Studies could lead to new prognostic biomarkers and clinical laboratory diagnostics for cancer
Might fungi be involved in human cancers? Two separately published studies have found fungal DNA in various cancers in the human body. However, the researchers are unclear on how the fungi got into the cancer cells and if it is affecting the cancers’ pathology. Nevertheless, these discoveries could lead to utilizing tumor-associated fungal DNA as clinical laboratory diagnostics or prognostic biomarkers in the fight against cancer.
“The finding that fungi are commonly present in human tumors should drive us to better explore their potential effects and re-examine almost everything we know about cancer through a ‘microbiome lens,’” said Ravid Straussman, MD, PhD (above), a principal investigator at Weizmann Institute of Science and one of the authors of the study in a UCSD press release. These findings could lead to new clinical laboratory diagnostics and prognostic biomarkers. (Photo copyright: Weizmann Institute of Science.)
Microbiome Key to Cancer Biology and Detection
To perform their research, the team examined 17,401 samples of patient tissues, blood, and plasma across 35 different types of cancers in four independent cohorts. They discovered fungal DNA and cells in low abundances in many human cancers.
“The existence of fungi in most human cancers is both a surprise and to be expected,” said biologist Rob Knight, PhD, founding Director of the Center for Microbiome Innovation and Professor of Pediatrics and Computer Science and Engineering at UC San Diego in a UCSD press release. “It is surprising because we don’t know how fungi could get into tumors throughout the body. But it is also expected because it fits the pattern of healthy microbiomes throughout the body, including the gut, mouth and skin, where bacteria and fungi interact as part of a complex community.”
The main highlights of this study include:
Fungi detected in the different cancer types were often intracellular.
Multiple fungal-bacterial-immune ecologies were detected across tumors.
Intratumoral fungi stratified clinical outcomes, including immunotherapy response.
Cell-free fungal DNA found in both healthy and cancer patients in early-stage disease.
Fungi found on the human body appear as either environmental fungi, such as yeasts and molds, and commensal fungi, which live either on or inside the body. Both are typically harmless to most healthy people and can provide some benefits, such as improving gut health, but they may also be a contributing factor in some disease.
The researchers found that there were notable parallels between specific fungi and certain factors, such as age, tumor subtypes, smoking status, immunotherapy responses, and survival measures.
“These findings validate the view that the microbiome in its entirety is a key piece of cancer biology and may present significant translational opportunities, not only in cancer detection, but also in other biotech applications related to drug development, cancer evolution, minimal residual disease, relapse, and companion diagnostics,” said Gregory Sepich-Poore, MD, PhD, one of the study’s authors and co-founder and chief analytics officer at biotechnology company Micronoma, in the UCSD press release.
New Clinical Laboratory Tests to Identify Fungal Species in Cancer
They found that “several Candida species were enriched in tumor samples and tumor-associated Candida DNA was predictive of decreased survival,” according to their paper.
Their analysis of multiple body sites revealed tumor-associated mycobiomes in fungal cells. The researchers found that fungal spores known as blastomyces were associated with tumor tissues in lung cancers, and that high rates of Candida were present in stomach and colon cancers.
The Duke/Cornell researchers hope their work can provide a framework to develop new tests that can distinguish fungal species in tumors and predict cancer progression and help medical professionals and patients chose the best treatment therapies.
“These findings open up a lot of exciting research directions, from the development of diagnostics and treatments to studies of the detailed biological mechanisms of fungal relationships to cancers,” said Iliyan Iliev, PhD, Associate Professor of Microbiology and Immunology in Medicine, Weill Cornell Medicine, and one of the authors of the study, in a Weill news release.
More research is needed to determine if fungal DNA plays a role in disease pathology or if its presence does not have any causal link.
“It’s plausible that some of these fungi are promoting tumor progression and metastasis, but even if they aren’t, they could be very valuable as prognostic indicators,” Iliev said.
The insights gleaned from these two studies will be of particular interest to microbiologists, clinical laboratory professionals, and anatomic pathologists. Additional research could answer questions about how and if fungi infect tumors and if such fungi is a factor that increases cancer risk and outcomes.
Study shows that access to early childhood treatment could have lasting effects and prevent premature adult aging
Researchers in New Zealand have found that people who experienced “daily smoking status, obesity, or a psychological disorder diagnosis” beginning early in life were “biologically older” at midlife than those who did not. The findings suggest that early access to treatments for these health concerns could decrease risk for “accelerated biological aging,” according to the study published in JAMA Pediatrics.
Although these findings do not currently provide a path to a diagnostic test for clinical laboratories, this study is yet another example of how researchers are increasingly using broad swaths of healthcare data to help identify people at risk for certain healthcare conditions.
