHRs. However, those EHRs were designed with GP input to best work with an NHS GP’s typical workflows and procedures. She also noted that overall usage is different in the UK, as EHRs there are not tied into billing systems.
As Dark Daily has reported, up to 70% of data stored in a patient’s electronic health record is clinical pathology laboratory related. As newer EHRs replace outdated models, it will remain critical for healthcare professionals—including clinical laboratory professionals who generate most of the data stored in EHRs—to assess, track, and report on what is working with various platforms and what is not.
Communicating this end-user data to EHR developers is essential to designing EHRs that reduce unneeded burden and clerical load on physicians, rather than increasing it.
Clinical laboratories tat wish to take proactive steps might contact physicians and other professionals in their workgroups to tailor data generation, reporting, and ordering processes to the EHRs in use at those practices.
—Jon Stone
Related Information:
Primary Care Doctors Spend More Than 50% of Workday on EHR Tasks, American Medical Association Study Finds
Tethered to the EHR: Primary Care Physician Workload Assessment Using EHR Event Log Data and Time-motion Observations
Study: EHRs Bloat Clerical Workload for Docs
Harried Doctors Hail the Rise of the Medical Scribe
Type and Click Tasks Drain Half the Primary Care Workday
Allocation of Physician Time in Ambulatory Practice: A Time and Motion Study in 4 Specialties
Doctors Wasting Over Two-Thirds of Their Time Doing Paperwork
Physician Activities During Time Out of the Examination Room
Heavy Burden of EHRs Could Contribute to Physician Burnout