Such research often presents opportunities for medical laboratories to participate in healthcare Big Data analysis, which in turn helps healthcare providers make precision medicine diagnoses for individual patients.
Study Assessments and Clinical Laboratory Biomarkers
The scientists found that participants who had one of three health conditions as an adolescent—obesity, smoking daily, or psychological disorder (anxiety, attention deficit/hyperactivity disorder, depression)—showed advanced signs of aging at age 45 when compared to others without those conditions, CNN reported.
The signs included:
Walking 11.2 centimeters per second slower.
Brain appears 2.5 years older.
Face appears four years older.
At age 11, 13, and 15, the Dunedin Study participants were assessed by pulmonary specialists and others for asthma, cigarette smoking, and obesity, Fox News reported.
According to an earlier DMHDRU statement, the biomarkers used at this point in the study included:
“Participants who had smoked daily, had obesity, or had a psychological disorder diagnosis during adolescence were biologically older at midlife compared with participants without these conditions. Participants with asthma were not biologically older at midlife compared with those without asthma,” the researchers wrote. These findings led the researchers to certain conclusions about receiving early treatments, CNN reported.
“No participants in this cohort were prescribed stimulants for attention-deficit/hyperactivity disorder, and selective serotonin reuptake inhibitors were not yet in use for adolescent depression and anxiety during the study period. Whereas 81.1% of the adolescents with asthma received some type of treatment, which could have mitigated the implications for biological aging,” the authors wrote in their study.
“Our paper reaffirms that those are important treatments and those kinds of investments younger in the lifespan could net big benefits in terms of both health and the cost of healthcare later on as well,” Kyle Bourassa, PhD, told CNN. Bourassa is the study’s First Author and a clinical psychology researcher and advanced research fellow at the Durham VA Health Care System.
Clinical Laboratories Curate Massive Amounts of Healthcare Data
For pathologists and medical laboratory scientists, the University of Otago study is a reminder that clinical laboratories provide a critical tool to diagnostics professionals: housing, sharing, and analyzing data that contribute to precision medicine diagnoses.
The DMHDRU researchers’ findings also highlight the importance of access to common treatments offered early in life for some people to reduce risk of accelerated aging and disease.
Jury also heard testimony about Holmes’ claims that the Edison device was doing clinical laboratory testing for the military in overseas theaters
During the seventh week of ex-Theranos CEO Elizabeth Holmes’ criminal fraud trial, headline-making testimony continued nearly non-stop. A former Theranos product manager took the stand offering damning testimony that tied Holmes to questionable product demonstrations and exaggerated claims about the military’s use of the Edison blood-testing device. And a Pfizer scientist testified to alleged improper use of the Pfizer logo by Theranos in a report that went to Walgreen executives.
CNN reported that former Senior Product Manager Daniel Edlin, who worked at Theranos from 2011-2016, acknowledged in court that the Edison device had never been used in a war zone or installed on a medivac helicopter. He also noted that Holmes had final say over his communications with the DOD.
According to CNN, “Edlin said he worked directly with Holmes to support the relationships with the military and Defense Department. He said, ‘the end goal’ for these discussions ‘was to start a research program that would compare Theranos’ testing to the testing available to the military at that time.”
Edlin testified that Holmes was ‘highly involved’ with these communications, CNN reported.
“I’d say any substantive communication I had with the military, I either discussed with her ahead of time … or email drafts were reviewed and approved before I sent them back out,” he testified.
During cross examination, Edlin walked back some of his damaging testimony. When asked by defense attorney Kevin Downey, JD, of Williams and Connelly, LLP, if he or anyone else at Theranos was intentionally trying to deceive investors or other visitors during the demonstrations, Edlin responded, “Of course not,” according to Palo Alto Online.
To counter the prosecution’s claims that Theranos’ Edison machines were unsuitable for military use because they could not operate in high temperatures, Downey introduced an email from an Army doctor at the US Command in Africa praising the Edison after examining it in high temperatures. The doctor also, according to court documents, proposed the Army provide more funding to test the Edison’s capabilities, Palo Alto Online reported.
Nevertheless, according to The Wall Street Journal (WSJ), the Edison was never sent to a US military laboratory in Afghanistan for study, nor was it used in Africa to run blood tests.
Former Pfizer Scientist Testifies to Misuse of Intellectual Property
In another broadside to the Holmes defense, former Pfizer scientist Shane Weber, PhD, testified Holmes used the Pfizer logo in investor materials without the company’s permission in order to pass off as credible a study aimed at validating the Edison device.
The WSJ reported Weber told jurors that in 2008 he had reviewed a 15-page Theranos study involving cancer patients, but that he had stated in his own internal report to Pfizer at that time that nine conclusions in the study—including a statement that the “Theranos system performed with superior performance”—were “not believable.” Pfizer eventually heeded Weber’s advice to not enter into a partnership with Theranos.
Prosecutors stated that as part of Theranos’ negotiations with Walgreens, which ultimately invested $140 million in the blood-testing company, Holmes had placed a Pfizer logo on the top of each page of the cancer study report before sending it to Walgreens executives, claiming it was an independent due-diligence report on Theranos technology.
Weber told jurors that he had not known about the altered report until he was shown the document by prosecutors. He stated the logo was added without Pfizer’s permission, the WSJ reported.
Unfortunately for Walgreens, the retail pharmacy chain entered into a business agreement with Theranos without extensively examining or testing the Edison device, which Theranos had claimed could quickly and accurately run 200 diagnostic tests using a finger-stick of blood. Instead, the company relied on the opinions of its own staff healthcare experts and outside experts, none of whom fully tested the technology either, the WSJ stated.
Testimony in the Elizabeth Holmes fraud trial is expected to continue through December. Therefore, clinical laboratory managers and pathologists should expect headline-making news to continue as well. Dark Daily will continue its coverage as the trial moves forward.
According to the researchers, the finding could reveal athletes who removed their blood, took out the red blood cells, and transfused the cells into their bodies before competition. When conducted by medical laboratory professionals, such autologous blood therapies can enhance oxygen intake and increase performance during sports. However, these “self-transfusions” have been difficult to detect using current methods and that highlights the importance of ensuring these procedures are carried out by authorized healthcare facilities.
The World Anti-Doping Agency (WADA), an international organization aimed at research and education for doping-free sport, funded the Duke University research. WADA currently uses the Athlete Biological Passport to assess, over time, competitors’ body chemistries.
As the Duke researchers explored nucleic acids in red blood cells, they found that the cells actually do have a nucleus, contrary to popular belief. From there, they honed in on RNA.
Short RNA pieces, called microRNA (miRNA), control production of proteins in a cell, according to the researchers.
“While once thought to lack nucleic acids, red blood cells actually contain diverse and abundant RNA species,” the scientists noted in their paper. “In addition, proteomic analyses of red blood cells have identified the presence of Argonaute 2 (AGO2), supporting the regulatory function of miRNAs.”
The methodology Duke researchers followed involved these steps, among others:
Three units of blood were drawn from volunteers;
The researchers removed the white blood cells and about 80% of the plasma;
The remaining red blood cells were pure, just as they would need to be by someone doing autologous transfusion;
The researchers analyzed cell RNA samples at specific daily intervals: 1, 3, 7, 10, 14, 28, 36, and, 42 days;
They then compared samples to day 1 and recorded changes in RNA due to storage.
The researchers found:
Two types of miRNA increased during storage and two declined; and,
miR-720 had the most dramatic and consistent changes.
They concluded that finding increased miR-720 in athletes’ blood could be used as a biomarker for detecting stored red blood cells, which could indicate blood doping had taken place.
“The difficulty has been that the tests [WADA] have couldn’t tell the difference between a young blood cell and an old one,” Jen-Tsan Ashley Chi, MD, PhD, lead researcher on the study and Duke’s Associate Professor in Molecular Genetics and Microbiology, noted in the news release. “This increase in miR-720 is significant enough and consistent enough that it could be used as a biomarker for detecting stored red blood cells.” Chi is affiliated with Duke’s Center for Genomic and Computational Biology. (Photo copyright: Duke University.)
Implications for Detecting Blood Doping
How does this help clinical laboratories detect blood doping in athletes?
The researchers explained that RNA changes were, indeed, tell-tale signs of old blood cells circulating with normal cells. Those old blood cells could identify an athlete who did a self-transfusion of their blood before a competition.
However, before the test is used in sports more research is needed. Activity by the enzyme angiogenin in stored cells also is worthy of more exploration, as is its role in breaking apart larger RNA, the researchers noted.
“While autologous blood transfusions in athletes is very difficult to identify using conventional tests, it may be detectable based on the presence of red blood cells with levels of miR-720 significantly higher than the normal circulating cells. Further investigations will be necessary to identify the signals during red blood cell storage that stimulate angiogenin activation,” the study paper concluded.
Clinical Laboratories Involved in Sports Testing
In its 2017 Anti-Doping Testing Figures Report, WADA reported 322,050 samples were analyzed, a 7.1% increase from 300,565 samples in 2016. WADA accredits medical laboratories worldwide for conducting such analyses according to the organization’s code. This presents opportunities in sports medicine for medical laboratories to increase revenue through a new line of diagnostic tests.
Clinical laboratory test claims make up a substantial proportion of all claims filed each year. Thus, any effort to streamline or reform claims adjudication and administration in the US will alter how labs and pathologists conduct business
Clinical laboratory managers and anatomic pathologists know how costly and complex the US healthcare system can be. However, expenses associated with care and treatment are only part of the total picture. Resources devoted to paperwork and administrative costs apparently increase overall expenditures associated with healthcare to a much higher degree than is generally known.
US Administrative Costs Higher than All Other Nations
One study conducted by The New England Journal of Medicine (NEJM) in 2003 estimated administrative costs account for approximately 30% of all healthcare expenditures in the US. The researchers examined data from 1999 to reach those conclusions. In today’s economy, those numbers are higher. On average, $5,700 of every $19,000 that US workers and their employers pay for family coverage each year goes towards administrative costs.
A 2014 study published by Health Affairs compared administrative costs for US hospital expenditures to those of seven other countries: Canada, England, France, Germany, the Netherlands, Scotland, and Wales. This study evaluated data from 2010/2011 and found that hospital administrative costs in the US far exceed rates in other nations. According to the study, administrative costs accounted for:
25.3% of total hospital expenditures in the US;
19.8% in the Netherlands;
15.5% in England; and,
12% in Canada and Scotland.
According to the Health Affairs study, more than $150 billion could have been saved in 2011 by reducing per capita spending for administrative costs to the levels observed in Canada and Scotland.
“The extraordinary costs we see are not because of administrative slack or because healthcare leaders don’t try to economize,” Kevin Schulman, MD, Professor, Department of Medicine, Duke University, and co-author of the Health Affairs study told The New York Times. “The high administrative costs are functions of the system’s complexity.” (Photo copyright: Duke University.)
Complexity of Payer System Partly to Blame
One reason for the costliness in the US healthcare system is the myriad of payers that healthcare organizations have to grapple with to receive payment. Private health insurers and public health programs like Medicare and Medicaid, each have their own procedures, regulations, and forms that need to be submitted to receive payments. This translates to more employee time devoted to billing.
Another factor driving costs is the staff time devoted to the collection of debts. A 2017 Health Affairs study examined medical claims data from 88,000 healthcare providers contracted with Athenahealth to determine the percentage of bills paid within one year from the initial service.
The study found that 93.8% of patient bills under $35 were paid within a year. However, that percentage decreased as the patient obligation increased:
90.5% of patients paid bills between $35 and $75 within one year;
83.7% paid bills between $75 and $200 in the same time period; however,
When bills increase to $200 or more, just 66.7% were paid within a year’s time.
Providers wrote off approximately 16% as abandoned or bad debts, with an additional 17% going to collection agencies.
Another study, published in Health Affairs in 2009, surveyed 895 physicians about the time they spent dealing with administrative tasks. On average, physicians reported spending 43 minutes per workday interacting with health plans. This number is the equivalent of three hours/week and almost three weeks/year. Those numbers have reportedly increased since then.
EHRs Do Not Reduce Administrative Costs, Contrary to Belief
Efforts have been made to reduce administrative costs in the US healthcare industry. One such measure involved increased use of certified electronic health record (EHR) systems, which the federal government spent billions of dollars promoting and incentivizing providers to adopt on the claim that EHRs would reduce healthcare costs, in part by removing most of the paperwork.
Their study determined the administrative costs for processing a single medical bill ranged from $20 for a doctor visit to $215 for an inpatient surgical procedure. These costs accounted for 3%-25% of total professional revenue for the provided services.
“We need to understand better how complexity is driving these enormous costs within the system, costs that do not add value to patients, employers, or providers,” noted Barak Richman, JD, PhD, Duke University School of Law and Margolis Center for Health Policy, one of the study’s authors.
Clinical Lab Test Claims a Major Portion of Administrative Costs
Nevertheless, administrative costs are a necessary part of doing business and not always as negative as perceived. An article published by Health Affairs in 1992 divided administrative costs in the healthcare industry into four categories:
Transaction-related: claims processing, billing, admissions, and tracking employee hiring/terminations;
Benefits Management: quality assurance, plan design, statistical and internal analyses, and management information systems;
Selling and Marketing: strategic planning, underwriting, and advertising; and,
Regulatory and Compliance: waste management, licensing requirements, and discharge planning.
“We hope that this work is the first step toward informing policy solutions that could reduce these non-value-added costs largely hidden within the healthcare system,” Schulman stated in a Duke University news release.
The issue of costly paperwork and administrative expenditures is significant for the clinical laboratory profession as lab test claims make up a substantial portion of all medical claims filed annually. Efforts to streamline or reform claims adjudication and administration will have an impact on the way clinical labs and anatomic pathology groups conduct business in the future.